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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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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Bipolar disorder.

Ankit Jain ; Paroma Mitra .

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Last Update: February 20, 2023 .

• Continuing Education Activity

Bipolar disorder, also known as bipolar affective disorder, is one of the top 10 leading causes of disability worldwide. Bipolar disorder is characterized by chronically occurring episodes of mania or hypomania alternating with depression and is often misdiagnosed initially. Treatment involves pharmacotherapy and psychosocial interventions, but mood relapse and incomplete response occur, particularly with depression. Continual reevaluation and treatment modification are commonly required during the long-term care of patients with bipolar disorder. Management of comorbid psychiatric and chronic medical conditions may also be necessary. This activity reviews the etiology, classification, evaluation, management, and prognosis of bipolar affective disorder, and it also highlights the role of the interprofessional team in managing and improving care for patients with this condition.

• Recognize patterns of symptoms suggestive of bipolar disorder, its various subtypes, and related disorders.
• Implement evidence-based management of bipolar disorder based on current published guidelines.
• Select individualized pharmacotherapy plans and adjunct therapies for bipolar disorder and comorbidities.
• Describe the necessity of an interprofessional holistic team approach that integrates psychiatric and medical healthcare in caring for patients with bipolar disorder to help achieve the best possible outcomes.
• Introduction

Bipolar disorder (BD) is characterized by chronically occurring episodes of mania or hypomania alternating with depression and is often misdiagnosed initially.

Bipolar and related disorders include bipolar I disorder (BD-I), bipolar II disorder (BD-II), cyclothymic disorder, other specified bipolar and related disorders, and bipolar or related disorders, unspecified. The diagnostic label of "bipolar affective disorders" in the International Classification of Diseases 10th Revision (ICD-10) was changed to "bipolar disorders" in the ICD-11. The section on bipolar disorders in the ICD-11 is labeled "bipolar and related disorders," which is consistent with the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). [1]

A World Health Organization study showed "remarkably similar" international prevalence rates, severity, impact, and comorbidities of bipolar spectrum disorder, defined as BD-I, BD-II, and subthreshold bipolar. The aggregate lifetime prevalence of the bipolar spectrum was 2.4%. [2]

BD is often difficult to recognize because symptoms overlap with other psychiatric disorders, psychiatric and somatic comorbidity is common, and patients may lack insight into their conditions, particularly hypomania. Treatment involves pharmacotherapy and psychosocial interventions, but mood relapse and incomplete response occur, particularly with depression. Continual reevaluation and treatment modification are commonly required during the long-term care of these patients. Management of comorbid psychiatric and chronic medical conditions may also be necessary. This activity provides an overview of the etiology, classification, evaluation, and management of bipolar affective disorder.

Currently, the etiology of BD is unknown but appears to be due to an interaction of genetic, epigenetic, neurochemical, and environmental factors. Heritability is well established. [3] [4] [5]  Numerous genetic loci have been implicated as increasing the risk of BD; the first was noted in 1987 with "DNA markers" on the short arm of chromosome 11. Since then, an association has been made between at least 30 genes and an increased risk of the condition. [6]

Although it is difficult to establish causation between life events and the development of BD, childhood maltreatment, particularly emotional abuse or neglect, has been linked to the later development of the condition. Other stressful life events associated with developing BD include childbirth, divorce, unemployment, disability, and early parental loss. [7] In adulthood, more than 60% of patients with BD report at least one "stressful life event" before a manic or depressive episode in the preceding 6 months. [6]

The etiology of BD is thought to involve imbalances in systems associated with monoaminergic neurotransmitters, particularly dopamine and serotonin, and intracellular signaling systems that regulate mood. However, no singular dysfunction of these neurotransmitter systems has been identified. [8]

In a recent neuroimaging review article, the ENIGMA Bipolar Disorder Working Group stated, "Overall, these studies point to a diffuse pattern of brain alterations including smaller subcortical volumes, lower cortical thickness and altered white matter integrity in groups of individuals with bipolar disorder compared to healthy controls." [9]  Neuroimaging studies have also shown evidence of changes in functional connectivity. [10] [11]

• Epidemiology

In the World Mental Health Survey Initiative, the use of mental health services for the bipolar spectrum (BD-I, BD-II, and subthreshold BD) concluded, “Despite cross-site variation in the prevalence rates of bipolar spectrum disorder, the severity, impact, and patterns of comorbidity were remarkably similar internationally.” The aggregate lifetime prevalence of BD-I was 0.6%, BD-II 0.4%, subthreshold BD 1.4%, and bipolar spectrum 2.4%. [2]

There are two peaks in the age of onset: 15-24 years and 45-54 years, with more than 70% of individuals manifesting clinical characteristics of the condition before 25 years of age. [12] [13]  Bipolar disorder shows a relatively equal distribution across sex, ethnicity, and urban compared to rural areas. [7] [14]

Cyclothymia is associated with a lifetime prevalence of approximately 0.4-1% and a male-to-female ratio of 1:1. [15]

• Pathophysiology

As with the etiology, the pathophysiology of BD is unknown and is thought to involve interactions between multiple genetic, neurochemical, and environmental factors. A recent neurobiology review article discusses in detail the “genetic components, signaling pathways, biochemical changes, and neuroimaging findings” in BD. [10]

Evidence supports a strong genetic component and an epigenetic contribution. Human studies have shown changes in brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in patients with BD, indicating neurotrophic signaling is a molecular mechanism associated with decreased neuroplasticity. Other proposed mechanisms include mitochondrial dysfunction, oxidative stress, immune-inflammatory imbalance, and compromised hypothalamic-pituitary-adrenal axis. Additionally, neuroimaging studies have shown “evidence of change in regional activity, functional connectivity, neuronal activity, and bioenergetics associated with BD,” and anatomic studies have revealed dendritic spine loss in the dorsolateral prefrontal cortex in the post-mortem brain tissue of patients with BD. [10] [16]

As mentioned, imbