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Diagnosis and management of bipolar disorders

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• Peer review
• Fernando S Goes , associate professor of psychiatry and behavioral sciences 1 2
• 1 Precision Medicine Center of Excellence in Mood Disorders, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
• 2 Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
• Correspondence to: F S Goes fgoes1{at}jhmi.edu

Bipolar disorders (BDs) are recurrent and sometimes chronic disorders of mood that affect around 2% of the world’s population and encompass a spectrum between severe elevated and excitable mood states (mania) to the dysphoria, low energy, and despondency of depressive episodes. The illness commonly starts in young adults and is a leading cause of disability and premature mortality. The clinical manifestations of bipolar disorder can be markedly varied between and within individuals across their lifespan. Early diagnosis is challenging and misdiagnoses are frequent, potentially resulting in missed early intervention and increasing the risk of iatrogenic harm. Over 15 approved treatments exist for the various phases of bipolar disorder, but outcomes are often suboptimal owing to insufficient efficacy, side effects, or lack of availability. Lithium, the first approved treatment for bipolar disorder, continues to be the most effective drug overall, although full remission is only seen in a subset of patients. Newer atypical antipsychotics are increasingly being found to be effective in the treatment of bipolar depression; however, their long term tolerability and safety are uncertain. For many with bipolar disorder, combination therapy and adjunctive psychotherapy might be necessary to treat symptoms across different phases of illness. Several classes of medications exist for treating bipolar disorder but predicting which medication is likely to be most effective or tolerable is not yet possible. As pathophysiological insights into the causes of bipolar disorders are revealed, a new era of targeted treatments aimed at causal mechanisms, be they pharmacological or psychosocial, will hopefully be developed. For the time being, however, clinical judgment, shared decision making, and empirical follow-up remain essential elements of clinical care. This review provides an overview of the clinical features, diagnostic subtypes, and major treatment modalities available to treat people with bipolar disorder, highlighting recent advances and ongoing therapeutic challenges.

Introduction

Abnormal states of mood, ranging from excesses of despondency, psychic slowness, diminished motivation, and impaired cognitive functioning on the one hand, and exhilaration, heightened energy, and increased cognitive and motoric activity on the other, have been described since antiquity. 1 However, the syndrome in which both these pathological states occur in a single individual was first described in the medical literature in 1854, 2 although its fullest description was made by the German psychiatrist Emil Kraepelin at the turn of the 19th century. 3 Kraepelin emphasized the periodicity of the illness and proposed an underlying trivariate model of mood, thought (cognition), and volition (activity) to account for the classic forms of mania and depression and the various admixed presentations subsequently know as mixed states. 3 These initial descriptions of manic depressive illness encompassed most recurrent mood syndromes with relapsing remitting course, minimal interepisode morbidity, and a wide spectrum of “colorings of mood” that pass “without a sharp boundary” from the “rudiment of more severe disorders…into the domain of personal predisposition.” 3 Although Kraepelin’s clinical description of bipolar disorder (BD) remains the cornerstone of today’s clinical description, more modern conceptions of bipolar disorder have differentiated manic depressive illness from recurrent depression, 4 partly based on differences in family history and the relative specificity of lithium carbonate and mood stabilizing anticonvulsants as anti-manic and prophylactic agents in bipolar disorder. While the boundaries of bipolar disorder remain a matter of controversy, 5 this review will focus on modern clinical conceptions of bipolar disorder, highlighting what is known about its causes, prognosis, and treatments, while also exploring novel areas of inquiry.

Sources and selection criteria

PubMed and Embase were searched for articles published from January 2000 to February 2023 using the search terms “bipolar disorder”, “bipolar type I”, “bipolar type II”, and “bipolar spectrum”, each with an additional search term related to each major section of the review article (“definition”, “diagnosis”, “nosology”, “prevalence”, “epidemiology”, “comorbid”, “precursor”, “prodrome”, “treatment”, “screening”, “disparity/ies”, “outcome”, “course”, “genetics”, “imaging”, “treatment”, “pharmacotherapy”, “psychotherapy”, “neurostimulation”, “convulsive therapy”, “transmagnetic”, “direct current stimulation”, “suicide/suicidal”, and “precision”). Searches were prioritized for systematic reviews and meta-analyses, followed by randomized controlled trials. For topics where randomized trials were not relevant, searches also included narrative reviews and key observational studies. Case reports and small observations studies or randomized controlled trials of fewer than 50 patients were excluded.

Modern definitions of bipolar disorder

In the 1970s, the International Classification of Diseases and the Diagnostic and Statistical Manual of Mental Disorders reflected the prototypes of mania initially described by Kraepelin, following the “neo-Kraepelinian” model in psychiatric nosology. To meet the primary requirement for a manic episode, an individual must experience elevated or excessively irritable mood for at least a week, accompanied by at least three other typical syndromic features of mania, such as increased activity, increased speed of thoughts, rapid speech, changes in esteem, decreased need for sleep, or excessive engagement in impulsive or pleasurable activities. Psychotic symptoms and admission to hospital can be part of the diagnostic picture but are not essential to the diagnosis. In 1994, Diagnostic and Statistical Manual of Mental Disorders , fourth edition (DSM-IV) carved out bipolar disorder type II (BD-II) as a separate diagnosis comprising milder presentations of mania called hypomania. The diagnostic criteria for BD-II are similar to those for bipolar disorder type I (BD-I), except for a shorter minimal duration of symptoms (four days) and the lack of need for significant role impairment during hypomania, which might be associated with enhanced functioning in some individuals. While the duration criteria for hypomania remain controversial, BD-II has been widely accepted and shown to be as common as (if not more common than) BD-I. 6 The ICD-11 (international classification of diseases, 11th revision) included BD-II as a diagnostic category in 2019, allowing greater flexibility in its requirement of hypomania needing to last several days.

The other significant difference between the two major diagnostic systems has been their consideration of mixed symptoms. Mixed states, initially described by Kraepelin as many potential concurrent combinations of manic and depressive symptoms, were more strictly defined by DSM as a week or more with full syndromic criteria for both manic and depressive episodes. In DSM-5, this highly restrictive criterion was changed to encompass a broader conception of subsyndromal mixed symptoms (consisting of at least three contrapolar symptoms) in either manic, hypomanic, or depressive episodes. In ICD-11, mixed symptoms are still considered to be an episode, with the requirement of several prominent symptoms of the countervailing mood state, a less stringent requirement that more closely aligns with Kraepelin's broader conception of mixed states. 7

Epidemiology

Using DSM-IV criteria, the National Comorbidity Study replication 6 found similar lifetime prevalence rates for BD-I (1.0%) and BD-II (1.1%) among men and women. Subthreshold symptoms of hypomania (bipolar spectrum disorder) were more common, with prevalence rate estimates of 2.4%. 6 Incidence rates, which largely focus on BD-I, have been estimated at approximately 6.1 per 100 000 person years (95% confidence interval 4.7 to 8.1). 8 Estimates of the incidence and lifetime prevalence of bipolar disorder show moderate variations according to the method of diagnosis (performed by lay interviewers in a research context v clinically trained interviews) and the racial, ethnic, and demographic context. 9 Higher income, westernized countries have slightly higher rates of bipolar disorder, 10 which might reflect a combination of westernized centricity in the specific idioms used to understand and elicit symptoms, as well as a greater knowledge, acceptance, and conceptualization of emotional symptoms as psychiatric disorders.

Causes of bipolar disorder

Like other common psychiatric disorders, bipolar disorder is likely caused by a complex interplay of multiple factors, both at the population level and within individuals, 11 which can be best conceptualized at various levels of analysis, including genetics, brain networks, psychological functioning, social support, and other biological and environmental factors. Because knowledge about the causes of bipolar disorder remains in its infancy, for pragmatic purposes, most research has followed a reductionistic model that will ultimately need to be synthesized for a more coherent view of the pathophysiology that underlies the condition.

Insights from genetics

From its earliest descriptions, bipolar disorder has been observed to run in families. Indeed, family history is the strongest individual risk factor for developing the disorder, with first degree relatives having an approximately eightfold higher risk of developing bipolar disorder compared with the baseline population rates of ~1%. 12 While family studies cannot separate the effects of genetics from behavioral or cultural transmission, twin and adoption studies have been used to confirm that the majority of the familial risk is genetic in origin, with heritability estimates of approximately 60-80%. 13 14 There have been fewer studies of BD-II, but its heritability has been found to be smaller (~46%) 15 and closer to that of more common disorders such as major depressive disorder or generalized anxiety. 15 16 Nevertheless, significant heritability does not necessarily imply the presence of genes of large effect, since the genetic risk for bipolar disorder appears likely to be spread across many common variants of small effect sizes. 16 17 Ongoing studies of rare variations have found preliminary evidence for variants of slightly higher effect sizes, with initial evidence of convergence with common variations in genes associated with the synapse and the postsynaptic density. 18 19

While the likelihood that the testing of single variants or genes will be useful for diagnostic purposes is low, analyses known as polygenic risk studies can sum across all the risk loci and have some ability to discriminate cases from controls, albeit at the group level rather than the individual level. 20 These polygenic risk scores can also be used to identify shared genetic risk factors across other medical and psychiatric disorders. Bipolar disorder has strong evidence for common variant based coheritability with schizophrenia (genetic correlation (r g ) 0.69) and major depressive disorder (r g 0.48). BD-I has stronger coheritability with schizophrenia compared with BD-II, which is more strongly genetically correlated with major depressive disorder (r g 0.66). 16 Lower coheritability was observed with attention deficit hyperactivity disorder (r g 0.21), anorexia nervosa (0.20), and autism spectrum disorder (r g 0.21). 16 These correlations provide evidence for shared genetic risk factors between bipolar disorder and other major psychiatric syndromes, a pattern also corroborated by recent nationwide registry based family studies. 12 14 Nevertheless, despite their potential usefulness, polygenic risk scores must currently be interpreted with caution given their lack of populational representation and lingering concerns of residual confounds such as gene-environment correlations. 21

Insights from neuroimaging

Similarly to the early genetic studies, small initial studies had limited replication, leading to the formation of large worldwide consortiums such as ENIGMA (enhancing neuroimaging genetics through meta-analysis) which led to substantially larger sample sizes and improved reproducibility. In its volumetric analyses of subcortical structures from MRI (magnetic resonance imaging) of patients with bipolar disorder, the ENIGMA consortium found modest decreases in the volume of the thalamus (Cohen’s d −0.15), the hippocampus (−0.23), and the amygdala (−0.11), with an increased volume seen only in the lateral ventricles (+0.26). 22 Meta-analyses of cortical regions similarly found small reductions in cortical thickness broadly across the parietal, temporal, and frontal cortices (Cohen’s d −0.11 to −0.29) but no changes in cortical surface area. 23 In more recent meta-analyses of white matter tracts using diffuse tension imaging, widespread but modest decreases in white matter integrity were found throughout the brain in bipolar disorder, most notably in the corpus callosum and bilateral cinguli (Cohen’s d −0.39 to −0.46). 24 While these findings are likely to be highly replicable, they do not, as yet, have clinical application. This is because they reflect differences at a group level rather than an individual level, 25 and because many of these patterns are also seen across other psychiatric disorders 26 and could be either shared risk factors or the effects of confounding factors such as medical comorbidities, medications, co-occurring substance misuse, or the consequences (rather than causes) of living with mental illness. 27 Efforts to collate and meta-analyze large samples utilizing longitudinal designs 28 task based, resting state functional MRI measurents, 29 as well as other measures of molecular imaging (magnetic resonance spectroscopy and positron emission tomography) are ongoing but not as yet synthesized in large scale meta-analyses.

Environmental risk factors

Because of the difficulty in measuring and studying the relevant and often common environmental risk factors for a complex illness like bipolar disorder, there has been less research on how environmental risk factors could cause or modify bipolar disorder. Evidence for intrauterine risk factors is mixed and less compelling than such evidence in disorders like schizophrenia. 30 Preliminary evidence suggests that prominent seasonal changes in solar radiation, potentially through its effects on circadian rhythm, can be associated with an earlier onset of bipolar disorder 31 and a higher likelihood of experiencing a depressive episode at onset. 31 However, the major focus of environmental studies in bipolar disorder has been on traumatic and stressful life events in early childhood 32 and in adulthood. 33 The effects of such adverse events are complex, but on a broad level have been associated with earlier onset of bipolar disorder, a worse illness course, greater prevalence of psychotic symptoms, 34 substance misuse and psychiatric comorbidities, and a higher risk of suicide attempts. 32 35 Perhaps uniquely in bipolar disorder, evidence also indicates that positive life events associated with goal attainment can also increase the risk of developing elevated states. 36

Comorbidity

Bipolar disorder rarely manifests in isolation, with comorbidity rates indicating elevated lifetime risk of several co-occurring symptoms and comorbid disorders, particularly anxiety, attentional disorders, substance misuse disorders, and personality disorders. 37 38 The causes of such comorbidity can be varied and complex: they could reflect a mixed presentation artifactually separated by current diagnostic criteria; they might also reflect independent illnesses; or they might represent the downstream effects of one disorder increasing the risk of developing another disorder. 39 Anxiety disorders tend to occur before the frank onset of manic or hypomanic symptoms, suggesting that they could in part reflect prodromal symptoms that manifest early in the lifespan. 37 Similarly, subthreshold and syndromic symptoms of attention deficit/hyperactivity disorder are also observed across the lifespan of people with bipolar disorder, but particularly in early onset bipolar disorder. 40 On the other hand, alcohol and substance misuse disorders occur more evenly before and after the onset of bipolar disorder, consistent with a more bidirectional causal association. 41

The association between bipolar disorder and comorbid personality disorders is similarly complex. Milder manifestations of persistent mood instability (cyclothymia) or low mood (dysthymia) have previously been considered to be temperamental variants of bipolar disorder, 42 but are now classified as related but separate disorders. In people with persistent emotional dysregulation, making the diagnosis of bipolar disorder can be particularly challenging, 43 since the boundaries between longstanding mood instability and phasic changes in mood state can be difficult to distinguish. While symptom overlap can lead to artificially inflated prevalence rates of personality disorders in bipolar disorder, 44 the elevated rates of most personality disorders in bipolar disorder, particularly those related to emotional instability, are likely reflective of an important clinical phenomenon that is understudied, particularly with regard to treatment implications. 45 In general, people with comorbidities tend to have greater symptom burden and functional impairment and have lower response rates to treatment. 46 47 Data on approaches to treat specific comorbid disorders in bipolar disorder are limited, 48 49 and clinicians are often left to rely on their clinical judgment. The most parsimonious approach is to treat primary illness as fully as possible before considering additional treatment options for remaining comorbid symptoms. For certain comorbidities, such as anxiety symptoms and disorders of attention, first line pharmacological treatment—namely, antidepressants and stimulants, should be used with caution, since they might increase the long term risks of mood switching or overall mood instability. 50 51

Like other major mental illnesses, bipolar disorder is also associated with an increased prevalence of common medical disorders such as obesity, hyperlipidemia, coronary artery disease, chronic obstructive pulmonary disease, and thyroid dysfunction. 52 These have been attributed to increase risk factors such as physical inactivity, poor nutrition, smoking, and increased use of addictive substances, 53 but some could also be consequences of specific treatments, such as the atypical antipsychotics and mood stabilizers. 54 Along with poor access to care, this medical burden likely accounts for much of the increased standardized mortality (approximately 2.6 times higher) in people with bipolar disorder, 55 highlighting the need to utilize treatments with better long term side effect profiles, and the need for better integration with medical care.

Precursors and prodromes: who develops bipolar disorder?

While more widespread screening and better accessibility to mental health providers should in principle shorten the time to diagnosis and treatment, early manifestation of symptoms in those who ultimately go on to be diagnosed with bipolar disorder is generally non-specific. 56 In particular, high risk offspring studies of adolescents with a parent with bipolar disorder have found symptoms of anxiety and attentional/disruptive disorders to be frequent in early adolescence, followed by higher rates of depression and sleep disturbance in later teenage years. 56 57 Subthreshold symptoms of mania, such as prolonged increases in energy, elated mood, racing thoughts, and mood lability are also more commonly found in children with prodromal symptoms (meta-analytic prevalence estimates ranging from 30-50%). 58 59 Still, when considered individually, none of these symptoms or disorders are sensitive or specific enough to accurately identify individuals who will transition to bipolar disorder. Ongoing approaches to consider these clinical factors together to improve accuracy have a promising but modest ability to identify people who will develop bipolar disorder, 60 emphasizing the need for further studies before implementation.

Screening for bipolar disorder

Manic episodes can vary from easily identifiable prototypical presentations to milder or less typical symptoms that can be challenging to diagnose. Ideally, a full diagnostic evaluation with access to close informants is performed on patients presenting to clinical care; however, evaluations can be hurried in routine clinical care, and the ability to recall previous episodes might be limited. In this context, the use of screening scales can be a helpful addition to clinical care, although screening scales must be regarded as an impetus for a confirmatory clinical interview rather than a diagnostic instrument by themselves. The two most widely used and openly available screening scales are the mood disorders questionnaire (based on the DSM-IV criteria for hypomania) 61 and the hypomania check list (HCL-32), 62 that represent a broader overview of symptoms proposed to be part of a broader bipolar spectrum.

Racial/ethnic disparities

Although community surveys using structured or semi-structured diagnostic instruments, have provided little evidence for variation across ethnic groups, 63 64 observational studies based on clinical diagnoses in healthcare settings have found a disproportionately higher rate of diagnosis of schizophrenia relative to bipolar disorder in black people. 65 Consistent with similar disparities seen across medicine, these differences in clinical diagnoses are likely influenced by a complex mix of varying clinical presentations, differing rates of comorbid conditions, poorer access to care, greater social and economic burden, as well as the potential effect of subtle biases of healthcare professionals. 65 While further research is necessary to identify driving factors responsible for diagnostic disparities, clinicians should be wary of making a rudimentary diagnosis in patients from marginalized backgrounds, ensuring comprehensive data gathering and a careful diagnostic formulation that incorporates shared decision making between patient and provider.

Bipolar disorder is a recurrent illness, but its longitudinal course is heterogeneous and difficult to predict. 46 66 The few available long term studies of BD-I and BD-II have found a consistent average rate of recurrence of 0.40 mood episodes per year in historical studies 67 and 0.44 mood episodes per year in more recent studies. 68 The median time to relapse is estimated to be 1.44 years, with higher relapse rates seen in BD-I (0.81 years) than in BD-II (1.63 years) and no differences observed with respect to age or sex. 1 2 In addition to focusing on episodes, an important development in research and clinical care of bipolar disorder has been the recognition of the burden of subsyndromal symptoms. Although milder in severity, these symptoms can be long lasting, functionally impairing, and can themselves be a risk factor for episode relapse. 69 Recent cohort studies have also found that a substantial proportion of patients with bipolar disorder (20-30%) continue to have poor outcomes even after receiving guideline based care. 46 70 Risk factors that contribute to this poor outcome include transdiagnostic indicators of adversity such as substance misuse, low educational attainment, socioeconomic hardship, and comorbid disorders. As expected, those with more severe past illness activity, including those with rapid cycling, were also more likely to remain symptomatically and psychosocially impaired. 46 71 72

The primary focus of treating bipolar disorder has been to manage the manic, mixed, or depressive episodes that present to clinical care and to subsequently prevent recurrence of future episodes. Owing to the relapse remitting nature of the illness, randomized controlled trials are essential to determine treatment efficacy, as the observation of clinical improvement could just represent the ebbs and flows of the natural history of the illness. In the United States, the FDA (Food and Drug Administration) requires at least two large scale placebo controlled trials (phase 3) to show significant evidence of efficacy before approving a treatment. Phase 3 studies of bipolar disorder are generally separated into short term studies of mania (3-4 weeks), short term studies for bipolar depression (4-6 weeks), and longer term maintenance studies to evaluate prophylactic activity against future mood episodes (usually lasting one year). Although the most rigorous evaluation of phase 3 studies would be to require two broadly representative and independent randomized controlled trials, the FDA permits consideration of so called enriched design trials that follow participants after an initial response and tolerability has been shown to an investigational drug. Because of this initial selection, such trials can be biased against comparator agents, and could be less generalizable to patients seen in clinical practice.

A summary of the agents approved by the FDA for treatment of bipolar disorder is in table 1 , which references the key clinical trials demonstrating efficacy. Figure 1 and supplementary table 1 are a comparison of treatments for mania, depression, and maintenance. Effect sizes reflect the odds ratios or relative risks of obtaining response (defined as ≥50% improvement from baseline) in cases versus controls and were extracted from meta-analyses of randomized controlled trials for bipolar depression 86 and maintenance, 94 as well as a network meta-analysis of randomized controlled trials in bipolar mania. 73 Effect sizes are likely to be comparable for each phase of treatment, but not across the different phases, since methodological differences exist between the three meta-analytic studies.

FDA approved medications for bipolar disorder

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Summary of treatment response rates (defined as ≥50% improvement from baseline) of modern clinical trials for acute mania, acute bipolar depression, and long term recurrence. Meta-analytic estimates were extracted from recent meta-analyses or network meta-analyses of acute mania, 73 acute bipolar depression, 86 and bipolar maintenance studies 94

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Acute treatment of mania

As mania is characterized by impaired judgment, individuals can be at risk for engaging in high risk, potentially dangerous behaviors that can have substantial personal, occupational, and financial consequences. Therefore, treatment of mania is often considered a psychiatric emergency and is, when possible, best performed in the safety of an inpatient unit. While the primary treatment for mania is pharmacological, diminished insight can impede patients' willingness to accept treatment, emphasizing the significance of a balanced therapeutic approach that incorporates shared decision making frameworks as much as possible to promote treatment adherence.

The three main classes of anti-manic treatments are lithium, mood stabilizing anticonvulsants (divalproate and carbamazepine), and antipsychotic medications. Almost all antipsychotics are effective in treating mania, with the more potent dopamine D2 receptor antagonists such as risperidone and haloperidol demonstrating slightly higher efficacy ( fig 1 ). 73 In the United States, the FDA has approved the use of all second generation antipsychotics for treating mania except for lurasidone and brexpriprazole. Compared with mood stabilizing medications, second generation antipsychotics have a faster onset of action, making them a first line treatment for more severe manic symptoms that require rapid treatment. 99 The choice of which specific second generation antipsychotic to use depends on a balance of efficacy, tolerability concerns, and cost considerations (see table 1 ). Notably, the FDA has placed a black box warning on all antipsychotics for increasing the risk of cerebral vascular accidents in the elderly. 100 While this was primarily focused on the use of antipsychotics in dementia, this likely class effect should be taken into account when considering the use of antipsychotics in the elderly.

Traditional mood stabilizers, such as lithium, divalproate, and carbamazepine are also effective in the treatment of active mania ( fig 1 ). Since lithium also has a robust prophylactic effect (see section on prevention of mood episodes below) it is often recommended as first line treatment and can be considered as monotherapy when rapid symptom reduction is not clinically indicated. On the other hand, other anticonvulsants such as lamotrigine, gabapentin, topiramate, and oxcarbazepine have not been found to be effective for the treatment of mania or mixed episodes. 101 Although the empirical evidence for polypharmacy is limited, 102 combination treatment in acute mania, usually consisting of a mood stabilizer and a second generation antipsychotic, is commonly used in clinical practice despite the higher burden of side effects. Following resolution of an acute mania, consideration should be given to transitioning to monotherapy with an agent with proven prophylactic activity.

Pharmacological approaches to bipolar depression

Depressed episodes are usually more common than mania or hypomania, 103 104 and often represent the primary reason for individuals with bipolar disorder to seek treatment. Nevertheless, because early antidepressant randomized controlled trials did not distinguish between unipolar and bipolar depressive episodes, it has only been in the past two decades that large scale randomized controlled trials have been conducted specifically for bipolar depression. As such trials are almost exclusively funded by pharmaceutical companies, they have focused on the second generation antipsychotics and newer anticonvulsants still under patent. These trials have shown moderate but robust effects for most recent second generation antipsychotics, five of which have received FDA approval for treating bipolar depression ( table 1 ). No head-to-head trials have been conducted among these agents, so the choice of medication depends on expected side effects and cost considerations. For example, quetiapine has robust antidepressant efficacy data but is associated with sedation, weight gain, and adverse cardiovascular outcomes. 105 Other recently approved medications such as lurasidone, cariprazine, and lumateperone have better side effect profiles but show more modest antidepressant activity. 106

Among the mood stabilizing anticonvulsants, lamotrigine has limited evidence for acute antidepressant activity, 107 possibly owing to the need for an 8 week titration to reach the full dose of 200 mg. However, as discussed below, lamotrigine can still be considered for mild to moderate acute symptoms owing to its generally tolerable side effect profile and proven effectiveness in preventing the recurrence of depressive episodes. Divalproate and carbamazepine have some evidence of being effective antidepressants in small studies, but as there has been no large scale confirmatory study, they should be considered second or third line options. 86 Lithium has been studied for the treatment of bipolar depression as a comparator to quetiapine and was not found to have a significant acute antidepressant effect. 88

Antidepressants

Owing to the limited options of FDA approved medications for bipolar depression and concerns of metabolic side effects from long term second generation antipsychotic use, clinicians often resort to the use of traditional antidepressants for the treatment of bipolar depression 108 despite the lack of FDA approval for such agents. Indeed, recent randomized clinical trials of antidepressants in bipolar depression have not shown an effect for paroxetine, 89 109 bupropion, 109 or agomelatine. 110 Beyond the question of efficacy, another concern regarding antidepressants in bipolar disorder is their potential to worsen the course of illness by either promoting mixed or manic symptoms or inducing more subtle degrees of mood instability and cycle acceleration. 111 However, the risk of switching to full mania while being treated with mood stabilizers appears to be modest, with a meta-analysis of randomized clinical trials and clinical cohort studies showing the rates of mood switching over an average follow-up of five months to be approximately 15.3% in people with bipolar disorder treated on antidepressants compared with 13.8% in those without antidepressant treatment. 111 The risk of switching appears to be higher in the first 1-2 years of treatment in people with BD-I, and in those treated with a tricyclic antidepressant 112 or the dual reuptake inhibitor venlafaxine. 113 Overall, while the available data have methodological limitations, most guidelines do not recommend the use of antidepressants in bipolar disorder, or recommend them only after agents with more robust evidence have been tried. That they remain so widely used despite the equivocal evidence base reflects the unmet need for treatment of depression, concerns about the long term side effects of second generation antipsychotics, and the challenges of changing longstanding prescribing patterns.

Pharmacological approaches to prevention of recurrent episodes

Following treatment of the acute depressive or manic syndrome, the major focus of treatment is to prevent future episodes and minimize interepisodic subsyndromal symptoms. Most often, the medication that has been helpful in controlling the acute episode can be continued for prevention, particularly if clinical trial evidence exists for a maintenance effect. To show efficacy for prevention, studies must be sufficiently long to allow the accumulation of future episodes to occur and be potentially prevented by a therapeutic intervention. However, few long term treatment studies exist and most have utilized enriched designs that likely favor the drug seeking regulatory approval. As shown in figure 1 , meta-analyses 94 show prophylactic effect for most (olanzapine, risperidone, quetiapine, aripiprazole, asenapine) but not all (lurasidone, paliperidone) recently approved second generation antipsychotics. The effect sizes are generally comparable with monotherapy (odds ratio 0.42, 95% confidence interval 0.34 to 0.5) or as adjunctive therapy (odds ratio 0.37, 95% confidence interval 0.25 to 0.55). 94 Recent studies of lithium, which have generally used it as a (non-enriched) comparator drug, show a comparable protective effect (odds ratio 0.46, 95% confidence interval 0.28 to 0.75). 94 Among the mood stabilizing anticonvulsant drugs, a prophylactic effect has also been found for both divalproate and lamotrigine ( fig 1 and supplementary table 1), although only the latter has been granted regulatory approval for maintenance treatment. While there are subtle differences in effect sizes in drugs approved for maintenance ( fig 1 and table 1 ), the overlapping confidence intervals and methodological differences between studies prevent a strict comparison of the effect measures.

Guidelines often recommend lithium as a first line agent given its consistent evidence of prophylaxis, even when tested as the disadvantaged comparator drug in enriched drug designs. Like other medications, lithium has a unique set of side effects and ultimately the decision about which drug to use among those which are efficacious should be a decision carefully weighed and shared between patient and provider. The decision might be re-evaluated after substantial experience with the medication or at different stages in the long term treatment of bipolar disorder (see table 1 ).

Psychotherapeutic approaches

The frequent presence of residual symptoms, often associated with psychosocial and occupational dysfunction, has led to renewed interest in psychotherapeutic and psychosocial approaches to bipolar disorder. Given the impairment of judgment seen in mania, psychotherapy has more of a supportive and educational role in the treatment of mania, whereas it can be more of a primary focus in the treatment of depressive states. On a broad level, psychotherapeutic approaches effective for acute depression, such as cognitive behavioral therapy, interpersonal therapy, behavioral activation, and mindfulness based strategies, can also be recommended for acute depressive states in individuals with bipolar disorder. 114 Evidence for more targeted psychotherapy trials for bipolar disorder is more limited, but meta-analyses have found evidence for decreased recurrence (odds ratio 0.56; 95% confidence interval 0.43 to 0.74) 115 and improvement of subthreshold interepisodic depressive and manic symptoms with cognitive behavioral therapy, family based therapy, interpersonal and social rhythm therapy, and psychoeducation. 115 Recent investigations have also focused on targeted forms of psychotherapy to improve cognition 116 117 118 as well as psychosocial and occupational functioning. 119 120 Although these studies show evidence of a moderate effect, they remain preliminary, methodologically diverse, and require replication on a larger scale. 121

The implementation of evidence based psychotherapy as a treatment faces several challenges, including clinical training, fidelity monitoring, and adequate reimbursement. Novel approaches, leveraging the greater tractability of digital tools 122 and allied healthcare workers, 123 are promising means of lessening the implementation gap; however, these approaches require validation and evidence of clinical utility similar to traditional methods.

Neurostimulation approaches

For individuals with bipolar disorder who cannot tolerate or do not respond well to standard pharmacotherapy or psychotherapeutic approaches, neurostimulation techniques such as repetitive transcranial magnetic stimulation or electric convulsive therapy should be considered as second or third line treatments. Electric convulsive therapy has shown response rates of approximately 60-80% in severe acute depressions 124 125 and 50-60% in cases with treatment resistant depression. 126 These response rates compare favorably with those of pharmacological treatment, which are likely to be closer to ~50% and ~30% in subjects with moderate to severe depression and treatment resistant depression, respectively. 127 Although the safety of electric convulsive therapy is well established, relatively few medical centers have it available, and its acceptability is limited by cognitive side effects, which are usually short term, but which can be more significant with longer courses and with bilateral electrode placement. 128 While there have been fewer studies of electric convulsive therapy for bipolar depression compared with major depressive disorder, it appears to be similarly effective and might show earlier response. 129 Anecdotal evidence also suggests electric convulsive therapy that is useful in refractory mania. 130

Compared with electric convulsive therapy, repetitive transcranial magnetic stimulation has no cognitive side effects and is generally well tolerated. Repetitive transcranial magnetic stimulation acts by generating a magnetic field to depolarize local neural tissue and induce excitatory or inhibitory effects depending on the frequency of stimulation. The most studied FDA approved form of repetitive transcranial magnetic stimulation applies high frequency (10 Hz) excitatory pulses to the left prefrontal cortex for 30-40 minutes a day for six weeks. 131 Like electric convulsive therapy, repetitive transcranial magnetic stimulation has been primarily studied in treatment resistant depression and has been found to have moderate effect, with about one third of patients having a significant treatment response compared with those treated with pharmacotherapy. 131 Recent innovations in transcranial magnetic stimulation have included the use of a novel, larger coil to stimulate a larger degree of the prefrontal cortex (deep transcranial magnetic stimulation), 132 and a shortened (three minutes), higher frequency intermittent means of stimulation known as theta burst stimulation that appears to be comparable to conventional (10 Hz) repetitive transcranial magnetic stimulation. 133 A preliminary trial has recently assessed a new accelerated protocol of theta burst stimulation marked by 10 sessions a day for five days. It found that theta burst stimulation had a greater effect on people with treatment resistant depression compared with treatment as usual, although larger studies are needed to confirm these findings. 134

Conventional repetitive transcranial magnetic stimulation (10 Hz) studies in bipolar disorder have been limited by small sample sizes but have generally shown similar effects compared with major depressive disorder. 135 However, a proof of concept study of single session theta burst stimulation did not show efficacy in bipolar depression, 136 reiterating the need for specific trials for bipolar depression. Given the lack of such trials in bipolar disorder, repetitive transcranial magnetic stimulation should be considered a potentially promising but as yet unproven treatment for bipolar depression.

The other major form of neurostimulation studied in both unipolar and bipolar depression is transcranial direct current stimulation, an easily implemented method of delivering a low amplitude electrical current to the prefrontal area of the brain that could lead to local changes in neuronal excitability. 137 Like repetitive transcranial magnetic stimulation, transcranial direct current stimulation is well tolerated and has been mostly studied in unipolar depression, but has not yet generated sufficient evidence to be approved by a regulatory agency. 138 Small studies have been performed in bipolar depression, but the results have been mixed and require further research before use in clinical settings. 137 138 139 Finally, the evidence for more invasive neurostimulation studies such as vagal nerve stimulation and deep brain stimulation remains extremely limited and is currently insufficient for clinical use. 140 141

Treatment resistance in bipolar disorder

As in major depressive disorder, the use of term treatment resistance in bipolar disorder is controversial since differentiating whether persistent symptoms are caused by low treatment adherence, poor tolerability, the presence of comorbid disorders, or are the result of true treatment resistance, is an essential but often challenging clinical task. Treatment resistance should only be considered after two or three trials of evidence based monotherapy, adjunctive therapy, or both. 142 In difficult-to-treat mania, two or more medications from different mechanistic classes are typically used, with electric convulsive therapy 143 and clozapine 144 being considered if more conventional anti-manic treatments fail. In bipolar depression, it is common to combine antidepressants with anti-manic agents, despite limited evidence for efficacy. 145 Adjunctive therapies such as bright light therapy, 146 the dopamine D2/3 receptor agonist pramipexole, 147 and ketamine 148 149 have shown promising results in small open label trials that require further study.

Treatment considerations to reduce suicide in bipolar disorder

The risk of completed suicide is high across the subtypes of bipolar disorder, with estimated rates of 10-15% across the lifespan. 150 151 152 Lifetime rates of suicide attempts are much higher, with almost half of all individuals with bipolar disorder reporting at least one attempt. 153 Across a population and, often within individuals, the causes of suicide attempts and completed suicides are likely to be multifactorial, 154 affected by various risk factors, such as symptomatic illness, environmental stressors, comorbidities (particularly substance misuse), trait impulsivity, interpersonal conflict, loneliness, or socioeconomic distress. 155 156 Risk is highest in depressive and dysphoric/mixed episodes 157 158 and is particularly high in the transitional period following an acute admission to hospital. 159 Among the available treatments, lithium has potential antisuicidal properties. 160 However, since suicide is a rare event, with very few to zero suicides within a typical clinical trial, moderate evidence for this effect emerges only in the setting of meta-analyses of clinical trials. 160 Several observational studies have shown lower mortality in patients on lithium treatment, 161 but such associations might not be causal, since lithium is potentially fatal in overdose and is often avoided by clinicians in patients at high risk of suicide.

The challenge of studying scarce events has led most studies to focus on the reduction of the more common phenomena of suicidal ideation and behavior as a proxy for actual suicides. A recent such multisite study of the Veterans Affairs medical system included a mixture of unipolar and bipolar disorder and was stopped prematurely for futility, indicating no overall effect of moderate dose lithium. 162 Appropriate limitations of this study have been noted, 163 164 including difficulties in recruitment, few patients with bipolar disorder (rather than major depressive disorder), low levels of compliance with lithium therapy, high rates of comorbidity, and a follow-up of only one year. Nevertheless, while the body of evidence suggests that lithium has a modest antisuicidal effect, its degree of protection and utility in complex patients with comorbidities and multiple risk factors remain matters for further study. Treatment of specific suicidal risk in patients with bipolar disorder must therefore also incorporate broader interventions based on the individual’s specific risk factors. 165 Such an approach would include societal interventions like means restriction 166 and a number of empirically tested suicide focused psychotherapy treatments. 167 168 Unfortunately, the availability of appropriate training, expertise, and care models for such treatments remains limited, even in higher income countries. 169

More scalable solutions, such as the deployment of shortened interventions via digital means could help to overcome this implementation gap; however, the effectiveness of such approaches cannot be assumed and requires empirical testing. For example, a recent large scale randomized controlled trial of an abbreviated online dialectical behavioral therapy skills training program was paradoxically associated with slightly increased risk of self-harm. 170

Treatment consideration in BD-II and bipolar spectrum conditions

Because people with BD-II primarily experience depressive symptoms and appear less likely to switch mood states compared with individuals with BD-I, 50 171 there has been a greater acceptance of the use of antidepressants in BD-II depression, including as monotherapy. 172 However, caution should be exercised when considering the use of antidepressants without a mood stabilizer in patients with BD-II who might also experience high rates of mood instability and rapid cycling. Such individuals can instead respond better to newer second generation antipsychotic agents such as quetiapine 173 and lumateperone, 93 which are supported by post hoc analyses of these more recent clinical trials with more BD-II patients. In addition, despite the absence of randomized controlled trials, open label studies have suggested that lithium and other mood stabilizers can have similar efficacy in BD-II, especially in the case of lamotrigine. 174

Psychotherapeutic approaches such as psychoeducation, cognitive behavioral therapy, and interpersonal and social rhythm therapy have been found to be helpful 115 and can be considered as the primary form of treatment for BD-II in some patients, although in most clinical scenarios BD-II is likely to occur in conjunction with psychopharmacology. While it can be tempting to consider BD-II a milder variant of BD-I, high rates of comorbid disorders, rapid cycling, and adverse consequences such as suicide attempts 175 176 highlight the need for clinical caution and the provision of multimodal treatment, focusing on mood improvement, emotional regulation, and better psychosocial functioning.

Precision medicine: can it be applied to improve the care of bipolar disorder?

The recent focus on precision medicine approaches to psychiatric disorders seeks to identify clinically relevant heterogeneity and identify characteristics at the level of the individual or subgroup that can be leveraged to identify and target more efficacious treatments. 1 177 178

The utility of such an approach was originally shown in oncology, where a subset of tumors had gene expression or DNA mutation signatures that could predict response to treatments specifically designed to target the aberrant molecular pathway. 179 While much of the emphasis of precision medicine has been on the eventual identification of biomarkers utilizing high throughput approaches (genetics and other “omics” based measurements), the concept of precision medicine is arguably much broader, encompassing improvements in measurement, potentially through the deployment of digital tools, as well as better conceptualization of contextual, cultural, and socioeconomic mechanisms associated with psychopathology. 180 181 Ultimately, the goal of precision psychiatry is to identify and target driving mechanisms, be they molecular, physiological, or psychosocial in nature. As such, precision psychiatry seeks what researchers and clinicians have often sought: to identify clinically relevant heterogeneity to improve prediction of outcomes and increase the likelihood of therapeutic success. The novelty being not so much the goals of the overarching approach, but the increasing availability of large samples, novel digital tools, analytical advances, and an increasing armamentarium of biological measurements that can be deployed at scale. 177

Although not unique to bipolar disorder, several clinical decision points along the life course of bipolar disorder would benefit from a precision medicine approach. For example, making an early diagnosis is often not possible based on clinical symptoms alone, since such symptoms are usually non-specific. A precision medicine approach could also be particularly relevant in helping to identify subsets of patients for whom the use of antidepressants could be beneficial or harmful. Admittedly, precision medicine approaches to bipolar disorder are still in their infancy, and larger, clinically relevant, longitudinal, and reliable phenotypes are needed to provide the infrastructure for precision medicine approaches. Such data remain challenging to obtain at scale, leading to renewed efforts to utilize the extant clinical infrastructure and electronic medical records to help emulate traditional longitudinal analyses. Electronic medical records can help provide such data, but challenges such as missingness, limited quality control, and potential biases in care 182 need to be resolved with carefully considered analytical designs. 183

Emerging treatments

Two novel atypical antipsychotics, amilsupride and bifeprunox, are currently being tested in phase 3 trials ( NCT05169710 and NCT00134459 ) and could gain approval for bipolar depression in the near future if these pivotal trials show a significant antidepressant effect. These drugs could offer advantages such as greater antidepressant effects, fewer side effects, and better long term tolerability, but these assumptions must be tested empirically. Other near term possibilities include novel rapid antidepressant treatments, such as (es)ketamine that putatively targets the glutamatergic system, and has been recently approved for treatment resistant depression, but which have not yet been tested in phase 3 studies in bipolar depression. Small studies have shown comparable effects of intravenous ketamine, 149 184 in bipolar depression with no short term evidence of increased mood switching or mood instability. Larger phase 2 studies ( NCT05004896 ) are being conducted which will need to be followed by larger phase 3 studies. Other therapies targeting the glutamatergic system have generally failed phase 3 trials in treatment resistant depression, making them unlikely to be tested in bipolar depression. One exception could be the combination of dextromethorphan and its pharmacokinetic (CYP2D6) inhibitor bupropion, which was recently approved for treatment resistant depression but has yet to be tested in bipolar depression. Similarly, the novel GABAergic compound zuranolone is currently being evaluated by the FDA for the treatment of major depressive disorder and could also be subsequently studied in bipolar depression.

Unfortunately, given the general efficacy for most patients of available treatments, few scientific and financial incentives exist to perform large scale studies of novel treatment in mania. Encouraging results have been seen in small studies of mania with the selective estrogen receptor modulator 185 tamoxifen and its active metabolite endoxifen, both of which are hypothesized to inhibit protein kinase C, a potential mechanistic target of lithium treatment. These studies remain small, however, and anti-estrogenic side effects have potentially dulled interest in performing larger studies.

Finally, several compounds targeting alternative pathophysiological mechanisms implicated in bipolar disorder have been trialed in phase 2 academic studies. The most studied has been N -acetylcysteine, a putative mitochondrial modulator, which initially showed promising results only to be followed by null findings in larger more recent studies. 186 Similarly, although small initial studies of anti-inflammatory agents provided impetus for further study, subsequent phase 2 studies of the non-steroidal agent celecoxib, 187 the anti-inflammatory antibiotic minocycline, 187 and the antibody infliximab (a tumor necrosis factor antagonist) 188 have not shown efficacy for bipolar depression. Secondary analyses have suggested that specific anti-inflammatory agents might be effective only for a subset of patients, such as those with elevated markers of inflammation or a history of childhood adversity 189 ; however, such hypotheses must be confirmed in adequately powered independent studies.

Several international guidelines for the treatment of bipolar disorder have been published in the past decade, 102 190 191 192 providing a list of recommended treatments with efficacy in at least one large randomized controlled trial. Since effect sizes tend to be moderate and broadly comparable across classes, all guidelines allow for significant choice among first line agents, acknowledging that clinical characteristics, such as history of response or tolerability, severity of symptoms, presence of mixed features, or rapid cycling can sometimes over-ride guideline recommendations. For acute mania requiring rapid treatment, all guidelines prioritize the use of second generation antipsychotics such as aripiprazole, quetiapine, risperidone, asenapine, and cariprazine. 102 192 193 Combination treatment is considered based on symptom severity, tolerability, and patient choice, with most guidelines recommending lithium or divalproate along with a second generation antipsychotic for mania with psychosis, severe agitation, or prominent mixed symptoms. While effective, haloperidol is usually considered a second choice option owing to its propensity to cause extrapyramidal symptoms. 102 192 193 Uniformly, all guidelines agree on the need to taper antidepressants in manic or mixed episodes.

For maintenance treatment, guidelines are generally consistent in recommending lithium if tolerated and without relative contraindications, such as baseline renal disease. 194 The second most recommended maintenance treatment is quetiapine, followed by aripiprazole for patients with prominent manic episodes and lamotrigine for patients with predominant depressive episodes. 194 Most guidelines recommend considering prophylactic properties when initially choosing treatment for acute manic episodes, although others suggests that acute maintenance treatments can be cross tapered with maintenance medications after several months of full reponse. 193

For bipolar depression, recent guidelines recommend specific second generation antipsychotics such as quetiapine, lurasidone, and cariprazine 102 192 193 For more moderate symptoms, consideration is given to first using lamotrigine and lithium. Guidelines remain cautious about the use of antidepressants (selective serotonin reuptake inhibitors, venlafaxine, or bupropion) in patients with BP-I, restricting them to second or third line treatments and always in the context of an anti-manic agent. However, for patients with BP-II and no rapid cycling, several guidelines allow for the use of carefully monitored antidepressant monotherapy.

Bipolar disorder is a highly recognizable syndrome with many effective treatment options, including the longstanding gold standard therapy lithium. However, a significant proportion of patients do not respond well to current treatments, leading to negative consequences, poor quality of life, and potentially shortened lifespan. Several novel treatments are being developed but limited knowledge of the biology of bipolar disorder remains a major challenge for novel drug discovery. Hope remains that the insights of genetics, neuroimaging, and other investigative modalities could soon be able to inform the development of rational treatments aimed to mitigate the underlying pathophysiology associated with bipolar disorder. At the same time, however, efforts are needed to bridge the implementation gap and provide truly innovative and integrative care for patients with bipolar disorder. 195 Owing to the complexity of bipolar disorder, few patients can be said to be receiving optimized care across the various domains of mental health that are affected in those with bipolar disorder. Fortunately, the need for improvement is now well documented, 196 and concerted efforts at the scale necessary to be truly innovative and integrative are now on the horizon.

Questions for future research

Among adolescents and young adults who manifest common mental disorders such as anxiety or depressive or attentional disorders, who will be at high risk for developing bipolar disorder?

Can we predict the outcomes for patients following a first manic or hypomanic episode? This will help to inform who will require lifelong treatment and who can be tapered off medications after sustained recovery.

Are there reliable clinical features and biomarkers that can sufficiently predict response to specific medications or classes of medication?

What are the long term consequences of lifelong treatments with the major classes of medications used in bipolar disorder? Can we predict and prevent medical morbidity caused by medications?

Can we understand in a mechanistic manner the pathophysiological processes that lead to abnormal mood states in bipolar disorder?

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: FSG performed the planning, conduct, and reporting of the work described in the article. FSG accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

Competing interests: I have read and understood the BMJ policy on declaration of interests and declare no conflicts of interest.

Patient involvement: FSG discussed of the manuscript, its main points, and potential missing points with three patients in his practice who have lived with longstanding bipolar disorder. These additional viewpoints were incorporated during the drafting of the manuscript.

Provenance and peer review: Commissioned; externally peer reviewed.

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• Open access
• Published: 06 November 2018

The challenges of living with bipolar disorder: a qualitative study of the implications for health care and research

• Eva F. Maassen   ORCID: orcid.org/0000-0003-0211-0994 1 , 2 ,
• Barbara J. Regeer 1 ,
• Eline J. Regeer 2 ,
• Joske F. G. Bunders 1 &
• Ralph W. Kupka 2 , 3  

International Journal of Bipolar Disorders volume  6 , Article number:  23 ( 2018 ) Cite this article

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In mental health care, clinical practice is often based on the best available research evidence. However, research findings are difficult to apply to clinical practice, resulting in an implementation gap. To bridge the gap between research and clinical practice, patients’ perspectives should be used in health care and research. This study aimed to understand the challenges people with bipolar disorder (BD) experience and examine what these challenges imply for health care and research needs.

Two qualitative studies were used, one to formulate research needs and another to formulate healthcare needs. In both studies focus group discussions were conducted with patients to explore their challenges in living with BD and associated needs, focusing on the themes diagnosis, treatment and recovery.

Patients’ needs are clustered in ‘disorder-specific’ and ‘generic’ needs. Specific needs concern preventing late or incorrect diagnosis, support in search for individualized treatment and supporting clinical, functional, social and personal recovery. Generic needs concern health professionals, communication and the healthcare system.

Patients with BD address disorder-specific and generic healthcare and research needs. This indicates that disorder-specific treatment guidelines address only in part the needs of patients in everyday clinical practice.

Bipolar disorder (BD) is a major mood disorder characterized by recurrent episodes of depression and (hypo)mania (Goodwin and Jamison 2007 ). According to the Diagnostic and Statistical Manual 5 (DSM-5), the two main subtypes are BD-I (manic episodes, often combined with depression) and BD-II (hypomanic episodes, combined with depression) (APA 2014 ). The estimated lifetime prevalence of BD is 1.3% in the Dutch adult population (de Graaf et al. 2012 ), and BD is associated with high direct (health expenditure) and indirect (e.g. unemployment) costs (Fajutrao et al. 2009 ; Michalak et al. 2012 ), making it an important public health issue. In addition to the economic impact on society, BD has a tremendous impact on patients and their caregivers (Granek et al. 2016 ; Rusner et al. 2009 ). Even between mood episodes, BD is often associated with functional impairment (Van Der Voort et al. 2015 ; Strejilevich et al. 2013 ), such as occupational or psychosocial impairment (Huxley and Baldessarini 2007 ; MacQueen et al. 2001 ; Yasuyama et al. 2017 ). Apart from symptomatic recovery, treatment can help to overcome these impairments and so improve the person’s quality of life (IsHak et al. 2012 ).

Evidence Based Medicine (EBM), introduced in the early 1990s, is a prominent paradigm in modern (mental) health care. It strives to deliver health care based on the best available research evidence, integrated with individual clinical expertise (Sackett et al. 1996 ). EBM was introduced as a new paradigm to ‘de - emphasize intuition’ and ‘ unsystematic clinical experience’ (Guyatt et al. 1992 ) (p. 2420). Despite its popularity in principle (Barratt 2008 ), EBM has also been criticized. One such criticism is the ignorance of patients’ preferences and healthcare needs (Bensing 2000 ). A second criticism relates to the difficulty of adopting evidence-based treatment options in clinical practice (Bensing 2000 ), due to the fact that research outcomes measured in ‘the gold standard’ randomized-controlled trials (RCTs) seldom correspond to the outcomes clinical practice seeks and are not responsive to patients’ needs (Newnham and Page 2010 ). Moreover, EBM provides an overview on population level instead of individual level (Darlenski et al. 2010 ). Thus, adopting research evidence in clinical practice entails difficulties, resulting in an implementation gap.

To bridge the gap between research and clinical practice, it is argued that patients’ perspectives should be used in both health care and research. Patients have experiential knowledge about their illness, living with it in their personal context and their care needs (Tait 2005 ). This is valuable for both clinical practice and research as their knowledge complements that of health professionals and researchers (Tait 2005 ; Broerse et al. 2010 ; Caron-Flinterman et al. 2005 ). This source of knowledge can be used in the process of translating evidence into clinical practice (Schrevel 2015 ). Moreover, patient participation can enhance the clinical relevance of and support for research and the outcomes in practice (Abma and Broerse 2010 ). Hence, it is argued that these perspectives should be explicated and integrated into clinical guidelines, clinical practice, and research (Misak 2010 ; Rycroft-Malone et al. 2004 ).

Given the advantages of including patients’ perspectives, patients are increasingly involved in healthcare services (Bagchus et al. 2014 ; Larsson et al. 2007 ), healthcare quality (e.g. guideline development) (Pittens et al. 2013 ) and health-related research (e.g. agenda setting, research design) (Broerse et al. 2010 ; Boote et al. 2010 ; Elberse et al. 2012 ; Teunissen et al. 2011 ). However, patients’ perspectives on health care and on research are often studied separately. We argue that to be able to provide care focused on the patients and their needs, care and research must closely interact.

We hypothesize that the challenges BD patients experience and the associated care and research needs are interwoven, and that combining them would provide a more comprehensive understanding. We hypothesize that this more comprehensive understanding would help to close the gap between clinical practice and research. For this reason, this study aims to understand the challenges people with BD experience and examine what these challenges imply for healthcare and research needs.

To understand the challenges and needs of people with BD, we undertook two qualitative studies. The first aimed to formulate a research agenda for BD from a patient’s perspective, by gaining insights into their challenges and research needs. A second study yielded an understanding of the care needs from a patient’s perspective. In this article, the results of these two studies are combined in order to investigate the relationship between research needs and care needs. Challenges are defined as ‘difficulties patients face, due to having BD’. Care needs are defined as that what patients ‘desire to receive from healthcare services to improve overall health’ (Asadi-Lari et al. 2004 ) (p. 2). Research needs are defined as that what patients ‘desire to receive from research to improve overall health’.

Study on research needs

In this study, mixed-methods were used to formulate research needs from a patient’s perspective. First six focus group discussions (FGDs) with 35 patients were conducted to formulate challenges in living with BD and hopes for the future, and to formulate research needs arising from these difficulties and aspirations. These research needs were validated in a larger sample (n = 219) by means of a questionnaire. We have reported this study in detail elsewhere (Maassen et al. 2018 ).

Study on care needs

This study was part of a nationwide Dutch project to generate a practical guideline for BD: a translation of the existing clinical guideline to clinical practice, resulting in a standard of care that patients with BD could expect. The practical guideline (Netwerk Kwaliteitsontwikkeling GGZ 2017 ) was written by a taskforce comprising health professionals, patients. In addition to the involvement of three BD patients in the taskforce, a systematic qualitative study was conducted to gain insight into the needs of a broader group of patients.

Participants and data collection

To formulate the care needs of people with BD, seven FGDs were conducted, with a total of 56 participants, including patients (n = 49) and caregivers (n = 9); some participants were both patient and caregiver. The inclusion criteria for patients were having been diagnosed with BD, aged 18 years or older and euthymic at time of the FGDs. Inclusion criteria for caregivers were caring for someone with BD and aged 18 years or older. To recruit participants, a maximum variation sampling strategy was used to collect a broad range of care needs (Kuper et al. 2008 ). First, all outpatient clinics specialized in BD affiliated with the Dutch Foundation for Bipolar Disorder (Dutch: Kenniscentrum Bipolaire Stoornissen) were contacted by means of an announcement at regular meetings and by email if they were interested to participate. From these outpatient clinics, patients were recruited by means of flyers and posters. Second, patients were recruited at a quarterly meeting of the Dutch patient and caregiver association for bipolar disorder. The FGDs were conducted between March and May 2016.

The FGDs were designed to address challenges experienced in BD health care and areas of improvement for health care for people with BD. The FGDs were structured by means of a guide and each session was facilitated by two moderators. The leading moderator was either BJR or EFM, having both extensive experience with FGD’s from previous studies. The first FGD explored a broad range of needs. The subsequent six FGDs aimed to gain a deeper understanding of these care needs, and were structured according to the outline of the practical guideline (Netwerk Kwaliteitsontwikkeling GGZ 2017 ). Three chapters were of particular interest: diagnosis, treatment and recovery. These themes were discussed in the FGDs, two in each session, all themes three times in total. Moreover, questions on specific aspects of care formulated by the members of the workgroup were posed. The sessions took 90–120 min. The FGDs were audiotaped and transcribed verbatim. A summary of the FGDs was sent to the participants for a member check.

Data analysis

To analyze the data on challenges and needs, a framework for thematic analysis to identify, analyze and report patterns (themes) in qualitative data sets by Braun and Clarke ( 2006 ) was used. First, we familiarized ourselves with the data by carefully reading the transcripts. Second, open coding was used to derive initial codes from the data. These codes were provided to quotes that reflected a certain challenge or care need. Third, we searched for patterns within the codes reflecting challenges and within those reflecting needs. For both challenges and needs, similar or overlapping codes were clustered into themes. Subsequently, all needs were categorized as ‘specific’ or ‘generic’. The former are specific to BD and the latter are relevant for a broad range of psychiatric illnesses. Finally, a causal analysis provided a clear understanding of how challenges related to each other and how they related to the described needs.

To analyze the data on needs regarding recovery, four domains were distinguished, namely clinical, functional, social and personal recovery (Lloyd et al. 2008 ; van der Stel 2015 ). Clinical recovery refers to symptomatic remission; functional recovery concerns recovery of functioning that is impaired due to the disorder, particularly in the domain of executive functions; social recovery concerns the improvement of the patient’s position in society; personal recovery concerns the ability of the patient to give meaning to what had happened and to get a grip on their own life. The analyses were discussed between BR and EM. The qualitative software program MAX QDA 11.1.2 was used (MaxQDA).

Ethical considerations

According to the Medical Ethical Committee of VU University Medical Center, the Medical Research Involving Human Subjects Act does not apply to the current study. All participants gave written or verbal informed consent regarding the aim of the study and for audiotaping and its use for analysis and scientific publications. Participation was voluntary and participants could withdraw from the study at any time. Anonymity was ensured.

This section is in three parts. The first presents the participants’ characteristics. The second presents the challenges BD patients face, derived from both studies, and the disorder-specific care and research needs associated with these challenges. The third part describes the generic care needs that patients formulated.

Characteristics of the participants

In the study on care needs, 56 patients and caregivers participated. The mean age of the participants was 52 years (24–75), of whom 67.8% were women. The groups varied from four to sixteen participants, and all groups included men and women. Of all participants 87.5% was diagnosed with BD, of whom 48.9% was diagnosed with BD I. 3.5% was both caregivers and diagnosed with BD. Of 4 patients the age was missing, and from 6 patients the bipolar subtype.

Despite the fact that participants acknowledge the inevitable diagnostic difficulties of a complex disorder like BD, in both studies they describe a range of challenges in different phases of the diagnostic process (Fig.  1 ). Patients explained that the general practitioner (GP) and society in general did not recognize early-warning signs and mood swings were not well interpreted, resulting in late or incorrect diagnosis. Patients formulated a need for more research on what early-warning signs could be and on how to improve GPs’ knowledge about BD. Formulated care needs were associated with GPs using this knowledge to recognize early-warning signs in individual patients. One participant explained that certain symptoms must be noticed and placed in the right context:

Challenges with diagnosis (squares) including relating research needs (white circles) and care needs (grey circles). (1): mentioned in study on research needs; (2): mentioned in study on care needs. Dotted lines: division of challenges into sub challenges. Arrows: causal relation between challenges

I call it, ‘testing overflow of ideas’. [….] When it happens for the first time you yourself do not recognize it. Someone else close to you or the health professional, who is often not involved yet, must signal it. (FG6)

Moreover, these challenges are associated with the need to pay attention to family history and to use a multidisciplinary approach to diagnosis to benefit from multiple perspectives. The untimely recognition of early symptoms also results in another challenge: inadequate referral to the right specialized health professional. After referral, people often face a waiting list, again causing delay in the diagnostic process. These challenges result in the need for research on optimal referral systems and the care need for timely referral. One participant described her process after the GP decided to refer her:

But, yes, at that moment the communication wasn’t good at all. Because the general practitioner said: ‘she urgently has to be seen by someone’. Subsequently, three weeks went by, until I finally arrived at depression [department]. And at that department they said: ‘well, you are in the wrong place, you need to go to bipolar [department ]’. (FG1)

The challenge of being misdiagnosed is associated with the need to be able to ask for a second opinion and to have a timely and thorough diagnosis. On the one hand, it is important for patients that health professionals quickly understand what is going on, on the other hand that health professionals take the time to thoroughly investigate the symptoms by making several appointments.

From both studies, two main challenges related to the treatment of BD were derived (Fig.  2 ). The first is finding appropriate and satisfactory treatment. Participants explained that it is difficult to find the right medication and dosage that is effective and has acceptable side-effects. One participant illustrates:

Challenges with treatment (squares) including relating research needs (white circles) and care needs (grey circles). (1): mentioned in study on research needs; (2): mentioned in study on care needs. Dotted lines: division of challenges into sub challenges. Arrows: causal relation between challenges

I think, at one point, we have to choose, either overweight or depressed. (FG1)

Some participants said that they struggle with having to use medication indefinitely, including the associated medical checks. The difficult search for the right pharmacological treatment results in the need for research on long-term side-effects, on the mechanism of action of medicine and on the development of better targeted medication with fewer adverse side-effects. In care, patients would appreciate all the known information on the side-effects and intended effects. One participant explained the importance of being properly informed about medication:

I don’t read anything [about medication], because then I wouldn’t dare taking it. But I do think, when you explain it well, the advantages, the disadvantages, the treatment, the idea behind it, that would help a lot in compliance. (FG1)

A second aspect is the challenge of finding non-pharmacological therapies that fit patients’ needs. They said they and the health professionals often do not know which non-pharmacological therapies are available and effective:

But we found the carefarm ourselves Footnote 1 [….]. You have to search for yourself completely. Yes, I actually hoped that that would be presented to you, like: ‘this would be something for you’. (FG3)

Participants mentioned a variety of non-pharmacological therapies they found useful, namely cognitive behavior therapy (CBT), EMDR, running therapy, social-rhythm training, light therapy, mindfulness, psychotherapy, psychoeducation, and training in living with mood swings. They formulated the care need to receive an overview of all available treatment options in order to find a treatment best suited to their needs. They would appreciate research on the effectiveness of non-pharmacological treatments.

A third aspect within this challenge is finding the right balance between non-pharmacological and pharmacological treatment. Participants differed in their opinion about the need for medication. Whereas some participants stated that they need medication to function, others pointed out that they found non-pharmacological treatments effective, resulting in less or no medication use. They explained that the preferred balance can also change over time, depending on their mood. However, they experience a dominant focus on pharmacological treatment by the health professionals. To address this challenge, patients need support in searching for an appropriate balance.

Next to the challenge of finding appropriate and satisfactory treatment, a second treatment-related challenge is hospitalization. Participants often had a traumatic experience, due to seclusion, the authoritarian attitudes of clinical staff, and not involving their family. Patients therefore found it important to try preventing being hospitalized, for example by means of home treatment, which some participants experienced positively. Despite the challenges relating to hospitalization, participants did acknowledge that in some cases it cannot be avoided, in which case they urged for close family involvement, open communication and being treated by their own psychiatrist. Still, in the study on research needs, hospitalization did not emerge as an important research theme.

In both studies, participants described challenges in all four domains of recovery: clinical, functional, social and personal (Fig.  3 ). In relation to clinical recovery, participants struggled with the symptoms of mood episodes, the psychosis and the fear of a future episode. In contrast, some participants mentioned that they sometimes miss the hypomanic state they had experienced previously due to effective medical treatment. In the domain of functional recovery, participants contended with having to function below their educational level due to residual symptoms, such as cognitive problems, due to the importance of preventing stress in order to reduce the risk of a new episode, and because of low energy levels. This leads to the care need that health professionals should pay attention to the level of functioning of their patients.

Challenges with recovery (squares) including relating research needs (white circles) and care needs (grey circles). (1): mentioned in study on research needs; (2): mentioned in study on care needs. Dotted lines: division of challenges into sub challenges. Arrows: causal relation between challenges

In the domain of social recovery, participants described challenges with maintaining friendships, due to stigma, being unpredictable and with deciding when to disclose the disorder. The latter resulted in the care need for tips on disclosure. Moreover, patients experienced challenges with reintegration to work, due to colleagues’ lack of understanding, problems with functioning during an episode, the complicating policy of the (Dutch) Employee Insurance Agency Footnote 2 in relation to the fluctuating course of BD and the negative impact of stress. These challenges are associated with the care need that health professionals should pay attention to work and the need for research on how to improve the Social Security Agency’s policy.

For their personal recovery, participants struggled with acceptance of the disorder, due to shame, stigma, having to live by structured rules and disciplines, and the chronic nature of BD. This results in care needs for grief counselling and attention to acceptance and the need for research on the impact of being diagnosed with BD. Limited understanding within society also causes problems with acceptance, corresponding with the care need for education for caregivers and for research on how to increase social acceptance. Another challenge in personal recovery was discovering what recovery means and what constitute meaningful daily activities. Patients appreciated the support of health professionals in this area. One participant described the difficult search for the meaning of recovery:

I have been looking to recover towards the situation [before diagnosis] for a long time; that I could do what I always did and what I liked. But then I was confronted with the fact that I shouldn’t expect that to happen, or only with a lot of effort. (…) Then you start thinking, now what? A compromise. I don’t want to call that recovery, but it is a recovered, partly accepted, situation. But it is not recovery as I expected it to be. (FG5)

In general, participants considered frequent contact with a nurse or psychiatrist supportive, to help them monitor their mood and help them find (efficient) self-management strategies. Most participants appreciated the involvement of caregivers in the treatment and contact with peers.

Generic care needs

We have described BD-specific needs, but patients mentioned also mentioned several generic care needs. The latter are clustered into three categories. The first concerns the health professionals . Participants stressed the importance of a good health professional, who carefully listens, takes time, and makes them feel understood, resulting in a sense of connection. Furthermore, a good health professional treats beyond the guideline, and focuses on the needs of the individual patient. When there is no sense of connection, it should be possible to change to another health professional. The second category concerns communication between the patient and the health professional . Health professionals should communicate in an open, honest and clear way both in the early diagnostic phase and during treatment. Open communication facilitates individualized care, in which the patient is involved in decision making. In addition, participants wanted to be treated as a person, not as a patient, and according to a strength-based approach. The third category concerns needs at the level of the healthcare system . Participants struggled with the availability of the health professionals and preferred access to good care 24/7 and being able to contact their health professional quickly when necessary. Currently, according to the participants, the care system is not geared to the mood swings of BD, because patients often faced waiting lists before they could see a health professional.

Is adequate treatment also having a number from a mental health institution you can always call when you are in need, that you can go there? And not that you can go in three weeks, but on a really short notice. So at least a phone call. (FG3)

Participants were often frustrated by the limited collaboration between health professionals, within their own team, between departments of the organization, and between different organizations, including complementary health professionals. They would appreciate being able to merge their conventional and complementary treatment, with greater collaboration among the different health professionals. Furthermore, they would like continuity of health professionals as this improves both the diagnostic phase and treatment, and because that health professional gets to know the patient.

We hypothesized that research and care needs of patients are closely intertwined and that understanding these, by explicating patients’ perspectives, could contribute to closing the gap between research and care. Therefore, this study aimed to understand the challenges patients with BD face and examine what these imply for both healthcare and research. In the study on needs for research and in the study on care needs, patients formulated challenges relating to receiving the correct diagnosis, finding the right treatment, including the proper balance between non-pharmacological and pharmacological treatment, and to their individual search for clinical, functional, social and personal recovery. The formulated needs in both studies clearly reflected these challenges, leading to closely corresponding needs. Another important finding of our study is that patients not only formulate disorder-specific needs, but also many generic needs.

The needs found in our study are in line with the current literature on the needs of patients with BD, namely for more non-pharmacological treatment (Malmström et al. 2016 ; Nestsiarovich et al. 2017 ), timely recognition of early-warning signs and self-management strategies to prevent a new episode (Goossens et al. 2014 ), better information on treatment and treatment alternatives (Malmström et al. 2016 ; Neogi et al. 2016 ) and coping with grief (Goossens et al. 2014 ). Moreover, the need for frequent contact with health professionals, being listened to, receiving enough time, shared decision-making on pharmacological treatment, involving caregivers (Malmström et al. 2016 ; Fisher et al. 2017 ; Skelly et al. 2013 ), and the urge for better access to health care and continuity of health professionals (Nestsiarovich et al. 2017 ; Skelly et al. 2013 ) are confirmed by the literature. Our study added to this set of literature by providing insights in patients’ needs in the diagnostic process and illustrating the interrelation between research needs and care needs from a patient’s perspective.

The generic healthcare needs patients addressed in this study are clustered into three categories: the health professional , communication between the patient and the health professional and the health system. These categories all fit in a model of patient-centered care (PCC) by Maassen et al. ( 2016 ) In their review, patients’ perspectives on good care are compared with academic perspectives of PCC and a model of PCC is created comprising four dimensions: patient, health professional, patient – professional interaction and healthcare organization. All the generic needs formulated in this study fit into these four dimensions. The need to be treated as a person with strengths fits the dimension ‘patient’, and the need for a good health professional who carefully listens, takes time and makes them feel understood, resulting in a good connection with the professional, fits the dimension ‘health professional’ of this model. Furthermore, patients in this study stressed the importance of open communication in order to provide individualized care, which fits the dimension of ‘patient–professional interaction’. The urge for better access to health care, geared to patients’ mood swings and the need for better collaboration between health professionals and continuity of health professionals fits the dimension of ‘health care organization’ of the model. This study confirms the findings from the review and contributes to the literature stressing the importance of a patient-centered care approach (Mills et al. 2014 ; Scholl et al. 2014 ).

In the prevailing healthcare paradigm, EBM, the best available evidence should guide treatment of patients (Sackett et al. 1996 ; Darlenski et al. 2010 ). This evidence is translated into clinical and practical guidelines, which thus facilitate EBM and could be used as a decision-making tool in clinical practice (Skelly et al. 2013 ). For many psychiatric disorders, treatment is based on such disorder - specific clinical and practical guidelines. However, this disease-focused healthcare system has contributed to its fragmented nature Stange ( 2009 ) argues that this fragmented care system has expanded without the corresponding ability to integrate and personalize accordingly. We argue that acknowledging that disorder - specific clinical and practical guidelines address only parts of the care needs is of major importance, since otherwise important aspects of the patients’ needs will be ignored. Because there is an increasing acknowledgement that health care should be responsive to the needs of patients and should change from being disease-focused towards being patient-focused (Mead and Bower 2000 ; Sidani and Fox 2014 ), currently in the Netherlands generic practical guidelines are written on specific care themes (e.g. co-morbidity, side-effects, daily activity and participation). These generic practical guidelines address some of the generic needs formulated by the patients in our study. We argue that in addition to disorder-specific guidelines, these generic practical guidelines should increasingly be integrated into clinical practice, while health professionals should continuously be sensitive to other emerging needs. We believe that an integration of a disorder-centered and a patient-centered focus is essential to address all needs a patient.

Strengths, limitations and future research

This study has several strengths. First, it contributes to the literature on the challenges and needs of patients with BD. Second, the study is conducted from a patient’s perspective. Moreover, addressing this aim by conducting two separate studies enabled us to triangulate the data.

This study also has several limitations. First, this study reflects the challenges, care needs and research needs of Dutch patient with BD and caregivers. Despite the fact that a maximum variation sampling strategy was used to derive a broad range of challenges and needs throughout the Netherlands, the Dutch setting of the study may limit the transferability to other countries. To understand the overlap and differences between countries, similar research should be conducted in other contexts. Second, given the design of the study, we could not differentiate between patients and caregivers since they participated together in the FGDs. More patients than caregivers participated in the study. For a more in-depth understanding of the challenges and needs faced by caregivers, in future research separate FGDs should be conducted. Third, due to the fixed outline of the practical guideline used to conduct the FGDs, only the healthcare needs for diagnosis, treatment and recovery of BD are studied. Despite the fact that these themes might cover a broad range of health care, it could have resulted in overlooking certain needs in related areas of well-being. Therefore, future research should focus on needs outside of these themes in order to provide a complete set of healthcare needs.

Patients and their caregivers face many challenges in living with BD. Our study contributes to the literature on care and research needs from a patient perspective. Needs specific for BD are preventing late or incorrect diagnosis, support in search for individualized treatment, and supporting clinical, functional, social and personal recovery. Generic healthcare needs concern health professionals, communication and the healthcare system. This explication of both disorder-specific and generic needs indicates that clinical practice guidelines should address and integrate both in order to be responsive to the needs of patients and their caregivers.

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Authors’ contributions

EFM designed the study, contributed to the data collection, managed the analysis and wrote the first draft of the manuscript. BJR designed the study and contributed to the data collection, data analysis, and writing of the manuscript. JFGB contributed to the study design and critical revision of the manuscript. EJR contributed to the study conception and critical revision of the manuscript. RWK contributed to the study design, acquisition of data, and critical revision of the manuscript. All authors contributed to the final manuscript. All authors read and approved the final manuscript.

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Maassen, E.F., Regeer, B.J., Regeer, E.J. et al. The challenges of living with bipolar disorder: a qualitative study of the implications for health care and research. Int J Bipolar Disord 6 , 23 (2018). https://doi.org/10.1186/s40345-018-0131-y

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Bipolar disorder is a mood disorder that includes at least one manic episode – characterized by elevated or agitated mood and often reduced need for sleep – accompanied by episodes of major depression.

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• 1 Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada. Electronic address: [email protected].
• 2 Institute for Mental and Physical Health and Clinical Translation Strategic Research Centre, School of Medicine, Deakin University, Melbourne, VIC, Australia; Mental Health Drug and Alcohol Services, Barwon Health, Geelong, VIC, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, VIC, Australia; Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health, Melbourne, VIC, Australia; Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia.
• 3 Department of Psychiatry, Adult Division, Kingston General Hospital, Kingston, ON, Canada; Department of Psychiatry, Queen's University School of Medicine, Queen's University, Kingston, ON, Canada; Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
• 4 Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
• 5 Department of Psychiatry, Faculty of Medicine, University of Antioquia, Medellín, Colombia; Mood Disorders Program, Hospital Universitario San Vicente Fundación, Medellín, Colombia.
• 6 Copenhagen Affective Disorders Research Centre, Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen, Denmark; Department of Psychiatry, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
• 7 Discipline of Psychiatry, Northern Clinical School, University of Sydney, Sydney, NSW, Australia; Department of Academic Psychiatry, Northern Sydney Local Health District, Sydney, Australia.
• 8 Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
• 9 Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Dauten Family Center for Bipolar Treatment Innovation, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
• 10 Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.
• 11 Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
• 12 Department of Psychiatry, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Psychiatric Research Unit, Psychiatric Centre North Zealand, Hillerød, Denmark.
• 13 Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London and South London and Maudsley National Health Service Foundation Trust, Bethlem Royal Hospital, London, UK.
• 14 Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
• PMID: 33278937
• DOI: 10.1016/S0140-6736(20)31544-0

Bipolar disorders are a complex group of severe and chronic disorders that includes bipolar I disorder, defined by the presence of a syndromal, manic episode, and bipolar II disorder, defined by the presence of a syndromal, hypomanic episode and a major depressive episode. Bipolar disorders substantially reduce psychosocial functioning and are associated with a loss of approximately 10-20 potential years of life. The mortality gap between populations with bipolar disorders and the general population is principally a result of excess deaths from cardiovascular disease and suicide. Bipolar disorder has a high heritability (approximately 70%). Bipolar disorders share genetic risk alleles with other mental and medical disorders. Bipolar I has a closer genetic association with schizophrenia relative to bipolar II, which has a closer genetic association with major depressive disorder. Although the pathogenesis of bipolar disorders is unknown, implicated processes include disturbances in neuronal-glial plasticity, monoaminergic signalling, inflammatory homoeostasis, cellular metabolic pathways, and mitochondrial function. The high prevalence of childhood maltreatment in people with bipolar disorders and the association between childhood maltreatment and a more complex presentation of bipolar disorder (eg, one including suicidality) highlight the role of adverse environmental exposures on the presentation of bipolar disorders. Although mania defines bipolar I disorder, depressive episodes and symptoms dominate the longitudinal course of, and disproportionately account for morbidity and mortality in, bipolar disorders. Lithium is the gold standard mood-stabilising agent for the treatment of people with bipolar disorders, and has antimanic, antidepressant, and anti-suicide effects. Although antipsychotics are effective in treating mania, few antipsychotics have proven to be effective in bipolar depression. Divalproex and carbamazepine are effective in the treatment of acute mania and lamotrigine is effective at treating and preventing bipolar depression. Antidepressants are widely prescribed for bipolar disorders despite a paucity of compelling evidence for their short-term or long-term efficacy. Moreover, antidepressant prescription in bipolar disorder is associated, in many cases, with mood destabilisation, especially during maintenance treatment. Unfortunately, effective pharmacological treatments for bipolar disorders are not universally available, particularly in low-income and middle-income countries. Targeting medical and psychiatric comorbidity, integrating adjunctive psychosocial treatments, and involving caregivers have been shown to improve health outcomes for people with bipolar disorders. The aim of this Seminar, which is intended mainly for primary care physicians, is to provide an overview of diagnostic, pathogenetic, and treatment considerations in bipolar disorders. Towards the foregoing aim, we review and synthesise evidence on the epidemiology, mechanisms, screening, and treatment of bipolar disorders.

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Bipolar Disorder

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Do you have periods of time when you feel unusually “up” (happy and outgoing, or irritable), but other periods when you feel “down” (unusually sad or anxious)? During the “up” periods, do you have increased energy or activity and feel a decreased need for sleep, while during the “down” times you have low energy, hopelessness, and sometimes suicidal thoughts? Do these symptoms of fluctuating mood and energy levels cause you distress or affect your daily functioning? Some people with these symptoms have a lifelong but treatable mental illness called bipolar disorder.

What is bipolar disorder?

Bipolar disorder is a mental illness that can be chronic (persistent or constantly reoccurring) or episodic (occurring occasionally and at irregular intervals). People sometimes refer to bipolar disorder with the older terms “manic-depressive disorder” or “manic depression.”

Everyone experiences normal ups and downs, but with bipolar disorder, the range of mood changes can be extreme. People with the disorder have manic episodes, or unusually elevated moods in which the individual might feel very happy, irritable, or “up,” with a marked increase in activity level. They might also have depressive episodes, in which they feel sad, indifferent, or hopeless, combined with a very low activity level. Some people have hypomanic episodes, which are like manic episodes, but not severe enough to cause marked impairment in social or occupational functioning or require hospitalization.

Most of the time, bipolar disorder symptoms start during late adolescence or early adulthood. Occasionally, children may experience bipolar disorder symptoms. Although symptoms may come and go, bipolar disorder usually requires lifelong treatment and does not go away on its own. Bipolar disorder can be an important factor in suicide, job loss, ability to function, and family discord. However, proper treatment can lead to better functioning and improved quality of life.

What are the symptoms of bipolar disorder?

Symptoms of bipolar disorder can vary. An individual with the disorder may have manic episodes, depressive episodes, or “mixed” episodes. A mixed episode has both manic and depressive symptoms. These mood episodes cause symptoms that last a week or two, or sometimes longer. During an episode, the symptoms last every day for most of the day. Feelings are intense and happen with changes in behavior, energy levels, or activity levels that are noticeable to others. In between episodes, mood usually returns to a healthy baseline. But in many cases, without adequate treatment, episodes occur more frequently as time goes on.

Some people with bipolar disorder may have milder symptoms than others. For example, hypomanic episodes may make an individual feel very good and productive; they may not feel like anything is wrong. However, family and friends may notice the mood swings and changes in activity levels as unusual behavior, and depressive episodes may follow hypomanic episodes.

Types of Bipolar Disorder

People are diagnosed with three basic types of bipolar disorder that involve clear changes in mood, energy, and activity levels. These moods range from manic episodes to depressive episodes.

• Bipolar I disorder is defined by manic episodes that last at least 7 days (most of the day, nearly every day) or when manic symptoms are so severe that hospital care is needed. Usually, separate depressive episodes occur as well, typically lasting at least 2 weeks. Episodes of mood disturbance with mixed features are also possible. The experience of four or more episodes of mania or depression within a year is termed “rapid cycling.”
• Bipolar II disorder is defined by a pattern of depressive and hypomanic episodes, but the episodes are less severe than the manic episodes in bipolar I disorder.
• Cyclothymic disorder (also called cyclothymia) is defined by recurrent hypomanic and depressive symptoms that are not intense enough or do not last long enough to qualify as hypomanic or depressive episodes.

“Other specified and unspecified bipolar and related disorders” is a diagnosis that refers to bipolar disorder symptoms that do not match the three major types of bipolar disorder outlined above.

What causes bipolar disorder?

The exact cause of bipolar disorder is unknown. However, research suggests that a combination of factors may contribute to the illness.

Bipolar disorder often runs in families, and research suggests this is mostly explained by heredity—people with certain genes are more likely to develop bipolar disorder than others. Many genes are involved, and no one gene can cause the disorder.

But genes are not the only factor. Studies of identical twins have shown that one twin can develop bipolar disorder while the other does not. Though people with a parent or sibling with bipolar disorder are more likely to develop it, most people with a family history of bipolar disorder will not develop it.

Brain Structure and Function

Research shows that the brain structure and function of people with bipolar disorder may differ from those of people who do not have bipolar disorder or other mental disorders. Learning about the nature of these brain changes helps researchers better understand bipolar disorder and, in the future, may help predict which types of treatment will work best for a person with bipolar disorder.

How is bipolar disorder diagnosed?

To diagnose bipolar disorder, a health care provider may complete a physical exam, order medical testing to rule out other illnesses, and refer the person for an evaluation by a mental health professional. Bipolar disorder is diagnosed based on the severity, length, and frequency of an individual’s symptoms and experiences over their lifetime.

Some people have bipolar disorder for years before it’s diagnosed for several reasons. People with bipolar II disorder may seek help only for depressive episodes and hypomanic episodes may go unnoticed. Misdiagnosis may happen because some bipolar disorder symptoms are like those of other illnesses. For example, people with bipolar disorder who also have psychotic symptoms can be misdiagnosed with schizophrenia. Some health conditions, such as thyroid disease, can cause symptoms like those of bipolar disorder. The effects of recreational and illicit drugs can sometimes mimic or worsen mood symptoms.

Conditions That Can Co-Occur With Bipolar Disorder

Many people with bipolar disorder also have other mental disorders or conditions such as anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), misuse of drugs or alcohol, or eating disorders. Sometimes people who have severe manic or depressive episodes also have symptoms of psychosis, such as hallucinations or delusions. The psychotic symptoms tend to match the person’s extreme mood. For example, someone having psychotic symptoms during a depressive episode may falsely believe they are financially ruined, while someone having psychotic symptoms during a manic episode may falsely believe they are famous or have special powers.

Looking at symptoms over the course of the illness and the person’s family history can help determine whether a person has bipolar disorder along with another disorder.

How is bipolar disorder treated?

Treatment helps many people, even those with the most severe forms of bipolar disorder. Mental health professionals treat bipolar disorder with medications, psychotherapy, or a combination of treatments.

Medications

Certain medications can help control the symptoms of bipolar disorder. Some people may need to try several different medications before finding the ones that work best. The most common types of medications that doctors prescribe include mood stabilizers and atypical antipsychotics. Mood stabilizers such as lithium or valproate can help prevent mood episodes or reduce their severity. Lithium also can decrease the risk of suicide. While bipolar depression is often treated with antidepressant medication, a mood stabilizer must be taken as well, as an antidepressant alone can trigger a manic episode or rapid cycling in a person with bipolar disorder. Medications that target sleep or anxiety are sometimes added to mood stabilizers as part of a treatment plan.

Talk with your health care provider to understand the risks and benefits of each medication. Report any concerns about side effects to your health care provider right away. Avoid stopping medication without talking to your health care provider first. Read the latest medication warnings, patient medication guides, and information on newly approved medications on the Food and Drug Administration (FDA) website  .

Psychotherapy

Psychotherapy (sometimes called “talk therapy”) is a term for various treatment techniques that aim to help a person identify and change troubling emotions, thoughts, and behaviors. Psychotherapy can offer support, education, skills, and strategies to people with bipolar disorder and their families.

Some types of psychotherapy can be effective treatments for bipolar disorder when used with medications, including interpersonal and social rhythm therapy, which aims to understand and work with an individual’s biological and social rhythms. Cognitive behavioral therapy (CBT) is an important treatment for depression, and CBT adapted for the treatment of insomnia can be especially helpful as a component of the treatment of bipolar depression. Learn more on NIMH’s psychotherapies webpage .

Other Treatments

Some people may find other treatments helpful in managing their bipolar disorder symptoms.

• Electroconvulsive therapy (ECT) is a brain stimulation procedure that can help relieve severe symptoms of bipolar disorder. ECT is usually only considered if an individual’s illness has not improved after other treatments such as medication or psychotherapy, or in cases that require rapid response, such as with suicide risk or catatonia (a state of unresponsiveness).
• Transcranial Magnetic Stimulation (TMS) is a type of brain stimulation that uses magnetic waves, rather than the electrical stimulus of ECT, to relieve depression over a series of treatment sessions. Although not as powerful as ECT, TMS does not require general anesthesia and presents little risk of memory or adverse cognitive effects.
• Light Therapy is the best evidence-based treatment for seasonal affective disorder (SAD), and many people with bipolar disorder experience seasonal worsening of depression in the winter, in some cases to the point of SAD. Light therapy could also be considered for lesser forms of seasonal worsening of bipolar depression.

Complementary Health Approaches

Unlike specific psychotherapy and medication treatments that are scientifically proven to improve bipolar disorder symptoms, complementary health approaches for bipolar disorder, such as natural products, are not based on current knowledge or evidence. For more information, visit the National Center for Complementary and Integrative Health website  .

Coping With Bipolar Disorder

Living with bipolar disorder can be challenging, but there are ways to help yourself, as well as your friends and loved ones.

• Get treatment and stick with it. Treatment is the best way to start feeling better.
• Keep medical and therapy appointments and talk with your health care provider about treatment options.
• Take medication as directed.
• Structure activities. Keep a routine for eating, sleeping, and exercising.
• Try regular, vigorous exercise like jogging, swimming, or bicycling, which can help with depression and anxiety, promote better sleep, and is healthy for your heart and brain.
• Keep a life chart to help recognize your mood swings.
• Ask for help when trying to stick with your treatment.
• Be patient. Improvement takes time. Social support helps.

Remember, bipolar disorder is a lifelong illness, but long-term, ongoing treatment can help manage symptoms and enable you to live a healthy life.

Are there clinical trials studying bipolar disorder?

NIMH supports a wide range of research, including clinical trials that look at new ways to prevent, detect, or treat diseases and conditions—including bipolar disorder. Although individuals may benefit from being part of a clinical trial, participants should be aware that the primary purpose of a clinical trial is to gain new scientific knowledge to help others in the future. Researchers at NIMH and around the country conduct clinical trials with patients and healthy volunteers. Talk to a health care provider about clinical trials, their benefits and risks, and whether one is right for you. For more information, visit the NIMH clinical trials webpage .

Finding Help

Behavioral health treatment services locator.

This online resource, provided by the Substance Abuse and Mental Health Services Administration (SAMHSA), can help you locate mental health treatment facilities and programs. Find a facility in your state by searching SAMHSA’s online Behavioral Health Treatment Services Locator  . For additional resources, visit NIMH's Help for Mental Illnesses webpage .

If you or someone you know is in immediate distress or is thinking about hurting themselves, call or text the 988 Suicide & Crisis Lifeline   at 988 or chat at 988lifeline.org. You can also contact the Crisis Text Line    ( text HELLO to 741741 ). For medical emergencies, call 911.

Talking to a Health Care Provider About Your Mental Health

Communicating well with a health care provider can improve your care and help you both make good choices about your health. Find tips to help prepare for and get the most out of your visit . For additional resources, including questions to ask a provider, visit the Agency for Healthcare Research and Quality website  .

The information in this publication is in the public domain and may be reused or copied without permission. However, you may not reuse or copy images. Please cite the National Institute of Mental Health as the source. Read our copyright policy to learn more about our guidelines for reusing NIMH content.

For More Information

MedlinePlus   (National Library of Medicine) ( en español  )

ClinicalTrials.gov  ( en español  )

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health NIH Publication No. 22-MH-8088 Revised 2022

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Early Intervention in Bipolar Disorder

• Eduard Vieta , M.D., Ph.D. ,
• Estela Salagre , M.D. ,
• Iria Grande , M.D., Ph.D. ,
• André F. Carvalho , M.D., Ph.D. ,
• Brisa S. Fernandes , M.D., Ph.D. ,
• Michael Berk , M.D., Ph.D. ,
• Boris Birmaher , M.D. ,
• Mauricio Tohen , M.D., Dr.P.H. ,
• Trisha Suppes , M.D., Ph.D.

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Bipolar disorder is a recurrent disorder that affects more than 1% of the world population and usually has its onset during youth. Its chronic course is associated with high rates of morbidity and mortality, making bipolar disorder one of the main causes of disability among young and working-age people. The implementation of early intervention strategies may help to change the outcome of the illness and avert potentially irreversible harm to patients with bipolar disorder, as early phases may be more responsive to treatment and may need less aggressive therapies. Early intervention in bipolar disorder is gaining momentum. Current evidence emerging from longitudinal studies indicates that parental early-onset bipolar disorder is the most consistent risk factor for bipolar disorder. Longitudinal studies also indicate that a full-blown manic episode is often preceded by a variety of prodromal symptoms, particularly subsyndromal manic symptoms, therefore supporting the existence of an at-risk state in bipolar disorder that could be targeted through early intervention. There are also identifiable risk factors that influence the course of bipolar disorder, some of them potentially modifiable. Valid biomarkers or diagnosis tools to help clinicians identify individuals at high risk of conversion to bipolar disorder are still lacking, although there are some promising early results. Pending more solid evidence on the best treatment strategy in early phases of bipolar disorder, physicians should carefully weigh the risks and benefits of each intervention. Further studies will provide the evidence needed to finish shaping the concept of early intervention.

AJP AT 175 Remembering Our Past As We Envision Our Future

April 1925: Interpretations of Manic-Depressive Phases

Earl Bond and G.E. Partridge reviewed a number of patients with manic-depressive illness in search of a unifying endo-psychic conflict. They concluded that understanding either phase of illness was “elusive” and “tantalizing beyond reach.” (Am J Psychiatry 1925: 81: 643–662 )

William J. Mayo (1861–1939) stated that “the aim of medicine is to prevent disease and prolong life; the ideal of medicine is to eliminate the need of a physician” ( 1 ). Hence, physicians have been trying for almost a century to find early interventions that would prevent the onset of diseases, or at least change their course. Big steps have been made in several fields of medicine, such as cardiology and oncology. When it comes to psychiatry, although there is ground for optimism, there is still a long way to go ( 2 ).

Difficulties concerning primary prevention and intervention in psychiatry arise mainly from the absence of a clear etiology. Consequently, psychiatry has focused more on tertiary prevention, that is, in the use of therapies aiming to minimize the consequences of clinically established disease rather than to prevent its occurrence ( 3 ). However, considering the high prevalence of mental illnesses, their significant contribution to global disease burden among young people, and their considerable impact on public health, the implementation of early interventions in psychiatry should be considered a major priority.

To achieve this goal, and since early intervention focuses on known risk factors and early signs of the illness, there is a growing interest in understanding the early course of psychiatric conditions. For bipolar disorder, until recently most information regarding early manifestations came from retrospective and cross-sectional studies, which have a high risk of recall bias and do not allow assessment of temporality. Still, current evidence suggests that bipolar disorder has a progressive nature ( 4 – 6 ), therefore supporting the existence of milder phases of the condition prior to the classic presentation of the illness. This progressive nature makes bipolar disorder an ideal candidate for early intervention strategies, especially considering that 50%−70% of people with bipolar disorder usually start to manifest mood symptoms before age 21 ( 7 – 12 ). This highlights the need for early interventions to prevent or at least delay the onset of the full syndromal illness during childhood, which is crucial to avoid impacts on normal developmental tasks and psychosocial or neurobiological deterioration ( 13 ) and to prevent future complications, such as the development of psychiatric comorbidities, impaired functioning, or premature death by suicide ( 14 ).

Noting that The American Journal of Psychiatry is commemorating its 175th year of publication, we see early intervention in bipolar disorder as one of the cutting-edge topics in psychiatry. Although there are limited data based on this concept arising from the area of psychoses, we believe that ongoing and forthcoming research in this field is going to have a long-lasting impact on the field as mental health care increasingly turns its focus to prevention ( 15 ). In fact, more than 20 years ago, The American Journal of Psychiatry published one of the first articles discussing the role of prodromes and precursors in major depression ( 16 ); 10 years later the journal published the first paper proposing early intervention to prevent substance abuse in first-episode bipolar disorder ( 17 ) and a landmark trial indicating that first-episode psychosis could be treated with lower dosages of antipsychotics than are used in multiple-episode psychoses ( 18 ). Hence, in this review we will focus on the results obtained in longitudinal studies assessing variables considered as predictors of conversion to bipolar disorder or of illness course, conducted in offspring at high familial risk for bipolar disorder, community cohorts, and pediatric populations with diagnoses of bipolar disorder. Finally, the available psychological and pharmacological intervention data in the early stages of bipolar disorder will be covered, as well as the point of view of the authors on future directions of the research on the issue.

Identifying Risk Factors and Prodromal Symptoms as Predictors of Bipolar Disorder Onset and Course

The identification of risk factors or prodromal symptoms defining an at-risk stage has important treatment implications, as early stages are anticipated to be likely to be more responsive to treatment and therefore may need less complex interventions ( 19 , 20 ). Moreover, psychiatric treatments likely have a more beneficial impact when applied at an earlier stage of the disease ( 21 ). A key issue is that the at-risk state in most disorders, including bipolar disorder, is pleomorphic and nonspecific and has the potential to evolve into diverse formed phenotypes or no disorder.

Environmental Risk Factors

Although bipolar disorder has a high genetic loading ( 22 ), it is considered a multifactorial disease that is influenced by environmental factors ( 23 ), some of which might be used as targets of early intervention strategies since they can be potentially modified ( 24 ). Life events have been proposed as triggers of future bipolar disorder ( 25 ), but results are controversial. While some studies ( 26 , 27 ) found a positive association between mean life events and risk of mood disorder, Wals and colleagues ( 28 ) found that stressful life events were not related to the onset of mood episodes after adjustment for prior anxious or depressive symptoms. Considering the impact of life events in illness trajectory, lifetime sexual abuse seems to be related to a worse course of bipolar disorder ( 29 – 32 ). Recent public outrage at institutional childhood sexual abuse and campaigns to address this in many countries are an exemplar of a policy approach that may have an impact on a critical risk ( 33 ). Antidepressant use in depressed youths also may be a risk factor ( 34 ), as antidepressants might induce (hypo)manic symptoms ( 35 ).

Substance misuse is a prevalent condition in mood disorders that worsens illness prognosis ( 36 ). Moreover, its presence has been related to an increased risk of bipolar disorder at follow-up in patients seeking help for depression, anxiety, or substance use disorder ( 37 ). Although some studies have found a lower prevalence of substance use disorder in patients with a first mania episode compared with multiple-episode patients ( 38 – 40 ), this finding suggests that primary prevention of a secondary condition, in this case substance abuse in patients with bipolar disorder, needs to be considered ( 40 ). Substance use disorder can be predicted by lifetime alcohol experimentation, lifetime oppositional defiant disorder and panic disorder, family history of substance use disorder, or low family cohesiveness ( 39 ); these risk factors show a compounding effect. Presence of mixed features also appears to increase the risk of developing substance use disorder ( 17 ). Smoking may be associated with an increased risk of psychiatric disorders from depression to schizophrenia ( 41 ). Of concern, even maternal smoking may increase risk in offspring ( 42 , 43 ).

Biological Risk Factors

Family history of bipolar disorder is one of the more solid risk factors for bipolar disorder ( 44 ) and is a primary threshold from universal to indicated prevention strategies. Longitudinal studies conducted in bipolar offspring found that age at onset and mood disorder subtype of the probands influence the heritability and course of bipolar disorder ( 38 , 45 , 46 ). For instance, these studies showed that offspring of early-onset bipolar disorder probands were at an increased risk for any bipolar disorder ( 45 , 46 ) and that lithium nonresponsiveness in parents was related to a poorer premorbid functioning, a more chronic course, and a higher prevalence of psychotic disorders in their offspring ( 38 ).

Neurodevelopmental factors are being studied as potential early markers of specific mental illness. A prebirth cohort study found that child developmental delay assessed with the Denver Developmental Screening Test, which measures fine and gross motor skills, language, and personal–social development, was a predictor of later mania but not of depression or psychosis ( 47 ). In the same study, premorbid cognitive ability predicted only psychosis ( 47 ). However, there are data indicating that children with the highest academic attainment may be at greatest risk of bipolar disorder, while those with the weakest grades were at moderately increased risk ( 48 ) ( Table 1 ).

a Proximal symptoms are those that appear closer to conversion to full symptomatic episode.

TABLE 1. Main Preliminary Findings on Bipolar and Psychosis Prodromal Stage

Prodromal Symptoms

Results from longitudinal studies indicate that bipolar offspring are at a higher risk of developing bipolar disorder than the general population ( 46 , 49 – 51 ), but they are equally at risk of developing other psychopathology, such as major depressive disorder, anxiety disorders, or psychotic disorders ( 28 , 38 , 44 , 45 , 52 – 54 ) ( Table 2 ). Similarly, adolescents from community cohort studies who developed bipolar disorder also exhibited significantly high rates of comorbid anxiety disorders and disruptive behavior disorders ( 55 ).

a BD=bipolar disorder; BDNOS=bipolar disorder not otherwise specified; BO=bipolar offspring; BSD=bipolar spectrum disorder; CADS=Childhood Affective Dysregulation Scale; CALS=Child Affective Lability Scale; CARE=Children and Adolescent Research Evaluation; CBCL=Child Behavior Checklist; CECA.Q=Childhood Experiences of Care and Abuse Questionnaire; CHI=Children’s Hostility Inventory; CO=control offspring; COBY=Course and Outcome of Bipolar Youth; DBD=Disruptive Behavioral Disorders Rating Scale; DBRS=Devereux School Behavior Rating Scales; EAS=Early Adolescent Temperament Scale; FH-RDC=Family History–Research Diagnostic Criteria; GAS=Global Assessment Scale; HARS=Hamilton Anxiety Rating Scale; K-SADS-PL=Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version; MCDQ=Mood Clinic Data Questionnaire; MDD=major depressive disorder; MDE=major depressive episode; MFQ=Mood and Feelings Questionnaire; PDS=Petersen Pubertal Developmental Scale; SADS-L=Schedule for Affective Disorders–Present and Lifetime; SCARED=Screen for Child Anxiety Related Disorders; SCAS=Spence Children’s Anxiety Rating Scale; SCID=Structured Clinical Interview for DSM-IV Axis I Disorders; SES=socioeconomic status; SSHS=School Sleep Habits Survey; SUD=substance use disorder; UMD=unipolar mood disorder.

TABLE 2. Main Findings of Longitudinal Studies Assessing Prodromal Symptoms in Offspring of Patients With Bipolar Disorder a

As there is strong evidence that the index (hypo)manic episode in both bipolar offspring and community cohorts is frequently preceded by other affective or nonaffective symptoms ( 38 , 49 , 52 , 55 ), longitudinal studies have tried to disentangle whether any of these conditions can be considered as early symptoms of bipolar disorder and help to predict future bipolar disorder onset. For instance, in the Dutch bipolar offspring cohort, 88% of the offspring who developed a bipolar spectrum disorder initially presented with a depressive episode, with an average time to bipolar conversion of 5.1 years ( 52 ) ( Table 2 ). Subjective sleep problems also may be related to the development of bipolar disorder ( 56 ) ( Table 2 ), but more evidence is needed before any firm conclusions can be drawn. Childhood anxiety disorder has been described as a prodromal symptom of major mood disorders, but it seems more related to unipolar depression than to bipolar disorder ( 44 , 54 ). Anxiety disorders, in turn, seem to be predicted by the temperamental traits of shyness and emotionality ( 54 ) ( Table 2 ). In contrast, subthreshold (hypo)manic symptoms have emerged as a key predictor of the development of (hypo)mania in community ( 37 , 57 , 58 ), high-risk ( 59 ), and bipolar offspring ( 45 , 49 , 50 , 60 , 61 ) cohorts ( Table 2 ), even after adjusting for risk factors associated with psychopathology, such as parental psychiatric morbidity ( 49 , 58 ). Moreover, greater intensity of hypomanic symptoms or earlier age at onset is associated with an increased risk of progressing to bipolar I or II disorder among children and adolescents initially meeting operationalized criteria for bipolar disorder not otherwise specified ( 62 , 63 ).

Some studies have focused on the predictive value of several dimensional factors and not only in categorical predictors ( 45 , 50 , 61 ). Data emerging from the Pittsburg Bipolar Offspring youth cohort ( 45 ) show that offspring of parents with bipolar disorder with significant symptoms of anxiety/depression, affective lability, and subsyndromal manic symptoms were at increased risk of developing bipolar spectrum disorders. While affective lability and anxiety/depression were elevated throughout follow-up in those who later developed bipolar disorder, manic symptoms increased up to the point of conversion. Offspring with all the above risk factors, and particularly those with parents with early-onset bipolar disorder, had a 49% risk of developing bipolar disorder. Similarly, in an Amish cohort of bipolar offspring ( 50 ), converters to bipolar disorder showed a higher prevalence of sensitivity, hyperalertness, anxiety, and somatic complaints during the preschool period and more mood and energy fluctuations, tearfulness, sleep disturbances, and fearfulness during school years. However, a meta-analysis reporting data on prodromal symptoms in pediatric and adult samples with bipolar disorder pointed out that even if there are some highly reported prodromal symptoms, the prodromal stage tends to differ between individuals ( 64 ).

As bipolar disorder usually first presents with a depressive episode ( 65 ), longitudinal studies have assessed the presence of prodromal symptoms of conversion from unipolar depression to bipolar disorder ( Figure 1 ). The main replicated finding is the relationship between diagnosis of psychotic depression and switching to (hypo)mania ( 66 – 69 ). A recent meta-analysis identified a family history of bipolar disorder, an earlier age at depression onset, and the presence of psychotic symptoms as most robustly predicting conversion from depression to bipolar disorder ( 70 ). When focusing only on patients diagnosed with psychotic depression, it has been found that conversion to bipolar disorder is mainly related to early age at onset ( 67 , 68 ), functional impairment ( 67 ), mixed features ( 69 , 71 ), and previous hypomanic symptoms ( 72 ).

FIGURE 1. Main Risk Factors of Conversion From Major Depressive Disorder to Bipolar Disorder

In summary, parental bipolar disorder, especially early-onset (e.g., <21 years old) parental bipolar disorder, is the most important single risk factor for developing bipolar disorder. In addition, if the youth has subsyndromal manic symptoms, which is the most consistent prodromal factor, and ongoing mood lability or irritability, anxiety, and depression, there is increased likelihood that this youth will develop bipolar disorder ( Figure 2 ). However, the onset and severity of these symptoms are heterogeneous.

FIGURE 2. Putative Risk Factors and Prodromal Symptoms of Bipolar Disorder a

a Several environmental risk factors for bipolar disorder have been proposed, such as stressful life events including sexual abuse, antidepressant use, or substance misuse like cocaine or alcohol misuse. Biological risk factors include family history of bipolar disorder or neurodevelopmental factors such as child developmental delay. Family history of bipolar disorder is one of the strongest risk factors for bipolar disorder, while sexual abuse has been consistently related to a worse illness course. Prodromal symptoms of bipolar disorder can be heterogeneous. Dimensional factors predictive of bipolar disorder include anxiety and depressive symptoms, mood lability, and psychosis or subjective sleep problems, but the most robust predictive factor is the presence of subthreshold (hypo)manic symptoms. Depressive episodes with an early onset and/or psychotic symptoms also seem to predict conversion to bipolar disorder. The interaction between risk factors and prodromal symptoms may lead to bipolar disorder, but the exact mechanisms remain unknown.

Helping Prediction of Bipolar Disorder Onset Through Screening Tools

The above predictors are based on studies that focus on groups as a whole, but they do not inform about the individual risk of developing bipolar disorder. Moreover, the prodromal symptoms are heterogeneous, requiring the assessment of each individual risk ( 64 ). Building on accumulated knowledge about early bipolar disorder symptoms, researchers have striven to design reliable screening tests and screening criteria that could help to predict conversion to bipolar disorder. However, reliable clinical scales to assess prodromal symptoms are still lacking. To date, the predictive value of four clinical scales has been tested in longitudinal studies: the General Behavior Inventory, a self-report measure useful to discriminate between mood and behavioral disorders; the Child Behavior Checklist–Pediatric Bipolar Disorder, a profile consisting of severe aggression, inattention, and mood instability; the Hypomanic Personality Scale; and the Hypomania Checklist–32 Revised scale ( 73 – 78 ). Higher scores on the depression scale of the General Behavior Inventory ( 74 ), higher scores on the Hypomanic Personality Scale ( 75 , 76 ), and positive subthreshold hypomanic symptoms identified by the Hypomania Checklist–32 ( 77 ) were related to an increased risk of future mood disorder among bipolar offspring. In turn, the Child Behavior Checklist–Bipolar seems useful for predicting comorbid and impairing psychopathology rather than any one specific DSM-IV diagnosis ( 73 , 78 ). It is worth mentioning that most participants without the Child Behavior Checklist–Bipolar phenotype did not manifest bipolar disorder, attention deficit hyperactivity disorder (ADHD), cluster B personality disorder, or multiple psychiatric comorbid conditions at young-adult follow-up assessment (negative predictive values of 86% to 95%) ( 78 ). An abbreviated version of the General Behavior Inventory, the Seven Up Seven Down, has also been proposed, but it failed to predict new onset of bipolar disorder ( 79 ).

Nevertheless, the combination of self-reports and clinical semistructured interviews might be a more accurate approach for clinical decision making than the use of a single scale. Moreover, the assessment of subsyndromal manic symptoms requires trained professionals, as subsyndromal symptoms are difficult to ascertain when assessing children or if comorbid disorders are present. When considering self-report measures, much discussion of the ideal informant has taken place (i.e., parents, offspring, or both), but findings consistently show the greatest validity for parent report, regardless of whether the parent has a diagnosis of mood disorder—one reason being that the degree of awareness of one’s own symptoms can influence youth self-report ( 80 ).

Besides these proposed screening tests, a set of ultra-high-risk criteria for bipolar disorder exists: the bipolar at-risk criteria developed by Bechdolf et al. ( 81 ). They comprise general criteria, such as being in the peak age range for the onset of the disorder, as well as subthreshold clinical and behavioral data and genetic risk. In a sample of help-seeking youths, individuals meeting the bipolar at-risk criteria transitioned significantly more to first-episode (hypo)mania than the group screening negative for the criteria ( 81 ). However, important potentially differentiating features such as Mitchell’s bipolar signature, including features such as psychomotor-retarded melancholia and atypical depression, are not explored in many risk indices ( 82 ). The Early Phase Inventory for Bipolar Disorders criteria ( 83 ) and the Bipolar Prodrome Symptom Scale, based on the At Risk for Mania Syndrome criteria ( 84 ), are promising screening tools, but they still need to be prospectively tested.

Similar to the existing risk calculators in medicine, the Pittsburgh Bipolar Offspring Study developed a risk calculator to predict the 5-year risk of developing bipolar disorder in offspring of parents with bipolar disorder ( 85 ). Including dimensional measures of mania, depression, anxiety, and mood lability; psychosocial functioning; and parental age of mood disorder, the model predicted onset of bipolar disorder with an area under the curve of 0.76. If replicated, in the future the risk calculator will be instrumental in the development of preventive treatments as well as for biological studies.

Helping Prediction of Bipolar Disorder Onset Through Biomarkers

Biological and behavioral biomarkers hold promise as objective and useful tools for identifying patients at higher risk of developing bipolar disorder ( 86 ). Although biomarkers and staging have not yet had an impact on the official classificatory systems for mental disorders, this is a stated goal of the DSM series ( 87 ).

Neuroimaging Biomarkers

In a sample of 98 young unaffected individuals at high familial risk of bipolar disorder and 58 healthy control subjects, the presence of maintained increased insula activation during a task involving executive and language processing could differentiate individuals at high risk of bipolar disorder who later develop depression from healthy control subjects and from those at high familial risk who did not develop a psychiatric disorder ( 88 ). Mourão-Miranda et al. ( 89 ) showed that the combination of machine learning techniques and functional MRI data collected during an emotional face gender-labeling task could not only discriminate control adolescents from bipolar offspring but also could be helpful in predicting which at-risk adolescents would eventually develop psychiatric disorders. Regarding differences between offspring of parents with schizophrenia and offspring of parents with bipolar disorder, Sugranyes et al. ( 90 ) found through repeated neuroimaging measures that schizophrenia offspring displayed cross-sectional reductions in surface area on the occipital lobe compared with bipolar offspring and community control subjects.

Peripheral Biomarkers

Antithyroid peroxidase antibody positivity ( 91 ), salivary cortisol levels ( 92 ), and cerebral metabolite concentrations measured by proton magnetic resonance spectroscopy ( 93 ) could not differentiate high-risk offspring from control offspring or predict conversion to bipolar disorder. However, preliminary findings from the Dutch Bipolar Offspring Study indicate that the monocytes of a large proportion of bipolar patients and their offspring, particularly those who later develop a mood disorder, aberrantly express messenger RNAs of inflammatory, trafficking, survival, and mitogen-activated protein kinase pathway genes compared with healthy control subjects ( 94 ). This aberrant neuroimmune state in bipolar offspring was found to be independent of lifetime or future mood disorders; hence, it might reveal a vulnerability for mood disorders rather than being a direct predictor ( 95 , 96 ). In a prospective general-population U.K. birth cohort childhood study, higher levels of the systemic inflammatory marker IL-6 in childhood were associated with hypomanic symptoms in young adulthood, even after adjusting for sociodemographic variables, past psychological and behavioral problems, body mass index, and maternal postnatal depression ( 97 ).

Nevertheless, most of the identified alterations in peripheral blood in ultra-high-risk populations are shared between different psychiatric disorders, potentially predicting the onset of bipolar disorder, depression, or schizophrenia, but alone they are not able to reliably predict occurrence of bipolar disorder over another disorder. One study proposed a blood-based biomarker panel for diagnosing bipolar disorder, employing several different biomarkers. This panel, consisting mostly of immune-related biomarkers, was able to discriminate between recently diagnosed (less than 30 days) bipolar disorder and both recently diagnosed schizophrenia and healthy control subjects ( 60 ). This suggests that a single blood biomarker will likely not be useful for ascertaining diagnosis, but that a composite of several biomarkers, and probably other sources of information, will be required in order to achieve sufficient diagnostic properties for clinical utility.

Behavioral Biomarkers

A newly emerging biomarker in the form of ecological momentary assessment is arising from the ability to track behavioral data through mobile devices ( 98 , 99 ). Hence, big data, such as geolocation, activity, Internet use, calls, and payments, can be analyzed and provide algorithms that might be used through machine learning techniques ( 100 ) as sources for risk surveillance and hence early personalized interventions ( 101 ).

Exploring Early Treatment Strategies in Bipolar Disorder

The underlying tenet of early diagnosis is to implement early treatment in order to prevent or delay progression to more advanced stages of the disease associated with greater disability ( 102 ). However, there are critical ethical issues pertaining to preventive interventions in at-risk individuals. Potential benefits need to be balanced against risks of preonset interventions. Key considerations include the individual’s knowledge, autonomy, and right to choose, ideally in an environment of stigma-free treatment ( 103 ).

Effective psychotherapeutic interventions, usually better received by patients and with a more favorable benefit–risk profile, can be an attractive first step in early intervention, although their effectiveness at these early stages needs to be determined ( 83 ). Post hoc analysis of many psychosocial interventions for bipolar disorder suggested greater efficacy if used earlier in the illness course ( 104 ). Psychoeducation programs have proven effective in preventing relapse in patients with established bipolar disorder and may be more useful earlier in the disorder ( 105 , 106 ), but they have not been assessed in at-risk populations or pediatric bipolar disorder. Hence, group psychoeducation may be particularly indicated in patients with an established diagnosis of bipolar disorder but with a limited number of recurrences ( 107 ). Family-focused therapy, which combines psychoeducation sessions and training in communication and problem-solving skills, is the only psychological intervention tested in these populations. Results on this therapy are still controversial, although they suggest that it is related to longer affective stability and milder symptoms during follow-up ( 108 , 109 ) when assessed in youths at high familial risk for bipolar disorder and diagnosis of bipolar disorder not otherwise specified, major depressive disorder, or cyclothymic disorder, or in adolescents with bipolar I or II disorder. Other interventions, such as multifamily psychoeducational psychotherapy ( 110 ) or interpersonal and social rhythm therapy ( 111 ), have shown some preliminary but promising results in reducing conversion rates and symptom severity among high-risk adolescents with a positive family history of bipolar disorder. Psychotherapies are not free of side effects ( 112 ); at early stages, when the diagnosis is not established, emphasis on diagnoses should be avoided, and it is more useful to target identified symptoms and helpful strategies ( 113 ). A number of online psychosocial interventions that are increasingly available have tentative data regarding their effectiveness ( 114 , 115 ).

Choosing preventive pharmacological treatments in at-risk individuals is particularly complex. In the at-risk stage, we may be treating a population that might not convert to bipolar disorder, and the treatment of prodromal symptoms or comorbid conditions may involve medications with a potential risk of precipitating a manic episode, such as psychostimulants or notably antidepressants. Hence, even though some pharmacological treatments, such as lithium, are known to be more effective when started early in the course of the disease ( 116 ), the long- and short-term tolerability of each treatment and its potential to prevent bipolar disorder need to be carefully weighed against the individual risk of developing bipolar disorder. Some pilot studies have assessed the protective properties of valproate sodium and quetiapine against the onset of mania, with mixed results ( 117 – 119 ). Moreover, treatment with mood stabilizers or antipsychotics has known short- and long-term adverse effects ( 120 ), so their use as first-line treatment in at-risk youths might not be recommendable ( 121 ). For instance, valproate sodium has been associated with reproductive–endocrine abnormalities and should be used with caution in women of childbearing age ( 122 , 123 ). Another scenario is posed when it comes to youths with bipolar disorder not otherwise specified. These youths have as much psychosocial impairment, as many comorbid disorders, and as much risk for suicide and substance abuse as those with bipolar disorder I, and they are at high risk of converting to bipolar I or II disorder ( 62 , 124 ). Thus, until further research is available, we recommend treating them with the existing psychological and pharmacological treatments for youths with bipolar disorder, depending on factors such as the impact of the symptoms on the youth’s functioning and well-being and the individual risk of converting to bipolar I or II disorder.

Considering the feasibility of using nutritional supplements for primary prevention and the reported link between folate deficiency or omega-3 fatty acids and mood symptoms, these compounds have been proposed as a possible treatment in at-risk samples ( 121 , 125 ). However, in a double-blind parallel-group placebo-controlled trial, Sharpley et al. ( 125 ) did not find any impact of folic acid supplementation on the incidence of mood disorder in a youth sample at increased familial risk of mood disorder. Post hoc analysis, though, suggested that folic acid might help to delay the time to onset of mood disorder ( 125 ). A recent study reported that omega-3 fatty acids failed to prevent conversion from at-risk mental state to threshold psychosis ( 126 ), yet results are limited by the low conversion rate in the placebo group. Thus, the efficacy of omega-3 fatty acids in high-risk populations needs further investigation ( 127 ). Anti-inflammatory strategies such as aspirin have demonstrated potential to reduce risk of depression in epidemiological studies. Aspirin is being explored as a potential preventive strategy for depression in a very large clinical trial of over 19,000 people ( 128 ). Hence, examining the potential protective effects of nutritional and tolerable pharmacological supplements remains a promising line of research ( 121 ). Potential treatments for cognitive dysfunction (cognitive enhancers) might come up in the near future and pose new ethical questions as to when and in whom to use them ( 129 ).

Regarding predictors of treatment response, there are no solid results yet ( 130 , 131 ), but reported results do suggest a number of regions meriting further investigation, such as the gene coding for a subunit of the ligand-gated ionotropic glutamate receptor, GluR2/GLURB ( 131 ). A recent genome-wide study from the International Consortium on Lithium Genetics of 2,563 patients found a single locus of four linked single-nucleotide polymorphisms on chromosome 21 that met genome-wide significance criteria for association with lithium response ( 132 ). Furthermore, in an independent prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carrying the response-associated alleles was associated with a significantly lower rate of relapse ( 132 ). The pharmacogenetics of pharmacodynamic pathways, such as P450 enzymes and blood-brain barrier polymorphisms, is being explored as a predictor of antidepressant response ( 133 ), although not yet for mood stabilizers. However, sensitivity and specificity limitations mean that these genetic findings are not yet robust enough to guide treatment decisions.

Summary and Future Directions

The findings of this review support the notion of a prodromal state and a progressive course in bipolar disorder. This dynamic course fits in the model of clinical staging proposed by several authors ( 14 , 134 – 137 ), which assumes that illnesses progress from an at-risk stage to a late and resistant stage.

A positive family history of bipolar disorder, particularly if the parents have early-onset bipolar disorder, is the most significant risk factor for developing a bipolar spectrum disorder. Regarding prodromal symptoms, the most robust result is that subthreshold (hypo)manic symptoms are the strongest predictor of bipolar conversion, both in studies focusing on bipolar offspring and in community youths. Consequently, this translates into a need for screening for attenuated mania-like symptoms when assessing young patients seeking help for mood lability, anxiety, depression, or behavioral disorders, especially among bipolar offspring ( 138 ). Moreover, preliminary findings indicate that bipolar offspring with an aberrant inflammatory state or changes in the volume or activity of the amygdala may be more vulnerable to developing a mood disorder, suggesting a potential role for these alterations as putative biomarkers for disease prediction in individuals at genetic risk ( 121 , 139 ).

However, even if there is a promising emerging set of putative prodromal symptoms, biomarkers, and environmental risk factors, the possible additive or synergistic associations between all these factors remains a mystery ( 121 ). Therefore, more studies are needed to build a clear picture of high-risk bipolar states that can help clinicians differentiate genuinely at-risk individuals from persons with benign and self-limiting states ( 140 , 141 ). Moreover, since prodromal symptoms are highly heterogeneous and particular to each individual, individualized risk assessment is needed. Novel bioinformatic techniques, such as machine learning approaches, present a valuable ally in the field of early intervention to overcome such limitations ( 142 , 143 ).

Early intervention is an ideal breeding ground for new randomized clinical trials looking for the most efficacious treatment strategy for early stages. Currently there are no specific treatments for symptomatic youths who do not fulfill diagnostic criteria for bipolar disorder not otherwise specified but are at very high risk of developing bipolar disorder because one or both of the parents are diagnosed with bipolar disorder, particularly early-onset bipolar disorder. Since these children already present psychopathology in the form of symptoms of depression, anxiety, mood lability, or subsyndromal mania, they require existing treatments to target these symptoms—either pharmacotherapy or psychological therapies such as cognitive-behavioral therapies, family-focused therapy, self-help programs, or mental health first aid. What we do not know yet is whether these treatments will also prevent the onset of bipolar disorder. Thus, the need to perform studies to prevent or at least delay the onset of bipolar disorder should be considered a priority in psychiatry, especially in countries with a higher prevalence of pediatric bipolar disorder ( 144 ). Furthermore, as pointed out by Lambert et al. ( 145 ), once the most efficacious therapy is identified, further efforts should be made to ensure that at-risk populations have access to these interventions. Providing specialty care in youth mental health clinical services may be preferable to standard outpatient care, as evidence suggests that specialized treatment is more clinically effective and cost-effective ( 146 , 147 ). Very gradual dosage escalation and cautious use of pharmacotherapy, potentially augmented by pharmacogenetics if positive data emerge, may help treatment choice when pharmacological treatment becomes necessary. In the early stages, prevention of potential side effects is paramount, since an initial adverse experience primes beliefs about medication and powerfully influences future adherence and engagement ( 148 ). In the case of bipolar disorder, there is some indication that critical factors for illness outcome, such as cognitive impairment, are heavily influenced by illness course and morbidity ( 149 , 150 ). Hence, the early implementation of prevention strategies as appropriate according to illness stage and clinical phenotype may already help in preventing functional impairment. For very early stages, promoting and enhancing cognitive reserve may be one way to go ( 151 – 154 ).

Early intervention strategies in bipolar disorder face the lack of specificity of prodromal symptoms, as evidence emerging from studies performed in populations at ultra-high risk for psychosis indicate that there might be a common risk syndrome for diverse major psychiatric illnesses prior to the development of full symptoms more characteristic of any particular disease ( 141 ). Fernandes and Berk ( 142 ) hypothesized that this might also be true for biomarkers, with biomarkers useful for staging being common across different psychiatric disorders. Indeed, many of the biomarkers found in populations at risk for bipolar disorder are predictive for major psychiatric disorders in general and are common across commonly comorbid noncommunicable medical disorders, such as diabetes and cardiovascular disorders. This raises the question of whether more general interventions oriented toward enhancing stress-management strategies or reducing the proinflammatory state identified in at-risk individuals should be preferable. Findings concerning neurodevelopment, though, indicate that there may already be subtle potential differences between some psychiatric diseases at the earliest stages ( 155 ). In any case, this highlights the urgency of performing studies to test whether any given early intervention would help reduce vulnerability to psychiatric illnesses in general and not only to bipolar disorder, as bipolar offspring are at high risk of developing a wide range of psychiatric illnesses. As mentioned before, testing the protective potential of a variety of psychological interventions such as cognitive-behavioral therapies, family-focused therapy, self-help programs, or mental health first aid, or compounds such as omega-3 fatty acids, N -acetylcysteine, or minocycline, might be a feasible line of research. Lifestyle modifications such as smoking cessation, encouragement of physical activity, and healthy diet are indicated across the psychiatric spectrum and commonly comorbid medical disorders as well ( 156 ).

Overall, this review supports the idea of the existence of an at-risk state in bipolar disorder, thereby laying the foundations for bringing early intervention to life. However, we cannot deny that further efforts are required to advance on the difficult road of primary prevention. Given that psychiatric and commonly comorbid medical disorders share common risk determinants and operative biological pathways, a shared framework for disease prevention and control is warranted. A cross-disciplinary, multitarget approach is essential for wide-scale implementation in real-world settings ( 156 ). The need for new prospective studies with a larger sample size and standardized recruitment criteria and assessment tools is unquestionable. These studies should assess the validity of the proposed predictive factors to better determine which individuals are at highest risk for conversion and therefore more likely to benefit from early interventions. Further studies on early psychological and pharmacological interventions, either alone or in combination, are equally warranted.

In conclusion, considering that the onset of bipolar disorder usually occurs during adolescence—a period of personal, social, and professional development that is often truncated by the illness—introducing early interventions in psychiatry is imperative. By the time The American Journal of Psychiatry commemorates its 200th year of publication, we look forward to seeing that early intervention in psychiatry has been integrated in common clinical practice.

Dr. Vieta has received support from the Instituto de Salud Carlos III, Ministry of Economy and Competitiveness of Spain (PI 12/00912), integrated into the Plan Nacional de I+D+I and cofunded by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER); Centro para la Investigación Biomédica en Red de Salud Mental (CIBERSAM), Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2014_SGR_398), Seventh European Framework Programme (ENBREC), and the Stanley Medical Research Institute. Dr. Grande is supported by the Instituto de Salud Carlos III, Ministry of Economy and Competitiveness of Spain (Juan Rodés Contract) (JR15/00012) and a grant (PI16/00187) integrated into the Plan Nacional de I+D+I and cofunded by ISCIII-Subdirección General de Evaluación and FEDER. Dr. Carvalho is supported by a research fellowship award from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil). Dr. Fernandes is supported by a postdoctoral fellowship from Deakin University, Australia, and by a research grant MCTI/CNPQ/Universal 14/2014461833/2014-0 from CNPq, Brazil. Dr. Berk is supported by a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship (grant 1059660).

Dr. Vieta has received grants and honoraria from AstraZeneca, Ferrer, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Janssen, Lundbeck, Otsuka, Pfizer, Sanofi-Aventis, Sunovion, and Takeda as well as from the CIBERSAM, Grups Consolidats de Recerca 2014 (SGR 398), the Seventh European Framework Programme (ENBREC), and the Stanley Medical Research Institute. Dr. Grande has consulted for Ferrer and has been a speaker for Ferrer and Janssen-Cilag. Dr. Berk has received grant/research support from the Stanley Medical Research Foundation, MBF, NHMRC, NHMRC Senior Principal Research Fellowship grant 1059660, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Rotary Health, Meat and Livestock Board, Woolworths, BeyondBlue, Geelong Medical Research Foundation, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Organon, Novartis, Mayne Pharma, and Servier; has been a speaker for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Lundbeck, Pfizer, Sanofi Synthelabo, Servier, Solvay, and Wyeth; has been a consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Bioadvantex, Merck, GlaxoSmithKline, Lundbeck, Janssen-Cilag, and Servier; and is a co-inventor of two provisional patents regarding the use of NAC and related compounds for psychiatric indications, which, while assigned to the Mental Health Research Institute, could lead to personal remuneration upon a commercialization event. Dr. Birmaher has received research support from NIMH and royalties from Random House, Lippincott Williams & Wilkins, and UpToDate. Dr. Tohen has been a consultant for AstraZeneca, Abbott, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Otsuka, Roche, Lundbeck, Elan, Allergan, Alkermes, Merck, Minerva, Neuroscience, Pamlab, Alexza, Forest, Teva, Sunovion, Gedeon Richter, and Wyeth; he was a full-time employee at Eli Lilly (1997–2008); and his spouse is a former employee at Lilly (1998–2013). Dr. Suppes has received grants from NIMH, the VA Cooperative Studies Program, Pathway Genomics, the Stanley Medical Research Institute, Elan Pharma International, and Sunovion; consulting fees from Lundbeck, Sunovion, and Merck; CME and honoraria from Medscape Education, Global Medical Education, and CMEology; royalties from Jones and Bartlett and UpToDate; and travel reimbursement from Lundbeck, Sunovion, and Merck. The other authors report no financial relationships with commercial interests.

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• Mood Disorders-Bipolar
• Early intervention
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• Research article
• Open access
• Published: 08 February 2021

Bipolar I disorder: a qualitative study of the viewpoints of the family members of patients on the nature of the disorder and pharmacological treatment non-adherence

• Nasim Mousavi 1 ,
• Marzieh Norozpour   ORCID: orcid.org/0000-0002-8894-9178 1 ,
• Zahra Taherifar 2 ,
• Morteza Naserbakht 3 &
• Amir Shabani 3  

BMC Psychiatry volume  21 , Article number:  83 ( 2021 ) Cite this article

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Bipolar disorder is a common psychiatric disorder with a massive psychological and social burden. Research indicates that treatment adherence is not good in these patients. The families’ knowledge about the disorder is fundamental for managing their patients’ disorder. The purpose of the present study was to investigate the knowledge of the family members of a sample of Iranian patients with bipolar I disorder (BD-I) and to explore the potential reasons for treatment non-adherence.

This study was conducted by qualitative content analysis. In-depth interviews were held and open-coding inductive analysis was performed. A thematic content analysis was used for the qualitative data analysis.

The viewpoints of the family members of the patients were categorized in five themes, including knowledge about the disorder, information about the medications, information about the treatment and the respective role of the family, reasons for pharmacological treatment non-adherence, and strategies applied by families to enhance treatment adherence in the patients. The research findings showed that the family members did not have enough information about the nature of BD-I, which they attributed to their lack of training on the disorder. The families did not know what caused the recurrence of the disorder and did not have sufficient knowledge about its prescribed medications and treatments. Also, most families did not know about the etiology of the disorder.

The lack of knowledge among the family members of patients with BD-I can have a significant impact on relapse and treatment non-adherence. These issues need to be further emphasized in the training of patients’ families. The present findings can be used to re-design the guidelines and protocols in a way to improve treatment adherence and avoid the relapse of BD-I symptoms.

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Bipolar I disorder (BD-I) is a chronic and recurrent psychiatric disorder in which a person has a manic episode for 1 week, which may present before or after hypomanic or major depressive episodes [ 1 ].

BD-I is accompanied by chronic stress, disability, increased risk of sudden mood swings, higher rates of comorbid disorders and moral, financial, and legal problems. The disorder is ranked the sixth debilitating disease according to the World Health Organization (WHO). BD-I is considered the most expensive mental disorder in terms of the health and behavioral care required by the patients and the burden on governmental institutions and insurance companies [ 2 , 3 , 4 ]. According to a report by the Central Bank of the Islamic Republic of Iran, the average annual income of an Iranian household in 2012 was 209,050,000 Rials. The direct annual cost of one BD-I patient consists of 10% of this average family income [ 5 ].

BD-I affects the patient’s life and has long-term consequences that are visible in the patient’s social performance and quality of life [ 6 , 7 ]. Severe impairment in job performance is observed in about 30% of the patients with BD-I. In such cases, functional improvement falls substantially behind symptom improvement [ 1 ].

Pharmacological treatment is the first-line treatment for BD-I. Evidence shows that about 40% of patients with BD-I do not have good medication adherence, which translates into a higher probability of symptom relapse, hospitalization, and increased suicide risk [ 8 ]. In a study in Tehran, Iran, poor treatment adherence was noticed in about 30% of BD-I patients [ 9 ]. Another study from Iran [ 10 ] also reported the prevalence of poor compliance in BD-I patients after the first episode of mania as 38.1% during a 17-month follow-up period. Therefore, it is of great importance to better understand and investigate the underlying reasons for treatment non-adherence in BD-I patients.

Given the changes implemented in health care systems over the last two decades and the resultant focus on community-based services, the role of families in caring for BD-I patients has become more prominent [ 6 ]. The insufficient knowledge of families about the disorder, its symptoms, and medications has made the management of BD-I more difficult and eventually imposes additional costs on them [ 6 ]. The higher is the cost imposed on the family, the more likely is it for the family members to show adverse reactions to the BD-I patients, which itself leads to a higher chance of disorder relapse [ 3 ].

In Iran, the general public is acquainted with various types of psychiatric illnesses through mass media and public educational websites such as the website of the Iranian Psychiatric Association ( https://iranmentalhealth.com ) and other Persian public written sources. Patients with BD-I and their families become familiar with the treatment process after consulting a general practitioner, a psychiatrist, or a psychologist, and, if necessary, the patients are admitted to the hospital through a psychiatrist. In addition to medical treatment, they receive the necessary training and information about their treatment process in the hospital. Furthermore, an association called ABR (Association of Mental Health Promotion), with an active website ( http://abrcharity.ir ), independently monitors patients, including those with bipolar disorder, after discharge.

Many studies have examined the views and roles of patients with BD-I and their caregivers and also the importance of family awareness and its impact on medication adherence. Tacchi & Scott [ 11 ] and Veligan et al. [ 12 ] suggest that the family members’ beliefs about the nature of BD-I and the information they have about the disorder affect the patient’s medication adherence. The review of literature showed no precise studies conducted to explore the knowledge, information, and opinions of family members of BD-I patients about the disorder and the causes of their medication non-adherence.

In a previous study in Iran [ 13 ], the authors held qualitative interviews with the family members of patients with BD-I and reported that treatment non-adherence is a major problem in these patients. They also reported that the patients and their families did not have sufficient knowledge about the nature of this disorder. Considering these findings about the insufficient knowledge of the family members of BD-I patients and the high rate of treatment non-adherence, it is necessary to conduct more studies to investigate the possible causes of treatment non-adherence and families’ knowledge and beliefs about this disorder in Iran. This study was thus carried out to explore the viewpoints of the family members of BD-I patients about the nature of this disorder and the potential causes of treatment non-adherence. The results can be used for revising the psychoeducation guidelines for BD-I patients, as clinical guidelines mandate the inclusion of psychoeducation in the treatment plan adopted for these patients. The results can also be used to design a protocol to address the disorder relapse, which can have substantial consequences in terms of reducing healthcare costs.

The findings of this study are reported according to the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist [ 14 ].

Study samples’ characteristics

The participants were the family members of patients diagnosed with BD-I. The patients had been admitted to Iran Psychiatry Hospital in Tehran, Iran, and were receiving pharmacological treatments.

This study used purposive sampling to select the participants. From November 2017 to April 2018, 12 patients were interviewed by two psychiatrists based on the DSM-5 criteria [ 1 ] and received the diagnosis of BD-I. Then these diagnoses were confirmed by A.SH. and their families were invited to participate in the study.

None of the family members refused to participate in the study and they all completed the entire course of the study. The mean age of the participants was 50.83 years. There were three male (25%) and nine female (75%) participants (Table  1 ). Table  2 shows further details on patients’ characteristics.

Data collection

After diagnosing patients with BD-I, and obtaining the written consent of the family members of patients to participate in this study, data were collected by in-depth interviews from family members of patients, conducted at the hospital’s conference hall. No one else was present at the time of the interviews except for the interviewer and the participant. Each interview lasted approximately 20 min and was digitally recorded for subsequent analyses. Two female PhD candidates (N. M. and M. N.) in clinical psychology at the University of Social Welfare and Rehabilitation Sciences, Tehran, Iran, who had already received training on the implementation of qualitative studies, held the interviews. They did not know any of the participants. The interviewers introduced themselves to the participants before the beginning of each interview. The interview questions were provided by the authors. The interviews were held only once and were not repeated. Data saturation was reached with 12 participants, and no further participants were interviewed after reaching this number. Data saturation occurs when no new information is obtained by conducting further interviews [ 15 ].

Data analysis

Thematic analysis was used for the qualitative data analysis [ 16 , 17 ]. To this end, the six steps proposed by Clark and Brown [ 17 ] were used.

The raw data derived from the interviews were used for the analysis. The content of the interviews were transcribed verbatim immediately after each interview. Field notes were made during the interviews and were reviewed in this stage. Three authors (M. N., N. M., and Z. T.) read the interviews several times for immersing in the data and getting familiar with it. Line-by-line coding was then applied to generate the initial codes. These steps were performed manually by the three authors without using any computer programs. One author encoded each interview and the interview was then read by another author and encoded again. The individually-extracted codes were then integrated and modified, if necessary.

In the next step, by linking the codes together, their common patterns and concepts were extracted and potential themes and subthemes were identified, keeping the research questions in mind. The data related to the themes were then collected and examined to verify the accuracy of the themes and subthemes, which resulted in five final themes.

Several statements were selected from the interviews as examples and are reported in the results section. To preserve participants’ anonymity, their names and ages are not mentioned in the results; instead, they are represented by random numbers.

Taking into account comprehensiveness, homogeneity, and overlap, the components of the family members’ viewpoints on the nature of the disorder and the reasons for pharmacological treatment non-adherence were categorized into five themes, including knowledge about the disorder, information about the medications, information about the treatment and the respective role of the family, reasons for pharmacological treatment non-adherence, and strategies applied by families to enhance treatment adherence in the patients.

Each of the themes contained several subthemes, which were themselves made up of some open codes. These subthemes contained recurrent codes and concepts that shared a common meaning.

Table  3 presents the themes, subthemes and examples of some of the codes.

Theme one: knowledge about the disorder

Most interviewees did not have sufficient or accurate knowledge about the nature of BD-I, the signs and symptoms of depression and mania cycles, and the outcome of the disorder. They mentioned the lack of training or inadequate training (especially by healthcare providers) as the main cause of insufficient knowledge about BD-I. Additionally, most families did not have a good understanding of the etiology of BD-I.

Some of them considered BD-I as a genetic abnormality, while others considered factors such as adolescent maltreatment, parents’ unusual conditions during sexual intercourse, and the lack of proper training before parenthood as potential causes of BD-I.

Participant No. 5 (a patient’s wife): “I was told that he has a nervous problem.” Participant No. 3 (a patient‘s mother): "I have a theory about having babies. I think that not everyone should have children. The husband and wife should be screened and monitored for two years to see if they understand the matter clearly. Do you see these anomalies now? ... These shameful movies they watch … The person is not feeling well when raising their kid … From an Islamic point of view, from a human’s point of view, both the husband and wife need to be monitored. Their food and other things should also be monitored to see if they can have a healthy baby.”

Participant No. 7 (a patient’s mother): "Because this boy is always impressed by me, sometimes I tell myself, maybe I didn’t fully understand him during his puberty. Sometimes I blame myself, as he has said this many times. I always blame myself … . Sometimes he says, ‘You did this to me, that’s why I’m sick now and take drugs’. For example, when hitting puberty, in the first or second year of high school, he used to get up late and so he got to school very late. Then the school’s principal complained to me, ‘Why is he late again?’ And he says, ‘Why did you wake me up early in the morning? You did this to me.” Participant No. 10 (a patient’s mother), referring to her son's divorce: "That's why he's so broken.” Participant No. 11 (a patient’s sister): "Bipolar disorder has a genetic background. I think there would be no one out there who suffered from the disorder unless they got the genes. It is a genetic disorder, but it emerges when a patient experiences a series of shocking events. Well, some have higher potentials, such as those who get very angry. I mean, the anger itself is not part of the disorder, but in angry people, shocking events affect the patient more rapidly.”

Theme two: information about the medications

Many family members had a misconception about the treatment of the disorder and the effects of psychotropic medications on the patients. In other words, they were unable to accurately identify the therapeutic effects of the administered medications and the time it took for the patients to show signs of improvement. Also, some participants were unaware of the side-effects of the prescribed medications. Some mentioned side-effects like memory loss and drug addiction; however, almost all the participants believed that pharmacological treatment is necessary for the patients despite the side-effects.

Participant No. 1 (a patient’s mother): "The problem of her running away from home with her boyfriend was a big burden for us, but as the prescribed meds began to show their effectiveness, this problem was gradually solved and we finally managed to put up with her aggressiveness and other problems. That is, we were saying to ourselves, ‘This is a period of angriness; we had better not said this, not done that’... We thought the medication was working. But now they’ve told me, ‘No, your patient has not recovered at all, has not been cured.”

Participant No. 1 (a patient's mother): "Her first psychiatrist, who has been visiting her for eight years, was frequently asking if she studies, watches TV or goes to work at all. ‘Whenever she goes back to these routines, then she has recovered,’ the therapist would say. Recently, she’s always been saying, ‘I would love to go to work’ and so on. Once, her employer told her to do some cleaning, and she had responded, ‘I’m not your servant.’ She suddenly broke it off and said, ‘I won’t go to work anymore.’ She didn’t sleep at all, saying, ‘I work so much, but I don’t feel exhausted at all.’ We were also excited and thought ‘Yeah, so this doctor's meds have been good; she’s getting back to normal, she’s working,’ She was frequently organizing her closet, like an obsession.”

Participant No. 3 (a patient’s mother): “I can’t remember the side-effects but I’ve heard about them in classes. My daughter is taking lithium now but she gets these chills. Her stomach is not well. Its side-effects are such that they affect her memory. However, when we compare the pros and cons, we have to take it. "

Theme three: information about the treatment

The regular intake of medications, stress control, work, exercise, regular visits to a psychiatrist or psychologist, and the need to provide insight into the patient’s illness through education were noted by the families in this part. Some participants believed that psychotherapy sessions cannot help treat this disorder while some had completely false or superstitious beliefs about treatment of the disorder.

Participant No. 4 (a patient's son): "Our patient doesn’t accept justifications. When you bring them to classes and convince them that ‘You are sick, and you have to take this medication because of this and that, and we have evidence that you have this disorder,’ and then we show it to them, prove it like in the movies, say that this disorder is serious because of so and so reasons, I think, it would be much easier.”

Participant No. 1 (a patient’s mother): "They sent us to get counseling. Of course, my daughter did not cooperate and didn’t come with. So, I got an appointment under my name to get information and find out how to deal with this disorder. Then the psychologist said, 'No, your daughter is diagnosed with bipolar disorder; this is an acute illness. Counseling does not work for her. She should take medications –a lot of them. And since the doc said those words, we withdrew from counseling altogether.”

Participant No. 5 (a patient’s wife): "My mother-in-law says, ‘If God gives him a baby, he’ll be fine.’ Because his ex-wife also failed to bear a child for him.”

Theme four: information about the role of the family in the treatment

Most families defined their role as helping the patient recover and adhere to their treatment, reminding them to take the medications, encouraging them to go to the doctor, not leaving them alone, and doing whatever they wanted to do so that things went as the patient wished. The patients also appeared to feel guilty when their families tried to comfort them, and this pattern was observed in several of the participants in this study.

Participant No. 6 (a patient’s husband): "We should put up with her, love her, not argue about what she says, listen to her, get her to do exercise to keep busy. I'm here now and I brought her with me too instead of leaving her alone to think about stuff.”

Participant No. 2 (a patient’s mother): "You should be good to them, listen to them, make home a peaceful environment, and not argue.”

Participant No. 8 (a patient’s wife): “I don't know. If he just thinks that everything is okay, all will be okay; but such feelings don’t last forever.”

Participant No. 2 (a patient’s mother): "I tell him to take his meds on time … Say, ‘Let's go to the park to take a look around ... Don't stay at home too much. God is merciful; it won’t be that bad’ … I talk to him, I comfort him sometimes, tell him that I’m ill too because I feel your pain.’ I really do. I’ve been crying alone at home many times. God, what will happen at the end?"(She cries).

Theme five: reasons for pharmacological treatment non-adherence

As for this theme, the participants noted issues that were mostly about the comments made by other people, including relatives or care-providers, such as doctors or specialists in other disciplines. An interesting observation was made by a participant who mentioned a celebrity talking on TV about the inefficiency of medications; following these comments, the patient had stopped taking his medications. Another issue was that the families’ constant changing of the patient’s physician contributed to their medication non-adherence. Another reason noted for non-adherence was that the patients did not suffer from mania symptoms and found that it was not so crucial for them to take the medications. Additionally, some patients reported the physical discomfort and weakness (e.g., impotence) experienced as side-effects of the prescribed medications a reason for their medication non-adherence.

Participant No. 2 (a patient’s mother): "She didn't take the meds for seven to eight months. Her friend had told her ‘Your eyes look different. When you take the medicine, your eyes turn into a strange shape. Get rid of them.’ After seven months, her disease relapsed.”

Participant No. 6 (a patient’s husband): "If we go to a party somewhere and someone asks her, ‘Oh, you take drugs?’ … But that person is not aware of the matter, cause she might look all well, and that person doesn’t know what’s actually happening in my wife’s mind, who then has to admit that she is alright."

Participant No. 7 (a patient’s mother): "At one point at work, some colleagues told him, ‘You will become addicted to the medicines, you will get sick.’ Then, he put the medicines aside and became pessimistic about his work. ‘This job has made me sick,’ so he said and left his job all of a sudden. He had a great job, not a difficult one. He could manage it by himself very easily.”

Participant No. 3 (a patient’s mother): “My son had gone to a doctor to remove the corn on his feet. The doctor had checked his medicine prescriptions and asked, ‘What are these you’re taking? You won’t be able to conceive a baby in the future. It’ll affect you poorly’ and so on. My son keeps repeating what the doctor told him.”

Participant No. 1 (a patient’s mother): "That emergency nurse who came to our house told us to change her doctor. Since then, she has kept repeating this sentence. She threw out all her medicines.”

Participant No. 3 (a patient’s mother): “Since the beginning of the new year, he’s began to no longer take his medications. In Khandevaneh, Footnote 1 Mr. Mehran Ghafourian (a famous Iranian actor) said, ‘I was in a bad mood ... I had depression. I put the medications aside and started exercising.’ My son stopped taking his medicines on hearing those words. I asked him many times to go see a doctor but he said no. He continued to not take his medicines and then his disorder worsened. He was frequently beating us up until we took him to the hospital with the help of the police.”

Participant No. 3 (a patient’s mother): “There was a child psychiatrist on a TV talk. We took our son to her office. We used to visit a counselor as well. The psychiatrist prescribed him some medications. We didn’t know what the medications were. He was taking his medicines. In the middle of therapy, we stopped it. Then, my son-in-law, who is a doctor, said ‘Dr. A -his professor- is a very good doctor.’ My son used to go to Dr. A. earlier when he was a college student. He was taking medicines and he believed in him so much. Then again, my eldest daughter, who is a physician, said ‘Dr. B. is a very helpful therapist. All the doctors, engineers, and educated people go to visit him.’ Then he went there ... And two years ago, I took him to Dr. S. too, to help him get rid of his substance abuse." (This participant named seven different doctors).

Participant No. 4 (a patient’s son) discussed the reasons for the patient’s refusal to take the medications and said: "Well, he doesn't actually believe in the disorder being a real one (in the manic episode). Maybe now he takes the pill in front of you, but you know that it is not something that bothers him. You take pills more easily if you have actual pain, but when you don’t, you ask yourself ‘Why do I have to take all these pills?”

Participant No. 11 (a patient’s sister): “We can note the poor behaviors of those around him. He considers any weaknesses he experiences (e.g., sexual problems) a side-effect of the medicines he’s taking. And he’s linking everything to the medicines and thinking they’re going to make him different from the others.”

The findings of this study regarding the viewpoints of the family members of patients with BD-I were categorized into five themes. Although qualitative studies do not allow for the identification of the extent and relative importance of every condition, recurrent themes and concepts stated by the participants at different individual and social levels were extracted.

Research suggests that there is a relationship between families’ knowledge and beliefs about the disorder and the patients’ medication adherence [ 12 ]. The attitudes and knowledge of the family members have a significant influence on the patient’s own beliefs and attitudes and affect the patient’s decision about treatment compliance [ 18 ]. In agreement with previous studies [ 19 , 20 ], the family caretakers in this study were shown to lack sufficient information and knowledge about the nature of BD-I. In addition, many participants had inaccurate or false information and insisted on these false beliefs. A review study on treatment acceptance found that brief interventions focused on relapse prevention and psychoeducation-based interventions have the greatest impact on relapse prevention [ 21 ]. Maintaining the patients’ circadian rhythms (especially sleep rhythm), controlling activity levels, verifying and controlling initial symptoms of mania and depressive episodes, and not using narcotics or stimulants have been recommended in approved psychotherapy protocols for bipolar patients [ 22 ]. Nonetheless, the participants in this study did not discuss any of these important factors. The lack of knowledge about these important issues among families can have a significant impact on relapse and treatment non-adherence in the patients. These points need to be further emphasized in training patients’ families.

In a qualitative study on bipolar patients and their families, Peters, Pontin, Lobban, and Morriss [ 23 ] found that the viewpoints of patients and their families play an important role in managing the disorder; however, the families usually get despondent about participating in this process, and their perception was that some mental health workers believe that family involvement makes their work more complicated. Meanwhile, the present study showed that, in Iran, families do not have enough information about their role in preventing disorder relapse and attribute their patient’s relapse only to factors such as medication withdrawal, unemployment, lack of community support, and financial problems. Most of them believed that if everything goes as the patient wishes, the disorder will not relapse.

Furthermore, the participants did not have adequate information about the non-pharmacological treatment options available for this disorder and the role that psychologists can play in helping the patients enhance their medication adherence and prevent the symptoms of relapse. A variety of behavioral, cognitive, and emotion-focused interventions are used in the management of bipolar disorders [ 22 ]. Nevertheless, the participants did not have sufficient knowledge about these treatments. The observation that many psychologists in Iran appear unwilling to participate in the treatment of bipolar disorder patients seems to play a role in this lack of knowledge. According to Farhoudian et al. [ 24 ], only about 1.5% of all the studies on psychiatric disorders conducted in Iran between 1973 and 2003 involved bipolar and cyclothymic patients. In a qualitative study on bipolar-II patients and their families, Fisher et al. [ 25 ] found that the number of resources available to patients for deciding about their treatment has increased and their priorities have been given increasing attention; yet, the patients’ and their families’ preferences are not fully considered.

Similar to the studies carried out by Jönsson, Wijk, Skärsäter & Danielson [ 26 ] and Shamsaei, Mohamad Khan Kermanshahi, and Vanaki [ 27 ], in the present study, the patients and their families were struggling with the acceptance, understanding, and management of the disorder. According to the participants, the families’ lack of insight into the patients’ disorder contributed significantly to their medication non-adherence. This finding is in line with Scott and Pope’s [ 28 ] research, but Delmas, Proudfoot, Parker, and Manicavasagar [ 29 ] stated that the rejection of treatment is a complex issue that depends on various factors.

Some of the results of this study are consistent with the findings reported by Clatworthy, Bowskill, Rank, Parham, and Horne [ 8 ], who noted that deliberate treatment non-adherence is associated with factors such as patients’ concerns about the prescribed medications and their side-effects in the case of continuous consumption. Proudfoot et al. [ 30 ] stated that the side-effects of medications, coping with unpleasant symptoms, the extent of awareness about the nature of the disorder, and the reactions to it as well as the stigma associated with the disorder affect the patient’s life path. Besides, these symptoms have a permanent impact on the disorder relapse [ 31 ]. The findings showed that the interaction of the disorder, patient, medications, psychiatric attitude, and cultural attitude with non-compliance is very complex [ 32 ].

In addition to the themes mentioned, there were some interesting results concerning the response process in all the interviews. For example, the majority of the participants only reported symptoms of the manic episode, while two major studies [ 33 , 34 ] have shown that people with bipolar I and II (especially type II) disorders spend most of their symptomatic days with depression. Patients suffer greatly during the depressive episodes but have elevated or irritable moods during the manic episode; in contrast, families find the mania symptoms more annoying and disruptive to themselves. This duality can negatively impact reaching a common understanding with the patient about visiting the doctor and taking medications. Moreover, the fact that some families do not have enough information about the depressive episode can eventuate in neglecting the patient’s need to take medications during this phase, which can then adversely affect medication adherence. These results are somewhat contradictory to the results of a previous study [ 29 ], which reported that both patients and their family members report symptoms of mania and hypomania to their physicians less often, as some of them enjoy the manic symptoms. Family members feel relieved when they see that their patient is happy and shows mania symptoms. A major cause of this discrepancy in findings may be the differences in the study populations. While Delmas et al. [ 29 ] studied patients with bipolar I and II, the present study examined only patients with BD-I. The discrepancy may also partially originate from cultural differences. It seems that when there is a pattern of greater attention to objective and apparent symptoms, very important mental symptoms such as suicidal thoughts, whether during the mania or depressive episode, are neglected by families.

This study showed that families with a higher educational and socioeconomic status tend to seek psychiatric care from different psychiatrists. Frequently changing the treating psychiatrist can cause treatment non-adherence in the patients. Furthermore, as the family members of such patients falsely think that they have greater medical information, they are more likely to encourage the patient to stop taking their prescribed medications.

A major limitation of this study was that most participants were the mothers of the patients, as it was hard to find other family members of the patients to participate in the study. For example, only one child of a patient and one sister were among the participants. Also, all the participants were from Tehran and were selected from one hospital; therefore, the generalization of the results to other cities in Iran should be pursued with caution.

The authors suggest using the findings of this qualitative study regarding the knowledge of the family members of patients with bipolar I disorder (BD-I) as well as the dominating cultural beliefs to design further quantitative studies. The quantitative assessment of individual, familial, and social reasons for treatment non-adherence is also a recommendation for future research. Conducting similar studies on the family members of patients with other types of bipolar disorder with an attention to the different processes and outcomes involved is also recommended. Since there are different ethnicities and subcultures in Iran, the results obtained by examining the residents of the country’s capital city cannot be generalized to the population of other cities and towns, and it is necessary to repeat the study in other populations in order to get familiar with other viewpoints in Iran.

Overall, the results of this study contribute to the emerging qualitative research on bipolar disorder and provide the readers with an insight into the viewpoints of the family members of patients with BD-I. Some inaccurate information might have been observed in participants’ statements due to some deeply-rooted cultural attitudes and beliefs and their correction may require extensive interventions.

The results of this study can be used to compile educational content for patients with bipolar disorder and their families as well as for psychologists, psychiatrists, psychiatry assistants, and hospital health workers.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors express their gratitude to all the staff of Iran Psychiatry Hospital for their generous cooperation in the study.

This research is funded by the Mental Health Research Center of Iran University of Medical Sciences (grant number 95–01–121-27963).

The views expressed are those of the authors and not necessarily those of the Mental Health Research Center of Iran University of Medical Sciences. The funders had no role in the study design, data collection and analysis, interpretation, decision to publish or the writing and preparation of the manuscript.

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Faculty of Behavioral Sciences and Mental Health, Tehran Psychiatry Institute, Iran University of Medical Sciences, Tehran, Islamic Republic of Iran

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Contributions

NM, MN and ASH conceived the study idea and design. NM, and MN conducted the interviews. NM, MN and ZT conducted transcription and data analysis. NM, MNA and ZT interpreted and presented the results, and contributed to the manuscript. ASH supervised the research activities and contributed to the interpretation of results. NM, MN and ZT wrote the manuscript. All authors have read, edited and approved the final manuscript for submission.

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Correspondence to Marzieh Norozpour .

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This research has been approved by the Research Ethics Committee of Iran University of Medical Sciences (Code of Ethics: IR.IUMS.REC 1395.95–01–121-27963). Written informed consent was obtained from all the research participants prior to participating in the study.

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Mousavi, N., Norozpour, M., Taherifar, Z. et al. Bipolar I disorder: a qualitative study of the viewpoints of the family members of patients on the nature of the disorder and pharmacological treatment non-adherence. BMC Psychiatry 21 , 83 (2021). https://doi.org/10.1186/s12888-020-03008-x

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An Update on Bipolar I Disorder

Our Mood Disorders Section Editor discusses the disorder in honor of World Bipolar Day.

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CLINICAL CONVERSATIONS

March 30, 2024, is World Bipolar Day. Psychiatric Times ® sat down with our Mood Disorders Section Editor Gustavo Alva, MD, DFAPA, to discuss bipolar I disorder—its clinical characteristics, its impact on patients’ lives, and the future of treatment.

Psychiatric Times: What is the prevalence of bipolar I disorder in the United States?

Gustavo Alva, MD, DFAPA: Bipolar I disorder, or BP-I, is one of the most severe and common forms of bipolar disorder, 1 affecting nearly 4.8 million American adults. 2 The prevalence of adults affected by BP-I makes it so important to foster an open dialogue surrounding this condition to empower those struggling to seek proper care and treatment from a health care professional.

World Bipolar Day on March 30 represents an opportunity to encourage awareness and increase education and conversations surrounding bipolar disorder with hopes of eliminating the social stigma associated with this condition.

PT: What are the risk factors for the development of bipolar I disorder?

Alva: There are many factors that contribute to an individual’s chance of having BP-I. Research shows that genetics play a role: Those who have a first-degree relative, such as a parent or sibling, 3 with BP-I are more at risk for developing the disorder. Periods of high stress, traumatic events, or substance abuse can also increase the risk of developing BP-I or act as a trigger for the first episode. 4

Some studies also suggest that individuals with bipolar have brains that may be structured and function differently 3 than those without bipolar, and those with other mental health disorders.

PT: How does bipolar I disorder impact the day-to-day lives of individuals with the disorder?

Alva: BP-I is a recurrent, lifelong mood disorder that results in functional and cognitive impairment, which is characterized by recurrent manic and depressive episodes that may last weeks or even months. BP-I patients may face periods of unusually intense emotions and changes in sleep patterns and activity levels, 3 all of which can negatively impact an individual's daily life.

Those diagnosed with BP-I tend to experience functional and cognitive impairment 5 that, understandably, can impact daily life. However, patients with BP-I who are stable on their prescribed treatment, along with support and self-care, can still lead healthy, fulfilling lives. 6

PT: What treatment options are currently available for bipolar I disorder?

Alva: There are many treatment options available for patients with BP-I, and the multitude of options is important because not every patient is the same. Treatment types and plans that work for some individuals may not work for others, depending on their lifestyle, schedule, occupation, family, and more.

Treatments typically revolve around pharmacological options, mainly medications prescribed by a health care provider, and psychological options, including different forms of therapy. 3 In addition to daily oral pills or tablets, long-acting injectables (LAIs)are another form of medication that can last for an extended period with just 1 dose. 7

It is important to keep in mind when evaluating options that there is no one-size-fits-all approach to treatment, so working closely with a health care professional to identify which treatment and management options work best for the patient is a crucial first step toward achieving stability.

PT: Are there any potential treatments on the horizon or in development that may impact the future of treatment?

Alva: In my practice, I have found that LAIs can be beneficial in managing BP-I disorder in patients who are already stable. LAIs are administered by a health care professional and provide continuous delivery of antipsychotic medication to help maintain appropriate blood levels of that medication, offering an additional treatment option to maintain stability for patients living with bipolar I disorder.

Because LAIs are administered differently and less frequently than daily oral medications, they allow one less daily disruption, while reducing the reminder of the disease every day.

Taking medication as prescribed is easier said than done, which is why LAIs are changing the conversation surrounding treatment. Of those diagnosed with bipolar disorder, about half have issues with their treatment plans long-term. 8

Considering that 90% of individuals with bipolar disorder experience recurrences during their lifetime, 9 arriving at a long-term treatment plan can be pivotal. I encourage all patients and their caregivers to speak with their health care professionals about the treatments available to them, to determine if an LAI is the right fit for them and their lifestyles.

For more information, I would recommend visiting www.otsukapatiented.com/mental-health .

Dr Alva is a board-certified psychiatrist, a paid consultant of Otsuka America Pharmaceutical, Inc, and Lundbeck, and Mood Disorders Section Editor for Psychiatric Times .

1. Datto C, Pottorf WJ, Feeley L, et al. Bipolar II compared with bipolar I disorder: baseline characteristics and treatment response to quetiapine in a pooled analysis of five placebo-controlled clinical trials of acute bipolar depression .  Ann Gen Psychiatry . 2016;15:9.

2. Blanco C, Compton WM, Saha TD, et al. Epidemiology of DSM-5 bipolar I disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions—III .  J Psychiatr Res . 2017;84:310-317.

3. What is bipolar disorder? National Institute of Mental Health. Last reviewed February 2024. Accessed March 4, 2024. https://www.nimh.nih.gov/health/topics/bipolar-disorder#part_2260

4. Bipolar disorder: overview. Mayo Clinic. December 13, 2022. Accessed March 4, 2024. https://www.mayoclinic.org/diseases-conditions/bipolar-disorder/symptoms-causes/syc-20355955

5. Bonnín CDM, Reinares M, Martínez-Arán A, et al. Improving functioning, quality of life, and well-being in patients with bipolar disorder .  Int J Neuropsychopharmacol . 2019;22(8):467-477.

6. Bipolar disorder. Substance Abuse and Mental Health Services Administration. Last updated April 24, 2023. Accessed March 4, 2024. https://www.samhsa.gov/mental-health/bipolar

7. Johnson K. What you need to know about long-acting injectables (LAIs). American Association of Psychiatric Pharmacists. 2022. Accessed March 4, 2024. https://www.nami.org/NAMI/media/NAMI-Media/Research/Long-Acting-Injectables_2022.pdf

8. Chou JC. Treatment-resistant bipolar disorder. Psychiatric Times . July 6, 2011. Accessed March 4, 2024. https://www.psychiatrictimes.com/view/treatment-resistant-bipolar-disorder

9. Leelahanaj T, Kongsakon R, Choovanichvong S, et al. Time to relapse and remission of bipolar disorder: findings from a 1-year prospective study in Thailand .  Neuropsychiatr Dis Treat . 2013;9:1249-1256.

The Week in Review: April 1-5

Blue Light, Depression, and Bipolar Disorder

FDA Approves Fanapt for Mixed, Manic Episodes Associated With Bipolar I Disorder

Four Myths About Lamotrigine

The Week in Review: March 25-29

Bipolar Disorder Research Roundup: March 29, 2024

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Prevalence of Mental Health Disorders Among Individuals Experiencing Homelessness : A Systematic Review and Meta-Analysis

• 1 Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
• 2 Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
• 3 Faculty of Social Work, University of Calgary, Calgary, Alberta, Canada
• 4 Mathison Centre for Mental Health Research and Education, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
• 5 Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
• 6 Department of Electrical and Software Engineering, University of Calgary, Calgary, Alberta, Canada
• 7 Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

Question   What is the prevalence of mental health disorders among people experiencing homelessness?

Findings   In this systematic review and meta-analysis, the prevalence of current and lifetime mental health disorders among people experiencing homelessness was high, with male individuals exhibiting a significantly higher lifetime prevalence of any mental health disorder compared to female individuals.

Meaning   These findings demonstrate that most people experiencing homelessness have mental health disorders, with current and lifetime prevalence generally much greater than that observed in general community samples.

Importance   Several factors may place people with mental health disorders, including substance use disorders, at increased risk of experiencing homelessness and experiencing homelessness may also increase the risk of developing mental health disorders. Meta-analyses examining the prevalence of mental health disorders among people experiencing homelessness globally are lacking.

Objective   To determine the current and lifetime prevalence of mental health disorders among people experiencing homelessness and identify associated factors.

Data Sources   A systematic search of electronic databases (PubMed, MEDLINE, PsycInfo, Embase, Cochrane, CINAHL, and AMED) was conducted from inception to May 1, 2021.

Study Selection   Studies investigating the prevalence of mental health disorders among people experiencing homelessness aged 18 years and older were included.

Data Extraction and Synthesis   Data extraction was completed using standardized forms in Covidence. All extracted data were reviewed for accuracy by consensus between 2 independent reviewers. Random-effects meta-analysis was used to estimate the prevalence (with 95% CIs) of mental health disorders in people experiencing homelessness. Subgroup analyses were performed by sex, study year, age group, region, risk of bias, and measurement method. Meta-regression was conducted to examine the association between mental health disorders and age, risk of bias, and study year.

Main Outcomes and Measures   Current and lifetime prevalence of mental health disorders among people experiencing homelessness.

Results   A total of 7729 citations were retrieved, with 291 undergoing full-text review and 85 included in the final review (N = 48 414 participants, 11 154 [23%] female and 37 260 [77%] male). The current prevalence of mental health disorders among people experiencing homelessness was 67% (95% CI, 55-77), and the lifetime prevalence was 77% (95% CI, 61-88). Male individuals exhibited a significantly higher lifetime prevalence of mental health disorders (86%; 95% CI, 74-92) compared to female individuals (69%; 95% CI, 48-84). The prevalence of several specific disorders were estimated, including any substance use disorder (44%), antisocial personality disorder (26%), major depression (19%), schizophrenia (7%), and bipolar disorder (8%).

Conclusions and Relevance   The findings demonstrate that most people experiencing homelessness have mental health disorders, with higher prevalences than those observed in general community samples. Specific interventions are needed to support the mental health needs of this population, including close coordination of mental health, social, and housing services and policies to support people experiencing homelessness with mental disorders.

Read More About

Barry R , Anderson J , Tran L, et al. Prevalence of Mental Health Disorders Among Individuals Experiencing Homelessness : A Systematic Review and Meta-Analysis . JAMA Psychiatry. Published online April 17, 2024. doi:10.1001/jamapsychiatry.2024.0426

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Bipolar Disorder

In this 2-part podcast series, NAMI Chief Medical Officer Dr. Ken Duckworth guides discussions on bipolar disorder that offer insights from individuals, family members and mental health professionals.  Read the transcript . Note:  Content includes discussions on topics such as suicide attempts and may be triggering.

Bipolar disorder is a mental illness that causes dramatic shifts in a person’s mood, energy and ability to think clearly. People with bipolar experience high and low moods—known as mania and depression—which differ from the typical ups-and-downs most people experience.

The average age-of-onset is about 25, but it can occur in the teens, or more uncommonly, in childhood. The condition affects men and women equally, with about  2.8%  of the U.S. population diagnosed with bipolar disorder and nearly  83%  of cases classified as severe.

If left untreated, bipolar disorder usually worsens. However, with a good treatment plan including psychotherapy, medications, a healthy lifestyle, a regular schedule and early identification of symptoms, many people live well with the condition.

Symptoms and their severity can vary. A person with bipolar disorder may have distinct manic or depressed states but may also have extended periods—sometimes years—without symptoms. A person can also experience both extremes simultaneously or in rapid sequence.

Severe bipolar episodes of mania or depression may include psychotic symptoms such as hallucinations or delusions. Usually, these psychotic symptoms mirror a person’s extreme mood. People with bipolar disorder who have psychotic symptoms can be wrongly diagnosed as having  schizophrenia .

Mania.  To be diagnosed with bipolar disorder, a person must have experienced at least one episode of mania or hypomania. Hypomania is a milder form of mania that doesn’t include psychotic episodes. People with hypomania can often function well in social situations or at work. Some people with bipolar disorder will have episodes of mania or hypomania many times throughout their life; others may experience them only rarely.

Although someone with bipolar may find an elevated mood of mania appealing—especially if it occurs after depression—the “high” does not stop at a comfortable or controllable level. Moods can rapidly become more irritable, behavior more unpredictable and judgment more impaired. During periods of mania, people frequently behave impulsively, make reckless decisions and take unusual risks.

Most of the time, people in manic states are unaware of the negative consequences of their actions. With bipolar disorder,  suicide  is an ever-present danger because some people become suicidal even in manic states. Learning from prior episodes what kinds of behavior signals “red flags” of manic behavior can help manage the symptoms of the illness.

Depression . The lows of bipolar depression are often so debilitating that people may be unable to get out of bed. Typically, people experiencing a depressive episode have difficulty falling and staying asleep, while others sleep far more than usual. When people are depressed, even minor decisions such as what to eat for dinner can be overwhelming. They may become obsessed with feelings of loss, personal failure, guilt or helplessness; this negative thinking can lead to thoughts of suicide.

The depressive symptoms that obstruct a person’s ability to function must be present nearly every day for a period of at least two weeks for a diagnosis. Depression associated with bipolar disorder may be more difficult to treat and require a customized treatment plan.

Scientists have not yet discovered a single cause of bipolar disorder. Currently, they believe several factors may contribute, including:

• Genetics.  The chances of developing bipolar disorder are increased if a child’s parents or siblings have the disorder. But the role of genetics is not absolute: A child from a family with a history of bipolar disorder may never develop the disorder. Studies of identical twins have found that, even if one twin develops the disorder, the other may not.
• Stress . A stressful event such as a death in the family, an illness, a difficult relationship, divorce or financial problems can trigger a manic or depressive episode. Thus, a person’s handling of stress may also play a role in the development of the illness.
• Brain structure   and function . Brain scans cannot diagnose bipolar disorder, yet researchers have identified subtle differences in the average size or activation of some brain structures in people with bipolar disorder.

To diagnose bipolar disorder, a doctor may perform a physical examination, conduct an interview and order lab tests. While bipolar disorder cannot be seen on a blood test or body scan, these tests can help rule out other illnesses that can resemble the disorder, such as hyperthyroidism. If no other illnesses (or medicines such as steroids) are causing the symptoms, the doctor may recommend mental health care.

To be diagnosed with bipolar disorder, a person must have experienced at least one episode of mania or hypomania. Mental health care professionals use the Diagnostic and Statistical Manual of Mental Disorders (DSM) to diagnose the “type” of bipolar disorder a person may be experiencing. To determine what type of bipolar disorder a person has, mental health care professionals assess the pattern of symptoms and how impaired the person is during their most severe episodes.

Four Types Of Bipolar Disorder

• Bipolar I Disorder  is an illness in which people have experienced one or more episodes of mania. Most people diagnosed with bipolar I will have episodes of both mania and depression, though an episode of depression is not necessary for a diagnosis. To be diagnosed with bipolar I, a person’s manic episodes must last at least seven days or be so severe that hospitalization is required.
• Bipolar II Disorder  is a subset of bipolar disorder in which people experience depressive episodes shifting back and forth with hypomanic episodes, but never a “full” manic episode.
• Cyclothymic Disorder or Cyclothymia  is a chronically unstable mood state in which people experience hypomania and mild depression for at least two years. People with cyclothymia may have brief periods of normal mood, but these periods last less than eight weeks.
• Bipolar Disorder, “other specified” and “unspecified”  is when a person does not meet the criteria for bipolar I, II or cyclothymia but has still experienced periods of clinically significant abnormal mood elevation.

Bipolar disorder is treated and managed in several ways:

• Psychotherapy , such as cognitive behavioral therapy and family-focused therapy.
• Medications , such as mood stabilizers, antipsychotic medications and, to a lesser extent, antidepressants.
• Self-management strategies ,  like education and recognition of an episode’s early symptoms.
• Complementary health approaches ,  such as aerobic exercise meditation, faith and prayer can support, but not replace, treatment.

The largest research project to assess what treatment methods work for people with bipolar disorder is the  Systematic Treatment Enhancement for Bipolar Disorder , otherwise known as Step-BD. Step-BD followed over 4,000 people diagnosed with bipolar disorder over time with different treatments.

Related Conditions

People with bipolar disorder can also experience:

• Attention-deficit hyperactivity disorder ( ADHD )
• Posttraumatic stress disorder ( PTSD )
• Substance use disorders/ dual diagnosis

People with bipolar disorder and psychotic symptoms can be wrongly diagnosed with  schizophrenia . Bipolar disorder  can be also misdiagnosed  as Borderline Personality Disorder ( BPD ).

These other illnesses and misdiagnoses can make it hard to treat bipolar disorder. For example, the antidepressants used to treat OCD and the stimulants used to treat ADHD may worsen symptoms of bipolar disorder and may even trigger a manic episode. If you have more than one condition (called co-occurring disorders), be sure to get a treatment plan that works for you.

Reviewed August 2017

Proper treatment helps most people living with bipolar disorder control their mood swings and other symptoms. Because bipolar disorder is a chronic illness, treatment must be ongoing. If left untreated, the symptoms of bipolar disorder get worse, so diagnosing it and beginning treatment early is important.

Treating bipolar disorder may include medication, psychotherapy, education, self-management strategies and external supports such as family, friends and support groups. There is no one approach to treating bipolar disorder.

Psychotherapy

Psychotherapy, support groups and psychoeducation about the illness are essential to treating bipolar disorder:

• Cognitive behavioral therapy  (CBT) helps change the negative thinking and behavior associated with depression. The goal of this therapy is to recognize negative thoughts and to teach coping strategies.
• Family-focused therapy helps people with bipolar disorder learn about the illness and carry out a treatment plan.
• Psychotherapy  focused on self-care and stress regulation, and helps a person improve self-care, recognize patterns of the onset of the symptoms and to manage stress.

An NIMH clinical trial, the  Systematic Treatment Enhancement Program for Bipolar Disorder  (STEP-BD) showed that patients taking medications to treat bipolar disorder are more likely to get well faster and stay well if they receive a combination of several intensive psychotherapy interventions. Individuals in the study received three types of psychotherapy, which focused on cognitive strategies, family involvement and stress regulation.

Medications

With the prescribing doctor, work together to review the options for medication. Different types of bipolar disorder may respond better to a particular type. The side effects can vary between medications and it may take time to discover the best medicine.

Lithium  (Lithobid, Eskalith) is effective at stabilizing mood and preventing the extreme highs and lows of bipolar disorder. Periodic blood tests are required because lithium can cause thyroid and kidney problems. Common side effects include restlessness, dry mouth and digestive issues. Lithium levels should be monitored carefully to ensure the best dosage and watch for toxicity.

Lithium is used for continued treatment of bipolar depression and for preventing relapse. There is evidence that lithium can lower the risk of suicide but the FDA has not granted approval specifically for this purpose.

Anticonvulsants

Many medications used to treat seizures are also used as  mood stabilizers . They are often recommended for treating bipolar disorder. Common side effects include weight gain, dizziness and drowsiness. But sometimes, certain anticonvulsants cause more serious problems, such as skin rashes, blood disorders or liver problems.

Valproic acid  and  carbamazepine  are used to treat mania. These drugs, also used to treat epilepsy, were found to be as effective as lithium for treating acute mania. They may be better than lithium in treating the more complex bipolar subtypes of rapid cycling and dysphoric mania.

Lamotrigine  is used to delay occurrences of bipolar I disorder. Lamotrigine does not have FDA approval for treatment of the acute episodes of depression or mania. Studies of lamotrigine for treatment of acute bipolar depression have produced inconsistent results.

Second-Generation Antipsychotics (SGAs)

SGAs are commonly used to treat the symptoms of bipolar disorder and are often paired with other medications, including mood stabilizers. They are generally used for treating manic or mixed episodes.

SGAs are often prescribed to help control acute episodes of mania or depression. Finding the right medication is not an exact science; it is specific to each person. Currently, only  quetiapine  and the combination of  olanzepine  and  fluoxetine  (Symbax) are approved for treating bipolar depression. Regularly check with your doctor and the FDA website, as side effects can change over time.

Standard Antidepressants

Antidepressants  present special concerns when used in treating bipolar disorder, as they can trigger mania in some people. A National Institute of Mental Health study showed that taking an antidepressant also to a mood stabilizer is no more effective that using a mood stabilizer alone for bipolar I. This is an essential area to review treatment risks and benefits.

Other Treatments

Electroconvulsive therapy (ect).

In rare instances,  ECT  can be considered as an intervention for severe mania or depression. ECT involves transmitting short electrical impulses into the brain. Although ECT is a highly effective treatment for severe depression, mania or mixed episodes, it is reserved for specific situations and for symptoms that have not responded to other treatments.

Treatment Considerations For Women And For Children

Women. Women with bipolar disorder who are of childbearing age, or who are considering getting pregnant, need special attention. A complex risk-benefit discussion needs to occur to look at the treatment options available. Some medicines can have risk to the developing fetus and to children in breast milk. However, there is also evidence that being off of all medications increases the likelihood of bipolar symptoms, which itself creates risks to both mother and fetus or baby. Planning ahead and getting good information from your health care team based on your individual circumstances improves your chance of a best outcome.

Children. The diagnosis of bipolar disorder in children has been controversial. Before receiving any psychiatric diagnosis, children must have a comprehensive evaluation of their physical and mental health. Children with bipolar disorder may also have other conditions including attention-deficit hyperactivity disorder, early childhood psychosis, posttraumatic stress disorder, learning disabilities or substance abuse problems. Each of these co-occurring conditions requires a thoughtful and individualized treatment plan. Children with bipolar disorder usually receive psychotherapy and psychosocial interventions before medications are considered.

The identification of a new mental health condition, Disruptive Mood Dysregulation Disorder (DMDD), could affect how bipolar disorder is diagnosed in children. DMDD better describes children who are intensely irritable, have temper tantrums, but do not have classic symptoms of mania. Early evidence suggests children with DMDD do not have an increased risk of developing bipolar disorder as adults, but they may have other co-occurring illnesses like depression.

Coping with the ups and downs of bipolar disorder isn’t easy. But if you or a family member or friend is struggling, there is help. NAMI and NAMI Affiliates are there to provide you with support for you and your family and information about community resources.

Contact the NAMI HelpLine at 1-800-950-NAMI (6264) or  [email protected]  if you have any questions about bipolar disorder or finding support and resources.

Helping Yourself

If you have bipolar disorder, the condition can exert control over your thoughts, interfere with relationships and if not treated, lead to a crisis. Here are some ways to help manage your illness.

Pinpoint your stressors and triggers.  Are there specific times when you find yourself stressed? People, places, jobs and even holidays can play a big role in your mood stability. Symptoms of mania and depression may start slow, but addressing them early can prevent a serious episode. Feelings of mania may feel good at first, but they can spiral into dangerous behavior such as reckless driving, violence or hypersexuality. Depression may begin with feeling tired and being unable to sleep.

Avoid drugs and alcohol .  These substances can disturb emotional balance and interact with medications. Both depression and mania make drugs and alcohol attractive options to help you “slow down” or “perk up,” but the potential damage can block your recovery.

Establish a routine.  Committing to a routine can help you take control and help prevent depression and mania from taking control. For example, to keep the energy changes caused by depression and mania in check, commit to being in bed only eight hours a night and up and moving the rest of the time. Aerobic exercise is a good strategy for regulating body rhythm.

Learn from past episodes.  Pattern recognition is essential to spotting the early symptoms of an impending manic episode. Accepting support from family members or friends who can recognize early symptoms is important. Symptoms often follow very specific patterns, and this can be learned and planned for. 2 nights of a small sleep change or the even the repeated use of a certain phrase can be examples of early warning signs.

Form healthy relationships.  Relationships can help stabilize your moods. An outgoing friend might encourage you to get involved with social activities and lift your mood. A more relaxed friend may provide you with a steady calm that can help keep feelings of mania under control.

If you live with a mental health condition, learn more about  managing your mental health and finding the support you need .

Helping A Family Member Or Friend

Recognize early symptoms.  You may be able to prevent a serious episode of the illness before it happens. Symptoms of mania and depression often have warning signs. The beginnings of mania typically feel good and that means your family member may not want to seek help. Identify signals such as lack of sleep and speaking quickly that signal impending mania. A deep depression often only begins with a low mood, feeling fatigued or having trouble sleeping.

Communicate.  Not everyone enjoys confronting problems head on, but doing so is critical to healthy communication. Make time to talk about problems. But know that not just any time is right. For example, if your family member has bipolar II and becomes angry, it might be safe to try and talk through the situation. But if your friend with bipolar I becomes angry, your reaction may need to be different. It’s more likely that this anger will turn to rage and become dangerous, including physical violence.

React calmly and rationally.  Even in situations where your family member or friend may “go off,” ranting at you or others, it’s important to remain calm. Listen to them and make them feel understood, then try to work toward a positive outcome.

Find out more  about taking care of your family member or friend and yourself.

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0965 Investigating Cardiac Autonomic Activity During Sleep in Individuals with Major Depression and Bipolar Disorder

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Chloe Leveille, Mysa Saad, Daniel Brabant, David Birnie, Elliott Lee, Alan Douglass, Georg Northoff, Katerina Nikolitch, Julie Carrier, Stuart Fogel, Caitlin Higginson, Tetyana Kendzerska, Rebecca Robillard, 0965 Investigating Cardiac Autonomic Activity During Sleep in Individuals with Major Depression and Bipolar Disorder, Sleep , Volume 47, Issue Supplement_1, May 2024, Page A414, https://doi.org/10.1093/sleep/zsae067.0965

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Autonomic nervous system dysfunction and reduced heart rate variability (HRV) have been reported in individuals with mood disorders, a phenomenon likely to be influenced by sleep disturbances. Several studies have previously assessed HRV in individuals with major depression or bipolar disorder across the entire sleep period. This study investigated whether distinct heart rate (HR) and HRV profiles across wake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep are linked to unipolar versus bipolar mood disorders in individuals with sleep complaints.

Polysomnographic data was retrospectively collated for 120 adult patients with sleep complaints and depressive symptoms referred to a specialized sleep clinic for sleep assessment [60 diagnosed with bipolar disorder (70% female, mean age= 43.4±11.6 years) and 60 age-matched cases diagnosed with a unipolar depressive disorder (68.3% female, mean age= 43.2±11.6 years)], and 60 age-matched healthy controls (68.3% female, mean age= 43.4±12.6 years). HR and time-based HRV parameters were computed on 30-second segments and averaged across the night for wake and sleep stages.

Significant group by sleep stage interactions showed that the unipolar and bipolar groups had lower standard deviation of normal-to-normal intervals (SDNN) and vagal tone root mean square of successive R-R interval differences (RMSSD) compared to controls during NREM sleep ( p≤.001) and REM sleep (p≤.003), but not during wake (p>.050). The unipolar group had significantly higher heart rate than controls regardless of sleep stages (all, p≤ .042), while the bipolar group had higher heart rate than controls only during NREM 2 (p=.012) and NREM 3 (p=.009) sleep. These interactions persisted after excluding individuals taking antipsychotic, lithium, anticonvulsant, and cardiovascular medications.

While additional research is required to account for manic and euthymic states, as well as the impact of psychotropic and cardiac medications, and potential confounders like variations in body mass index, the present findings suggest that the sleep-based autonomic signature of depressive states differs across different types of mood disorders and could potentially inform the development of biomarkers and therapeutic targets.

This project was supported by the Ottawa Region for Advanced Cardiovascular Research Excellence (ORACLE) funding program.

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The Emerging Neurobiology of Bipolar Disorder

Paul j. harrison.

1 Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK

2 Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, OX3 7JX, UK

John R. Geddes

Elizabeth m. tunbridge.

Bipolar disorder (BD) is a leading cause of global disability. Its biological basis is unknown, and its treatment unsatisfactory. Here, we review two recent areas of progress. First, the discovery of risk genes and their implications, with a focus on voltage-gated calcium channels as part of the disease process and as a drug target. Second, facilitated by new technologies, it is increasingly apparent that the bipolar phenotype is more complex and nuanced than simply one of recurring manic and depressive episodes. One such feature is persistent mood instability, and efforts are underway to understand its mechanisms and its therapeutic potential. BD illustrates how psychiatry is being transformed by contemporary neuroscience, genomics, and digital approaches.

BD is highly heritable and mostly attributable to common variants of small effect. Several risk genes and gene networks have been identified.

Calcium signalling is prominent among the genetic risk pathways, and currently appears to have the greatest therapeutic traction.

Digital technologies and sophisticated mathematical and computational analyses are being used to quantify and understand BD.

These new methods reflect, and are promoting, reconceptualisation of BD as a chronic instability of mood and neural circuitry.

Stem cells are becoming an integral part of the approaches to understanding BD and its pharmacotherapy.

New experimental medicine models are being applied to identify and rapidly test potential mood-stabilising treatments.

Bipolar Disorder and the New Psychiatry

Psychiatry still relies largely on 19th-Century diagnostic categories. These are based on clusters of symptoms rather than biological markers, and are treated with drugs discovered serendipitously several decades ago. BD typifies this unsatisfactory state of affairs. Although its name has changed [it was formerly known as manic depression (see Glossary )], its cardinal features, and how it is assessed and treated ( Box 1 ) have barely altered. An important reason for this stagnation has been the lack of any real traction on its causes and underlying biology, beyond its well-established high heritability [1] . Although there is evidence for altered structural and functional brain connectivity 2 , 3 , 4 , and changes in markers of oxidative stress [5] , mitochondrial function [6] , inflammation [7] , circadian rhythms [8] , and dopamine [9] , it remains difficult to integrate these diverse findings, and to disentangle causative changes from those that are secondary to the disorder and its treatment.

Bipolar Disorder: A Clinical Primer

The classic picture of BD is like a modified sine wave, with mood fluctuating between episodes of mood elevation (mania) and depression, interspersed with periods of euthymia. The number of episodes in each mood phase, and their duration, varies markedly between individuals, but for most patients the depressive episodes are more prolonged and are responsible for much of the morbidity of the disorder.

The depressive episodes of BD are broadly similar in nature and severity to those of ‘ordinary’ depression. A manic episode includes not only significant elevation of mood, but also related changes in behaviour, such as a reduced need for sleep, increased energy, grandiose thoughts and beliefs, rapid speech, increased libido, and reckless behaviour (e.g., spending excessively). In severe episodes, psychotic symptoms (delusions and hallucinations) may also be present; for example, the person may believe, or hear voices telling them, that they have superpowers (and they may then act accordingly). ‘Hypomania’ refers to a milder and less prolonged form of mania. The exact criteria depend upon the classificatory system used ( ICD-10 or DSM-5 ); the latter subdivides BD into bipolar I and bipolar II. Although not part of the diagnostic criteria, cognitive impairment is a notable aspect of BD; it is present at first episode and persists during euthymia. Attention, processing speed, and verbal learning and fluency are the domains most affected. At least half of patients with BD also have an anxiety disorder or substance use disorder. Patients are typically diagnosed during their 20s, following a long prodrome, and actual onset is often in adolescence. The lifetime prevalence of BD is approximately 1%, rising to 4% if a broader definition of bipolar spectrum disorder is used. The major risk factors are genetic (see the main text), but environmental factors, including childhood adversity, also have a role. Of patients with BD, 10% die by suicide and this, coupled with an excess mortality from natural causes, shortens average life expectancy by approximately 15 years.

The mainstay of BD treatment is pharmacological, with lithium salts or the antiepileptic drug sodium valproate used for prophylaxis. Antipsychotics, antidepressants, and antiepileptic drugs are given to treat the mood episodes. Psychoeducation and psychological treatments also have an important supporting role. All current treatments have limited efficacy, and the drugs can have serious adverse effects.

For an introduction to clinical aspects of BD, see 10 , 95 .

Alt-text: Box 1

The situation is belatedly improving. While optimism must be tempered by appreciation of the many complexities, there are realistic prospects for a transformation in our understanding of BD and how it is diagnosed and treated. Here, we highlight two areas of current interest: the discovery of the first BD risk genes and their implications, and the application of novel technologies with the potential to refine, or redefine, the BD phenotype. These developments exemplify how genomics, neuroscience, and digital technologies are heralding a new era for psychiatry. For broader reviews of BD, see 10 , 11 .

The Genomics of Bipolar Disorder

A child of an affected parent has about a tenfold increased risk of developing BD, and twin studies estimate a heritability of 0.7–0.8 [1] . There is no evidence for Mendelian inheritance or for genes of major effect. Instead, as with most psychiatric disorders, there are multiple susceptibility loci, each of small effect, which genome-wide association studies (GWAS) are beginning to identify. Several GWAS, and meta-analyses thereof, have been carried out since 2007; Table 1 lists the loci and implicated genes that have emerged to date. The combined sample sizes remain small by GWAS standards, and more loci remain to be identified; indeed, the forthcoming Psychiatric Genomics Consortium analysis, comprising over 20 000 BD cases and 30 000 controls, identifies 19 significant loci, including 12 novel ones. Initial exome and genome sequencing data suggest that rare deleterious variants also have a role in some BD cases, but their identity and overall contribution to the disorder remain unclear 12 , 13 , 14 . Within BD, there is modest clinicogenetic heterogeneity, for example, based on the predominant symptoms, or between bipolar I and bipolar II subtypes [15] . However, there is little evidence for BD-specific genes; joint GWAS analyses show substantial commonalities in risk loci for BD and schizophrenia [16] , as well as significant overlap with other major psychiatric disorders [17] and with intermediate phenotypes, including circadian traits 18 , 19 . One distinction between schizophrenia and BD is that copy number variation is much less prominent in the latter [20] .

GWAS Hits for BD a

Although the genomics of BD are in their infancy, efforts have begun to understand the biological basis for the associations identified to date. Interest has centred on two genes ( CACNA1C and ANK3 ) because of what was already known of their functions. CACNA1C is discussed in detail below. ANK3 encodes ankyrin G, which couples axonal voltage-gated sodium channels to the cytoskeleton and also has roles in dendrites and glia; another risk gene, TRANK1 , contains multiple ankyrin repeat domains, suggesting some shared functions. Complementing the focus on specific risk genes, the first attempts have been made to identify the pathways that they influence. Using data from four of the GWAS, Nurnberger et al. [21] reported six pathways that showed replicable association with BD, involving glutamate and calcium signalling, second messengers, and hormones. Together, these findings support the possibility that BD is, at least in part, an ion channelopathy [22] , in which aberrant calcium signalling is important [23] .

Calcium Signalling in Bipolar Disorder: Linking Genetics, Pathophysiology, and Therapeutics

Calcium dysregulation has long been implicated in BD, based primarily on ex vivo studies in cells taken from patients and controls. The findings are disparate, but on balance indicate that measures of intracellular calcium signalling are increased in BD, especially after stimulation (reviewed in 23 , 24 ). The abnormalities appear largely independent of current mood state (i.e., they are trait rather than state related). Moreover, they are attenuated by lithium, which is used in the treatment of the disorder ( Box 1 ). Despite the many uncertainties, these findings led to L-type voltage-gated calcium channel (VGCC) antagonists, with existing indications in angina and hypertension, being evaluated for the treatment of BD [25] . Antiepileptic drugs, such as pregabalin, which act via VGCC α 2 δ subunits ( Box 2 ) have also been tested [26] , and lamotrigine, another antiepileptic drug that may block calcium channels, among its various actions [27] , is an effective treatment for bipolar depression [28] .

VGCC Genes, Their Isoforms, and Relevance in Bipolar Disorder

Identifying the specific VGCCs most relevant for BD is a significant challenge, because their genes give rise to a vast diversity of functional channels (named Ca v channels) 96 , 97 . VGCCs comprise multiple subunits, each encoded by one of a subfamily of separate genes. The properties of the ten distinct α1 subunits (encoded by the CACNA1 - gene family) depend on the accessory subunits to which it is bound ( Figure I ). The main accessory subunits are the β (encoded by CACNB1 – 4 ) and α 2 δ (encoded by CACNA2D1 – 4 ) subunits, which are obligate in most cases [98] . Current VGCC antagonists block the L-type channels; the anticonvulsant/analgesic drugs pregabalin and gabapentin are α 2 δ ligands [30] .

The Voltage-Gated Calcium Channel (VGCC) Family of Proteins. (A) Structure of VGCCs, showing the transmembrane topology of the α1 subunit, its long intracellular C terminus and interactions with accessory (β and α 2 δ) subunits. (B) Dendrogram and nomenclature of the VGCC family.

Further channel diversity arises because each gene gives rise to multiple isoforms. The human CACNA1C mRNA has at least 50 exons and over 40 predicted isoforms (arising from transcriptional and splicing mechanisms). CACNA1C splicing gives rise to channel isoforms that are differentially expressed in brain compared with heart, and which differ in their biophysical properties, including voltage-gating characteristics [97] . Another feature affected by splicing is the isoform sensitivity to existing VGCC antagonists [98] . This suggests that it might be possible to selectively target splice variants that mediate disease risk and/or are preferentially expressed in the brain, compared with peripheral tissues (particularly the cardiovascular system, where VGCCs are also abundant), thereby maximising their therapeutic potential and tolerability in BD [25] .

Given these considerations, defining the repertoire of VGCCs present in different human tissues is important, as is identifying which ones are impacted by the BD-associated risk variants or by BD itself. However, information on the transcript diversity of human VGCC subunits is sparse, particularly in brain. Furthermore, because VGCC subunit genes are large (full-length CACNA1C mRNA, for instance, is over 10 kb long), the transcript structure of most isoforms remains unclear. Characterising the profile of full-length VGCCs isoforms in the human brain, compared with other tissues, and assessing which are altered in association with genetic risk for BD, are critical first steps in translating the VGCC genomic findings into pathophysiological insights and novel treatment targets. The availability of large, high-quality human postmortem brain series and technological advances in the field of RNA sequencing make this goal achievable.

Alt-text: Box 2

The results of the recent genomic studies strongly suggest that the involvement of calcium signalling in BD is at least partly causal [29] , and have rekindled attempts to explain more precisely the nature of the alterations, not least because this may provide clues to more-effective and tolerable drug strategies to normalise them [30] . However, the discovery of genetic variants is only the first step, and provides many more questions than answers. Calcium signalling offers an informative exemplar to highlight the opportunities and complexities associated with moving from psychiatric genomic discoveries to pathophysiological insights and therapeutic advances 31 , 32 .

Genomic data provide a starting point to identify the molecules involved in the core ‘calcium pathophysiology’ of BD. They focus attention on the VGCCs, especially of the L-type, and their accessory subunits (encoded by the CACNx genes; Box 2 ). As indicated above, the best evidence is for CACNA1C (encoding the α1 subunit of Ca v 1.2), but pathway analysis also suggests a role for CACNA1D and CACNB3 29 , 33 , and other VGCC genes are implicated in BD by rare variant studies [13] . Of note, apart from BD, CACNA1C is associated with schizophrenia [34] and major depression [35] , and CACNB2 confers susceptibility to multiple psychiatric disorders [17] . Involvement of VGCC genes has also been reported in large-scale genomic studies of BD-relevant phenotypes, such as working memory performance and the associated patterns of brain activation [36] , as well as in general cognitive functioning [37] . There are also smaller candidate gene studies that suggest effects of CACNA1C genetic variation on brain imaging phenotypes 38 , 39 and on cognitive domains, such as reward responsiveness [40] .

Identification of the molecular basis for disease associations is a key step in understanding the mechanisms linking VGCC genes with BD. The VGCC loci revealed by GWAS are noncoding, and while large-scale exome studies may identify rare variants that disrupt the coding sequence of VGCCs, it is unlikely that the BD-associated GWAS loci tag as-yet-unidentified, disease-causing mutations. Instead, they probably act by influencing aspects of gene expression, including methylation [41] , alternative promoter usage, and RNA splicing [42] . In the case of CACNA1C , the index risk polymorphism for BD (rs1006737) is located in the third intron. On balance, the available data indicate that the risk allele is associated with enhanced expression and activity of the gene product 43 , 44 , but there are conflicting findings 45 , 46 , precluding firm conclusions. Some of the variability in these results may be due to differences in the effect of rs1006737 on CACNA1C expression between brain regions. Inconsistencies may also result from the risk single nucleotide polymorphism (SNP) differentially altering the abundance of particular splice variants, as has been observed for other BD-relevant genes, including ANK3 [47] and ZNF804A [48] . In the case of ANK3 , there is evidence that the shift in isoform ratios has functional consequences for neuronal physiology [49] . Efforts to identify and understand whether altered splicing is also relevant for CACNA1C and other VGCCs are hampered by the limited information about their isoform profile in the human brain ( Box 2 ). This information is critical since splicing patterns are poorly conserved and the brain shows one of the greatest diversities of alternative splicing [50] , meaning that the current data, which pertain to other species and tissues, are insufficient.

While the identification of specific VGCC subunits and isoforms that mediate BD risk is important, better understanding of the underlying biology is also crucial. This requires the use of appropriate cellular and animal model systems, as well as in vivo approaches in humans. For cellular analyses, in addition to standard cell lines, which are useful for studying the function of individual genes, induced pluripotent stem cells (iPSCs) may prove valuable. Indeed, iPSC-derived neurons have already provided intriguing data to support the presence of cellular BD-related phenotypes, including alterations in calcium signalling ( Box 3 ).

Stem Cells and the Calcium Pathophysiology of Bipolar Disorder

The potential of iPSCs for studying cellular phenotypes of psychiatric disorders such as BD is considerable, and the approach has already been exploited in several studies. These have been of three designs: comparison of BD with healthy patients; contrasting lithium-responsive versus lithium-unresponsive BD cases; or evaluating the effect of BD risk genotypes (reviewed in [99] ).

Mertens et al . [100] generated dentate gyrus-like neurons and showed that cells from patients with BD were hyperexcitable, with differences in several electrophysiological and transcriptional parameters; moreover, the excitability was normalised by lithium, but only in cells derived from patients who had responded clinically to the drug. Notably, these findings were largely replicated in a separate cohort and using a different methodology [101] . Taking a genetic strategy, Yoshimizu et al. [44] made induced neurons from 24 people, genotyped for the CACNA1C rs1006737 polymorphism, and showed that CACNA1C gene expression and calcium current density were greater in risk allele homozygotes compared with nonrisk carriers.

3D differentiation approaches are now being used to produce ‘brain spheroids’. Although no studies of this kind have yet been reported using iPSCs from patients with BD, Birey et al. [102] reported that, intriguingly, spheroids made with iPSCs from patients with Timothy syndrome (caused by a gain-of-function coding CACNA1C mutation) exhibited interneuron migratory abnormalities that could be normalised by a VGCC antagonist. The finding draws attention to a possible role for early developmental events and specific interneuron populations in mediating the role of calcium signalling in the pathogenesis of BD. Studies using spheroids in BD may be valuable in helping identify circuit-level phenotypes, while CRISPR techniques to selectively manipulate disease-relevant VGCC isoforms and variants could aid the identification of the key molecular mechanisms.

These findings, and others (e.g., [103] ), illustrate how iPSCs are providing new clues regarding the neuronal phenotypes of BD, and support an involvement of calcium signalling in these processes. The results encourage further efforts to extend and scale up the work [104] .

Alt-text: Box 3

The molecular findings can also help guide the development of rodent models overexpressing or lacking specific VGCC genes 51 , 52 , 53 or splice variants thereof [54] , in which their functional impact can be studied in the intact animal. For example, embryonic deletion of Cacna1c from forebrain glutamatergic neurons in mice produced BD-relevant behavioural and cognitive effects and an increased susceptibility to stress, whereas the same deletion during adulthood caused a lesser and, in some instances, opposite phenotype [51] . This effect of developmental stage on the phenotype is intriguing, given the characteristic early adulthood age of BD onset, and its childhood antecedents ( Box 1 ). In a separate study, the phenotype of Cacna1c-deficient mice could be rescued using a small-molecule inhibitor of the translation initiation factor eIF2α [52] , giving clues as to the possible intervening biochemical mechanisms.

In parallel with these various genetically driven approaches, pharmacological investigations of VGCCs in humans are possible because of the existing L-type VGCC antagonists, which can be used as experimental tools and for proof-of-principle studies. Their availability is a distinct advantage compared with most other genetically supported therapeutic targets in BD, for which no such drugs are available. To date, the clinical trial data linking L-type VGCC blockade with therapeutic outcome in BD (and, indeed, their psychiatric effects more generally) are wholly inconclusive [25] . Hence, a priority is to investigate in detail the impact of brain-penetrant VGCC blockers on BD-relevant phenotypes, including detailed measures of mood, cognition, sleep, and brain activity [55] , and with the incorporation of genotype as a factor [56] . The potential psychiatric effects of VGCC antagonists can also be assessed using routinely collected clinical data; for example, a study of electronic medical records in Scotland reported higher hospital admission rates for depression in patients given VGCCs compared with those prescribed other antihypertensives [57] .

In summary, a range of methods are needed to make the most of the genomic discoveries in BD, to understand their molecular mechanisms and implications for cellular and systems functioning, and to evaluate their therapeutic potential. The conceptual approach is illustrated in Figure 1 (Key Figure), which uses VGCCs as the exemplar.

Key Figure: Genomics, Neuroscience, and Treatment Innovation in Bipolar Disorder (BD)

The study of voltage-gated calcium channels (VGCCs) in BD exemplifies the potential and the challenges of translating genomic discoveries into pathophysiology and therapeutics. Although sometimes portrayed as a one-way, bottom-up, process from genes to treatments, the wheel-like figure emphasises that it is iterative. Underpinning this approach is the increasing wealth of ‘big data’, since it is the scale of both the genomics and the contemporary digital approaches to phenotyping that have driven the developments discussed in this review. Looking ahead, an integrative, collaborative approach will be essential to link the power of big data with the more-focussed, hypothesis-driven studies that are required for most of the intervening segments.

New Approaches to the Bipolar Phenotype

Digital psychiatry.

Complementing the developments from genomics-driven discovery science, novel methods are being applied to characterise the BD phenotype, and thereby provide new perspectives on its key elements.

Conventional psychiatric assessments rely on cross-sectional, retrospective analysis of the pattern of symptoms over weeks or months. Being based on a patient’s or informant’s recall, this approach is subject to inherent biases and unreliability, especially when, as in BD, the key feature is not simply a symptom (mood), but its profile of variation over time. Several approaches have been used to try to improve the reliability and validity of BD assessments 58 , 59 . The main advances are emerging from developments in information technology, including the increasingly widespread use of connected and wearable devices: we are entering an era of ‘digital phenotyping’ in psychiatry [60] , with BD, we would argue, at the forefront [61] . One early example is the True Colours platform, which allows patients to submit (by text, email, web, or app) their ratings of depression, mania, and other symptoms, in response to a weekly or daily prompt, resulting in a longitudinal and graphical representation of symptom course [62] .

Importantly, smartphones and other devices allow the remote capture of not only contemporaneous self-reporting of symptoms, but also behavioural, cognitive and physiological measures, such as heart rate, activity, geolocation, speech, and environmental interactions 63 , 64 , 65 , 66 , 67 , 68 . In turn, digital methods can facilitate a change from entirely symptom-based characterisation of psychiatric disorders, such as BD, towards a more multimodal, biologically informed one. Thus, they raise the prospect of more-objective, data-driven diagnoses, and ultimately personalised predictions of illness and treatment response. However, this promise has yet to be realised; the initial hype about digital phenotyping, including its application to BD, has been tempered by increasing awareness of the significant technical, analytical, and other issues involved ( Box 4 ).

Digital and Mathematical Approaches to Bipolar Disorder

Collection of multidimensional data, as in the remote monitoring of symptoms, behaviours, and physiology, has considerable potential in the study and treatment of BD and other disorders, but also throws up several significant challenges 105 , 106 .

First, there are many technical and practical issues to overcome, ranging from ensuring the compatibility of data collection between operating systems and software versions, to maintaining compliance over long time periods. There are also privacy, acceptability, and engagement issues raised by the recording and storage of personal data [107] .

Second, the resulting data sets are large and complex, and the extraction, analysis, and interpretation of information are not straightforward [108] . One key question to consider is the mathematical approach chosen for analysing the data. Options include linear and nonlinear time series methods 109 , 110 , 111 as well as more-flexible and advanced techniques, such as relaxation oscillator frameworks [112] and machine-learning methods [90] . Another mathematical technique of interest is rough paths theory [113] . By taking account of lead-lag relationships, rough paths can reduce time-stamped data sets from complex interacting nonlinear systems to their critical information content or ‘signature’. This transformation provides a structured sequence of low-dimensional summaries of the primary data that completely characterise their complexity but are amenable to linear analysis. This greatly facilitates efforts to use the data for classification and prediction. For example, a rough path signature, based on daily measures of mood instability, can differentiate BD from borderline personality disorder [114] .

Progress in this developing field will need to be interdisciplinary, combining advanced mathematical analyses with digital phenotyping technologies that produce robust data and that are sufficiently acceptable, and rewarding, to patients to secure their long-term engagement 115 , 116 .

Alt-text: Box 4

Persistent Mood Instability

Notwithstanding the many challenges, the longitudinal, long-term collection of data using digital approaches has already contributed to a renewed focus on the ‘real-world’ phenotype of BD. One example is the appreciation that many patients have chronic mood instability (also called affective lability), persisting during euthymia . This contrasts with the simplistic textbook description of BD as comprising periods of normal, stable mood in between the episodes of depression and mania ( Box 1 ). Although this reality was already appreciated by experienced clinicians 69 , 70 , it is the use of digital methods that has led to a greater awareness of mood instability, which in turn has encouraged research to understand its origins and significance. Here, we briefly review some of these implications.

Mood (in)stability is a continuous variable, and is present to varying extents in healthy individuals 71 , 72 . Therefore, it is a useful phenotype for studies seeking to identify mechanisms underlying mood (dys)regulation per se , and a range of experimental approaches are being taken. For example, it can be viewed from a computational perspective, with models showing how mood instability interacts with reward sensitivity to alter performance [73] . One can also ask how mood instability relates to variation in neural activity across a range of temporal resolutions, using functional MRI [74] and magnetoencephalography [75] . In addition, mathematical analyses, such as those outlined in Box 4 , can help explain the relationships between fluctuations in mood and other parameters, ranging from environmental exposures to behavioural variables 66 , 67 .

Mood instability is prominent not only in BD, but also in several other psychiatric disorders, such as attention deficit disorder, borderline personality disorder, and schizophrenia 76 , 77 . It is therefore a trans-diagnostic construct, compatible with the NIMH Research Domain Criteria project [78] . Thus, understanding the origins and mechanisms of mood instability, and the biological and behavioural sequelae of interventions which modify it – is therefore likely to have value beyond BD. Indeed, mood instability is a moderately heritable trait in the general population, and the first genome-wide significant loci have been reported [79] . Apart from studying the implicated molecules and pathways in their own right, it will be of interest to investigate the extent to which the risk loci for mood instability overlap with those for BD specifically, and other disorders involving mood instability. Moreover, the specific characteristics of mood instability (e.g., its frequency, amplitude, or impact on behaviour), while partially overlapping, may differ sufficiently between disorders [80] to help gain traction on the underlying neural mechanisms, providing further clues to the biological bases of these illnesses and leading to refinements in classification.

Finally, mood instability has potential immediate value as a therapeutic target. First, it may provide a way to screen novel treatments for BD more rapidly and cost-effectively than conventional clinical trials, in which treatment or prevention of depressive or manic episodes are the usual outcomes, requiring prolonged periods of observation. In this sense, early mood stabilisation could prove to predict therapeutic efficacy in the way that rapid effects on emotional processing predict subsequent therapeutic response in unipolar depression [81] . Moreover, the rapid effects of antidepressants on emotional processing are seen in euthymic subjects as well as in those with depression; similarly, new treatments for BD, such as novel VGCC-acting drugs, could be screened in patients who have unstable mood but who do not have a formal diagnosis. Second, stabilisation of mood may be beneficial in its own right, above and beyond simply preventing clinical episodes of depression and mania, because mood instability independently predicts poor functional recovery in BD, and worse outcomes of various kinds 76 , 82 , 83 , 84 . In addition, since mood instability often occurs before the onset of BD 85 , 86 , such treatments might have a preventative role.

In summary, the emergence of persistent mood instability as a construct illustrates how digital methods can highlight neglected or hard-to-characterise psychiatric phenomena, and stimulate a range of studies into their origins, mechanisms, and therapeutic implications. Comparable approaches are being taken to other components of BD, such as circadian dysregulation and reward sensitivity. Although the work is at an early stage, it is likely ultimately to alter the view of the core phenotype of BD, with a greater role for biological and quantitative data in BD diagnosis, prognosis, and management.

Concluding Remarks

Our understanding of BD remains frustratingly limited. It continues to be a descriptive syndrome, since we lack sufficient knowledge to allow its characterisation or conceptualisation based on aetiology or mechanism. Certainly, many questions remain (see Outstanding Questions). However, there are reasons for optimism. First, the discovery of some of the BD risk genes has the potential to revolutionise our understanding of its pathogenesis and neurobiology. Second, the use of digital technologies and remote sensors, coupled with advanced analyses of the resulting data, is already allowing a more-quantitative, longitudinal approach to the BD phenotype. This raises the potential for better prediction of an individual’s clinical course, and also provides a more-sophisticated phenotype for behavioural and biological studies. In both of these domains, a common feature is the increasing importance of ‘big data’, whether in terms of the genomic studies, or the multidimensional data streams captured by digital devices. Third, although not discussed here, structural and functional brain imaging is helping to identify the key neural circuits of BD and may also have diagnostic and prognostic value 2 , 3 , 4 , 87 , 88 , 89 , 90 .

The ultimate goal of these contemporary approaches is to allow a more scientifically informed, evidence-based approach to how BD is classified, measured, and treated [91] . Possible changes include redrawing or removing the diagnostic boundaries between BD and other disorders involving lability of mood, emotion, and behaviour; the inclusion of behavioural and physiological correlates of mood and mood instability (or other symptoms) into clinical practice; a focus on identifying interventions that can stabilise mood independent of the underlying diagnosis; and new, genetically informed treatments, such as those targeting VGCCs.

It is not always appreciated that BD causes a global health burden comparable with that of schizophrenia [92] , yet it has attracted considerably less research funding and interest from policy makers [93] . We would argue that, for various reasons, BD currently has a greater potential for transformative advances. More generally, BD is a useful case study for illustrating how psychiatric disorders are belatedly embarking on the journey from being descriptive syndromes towards more neurobiologically grounded, quantitative, and digital phenotypes [94] . Despite the many difficulties this process entails, it is not unreasonable to hope that it will be successful, and accompanied by the development of more rational, effective, and personalised treatments.

Outstanding Questions

What is the overall genetic architecture of BD? What are the main pathways impacted by the genes?

How will genetics alter the diagnosis of BD and its relationship to other disorders?

What are the causes and mechanisms of altered calcium signalling in BD?

What is the core neurobiology of BD, at systems and cellular levels?

Will genetic findings and novel phenotyping lead to improved therapies for BD?

Acknowledgments

J.R.G. is a National Institute of Health Research (NIHR) Senior Investigator. E.M.T. is a Royal Society University Research Fellow. Research supported by Wellcome Trust strategic awards102616 and 09846, Medical Research Council grant P026028/1, and by the Oxford Health NIHR Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR or the Department of Health. We thank Kia Nobre for the idea for Figure 1 and Ruth Abrahams and Noel Buckley for supplying images. We apologise to the many authors whose studies could not be cited due to reference restrictions.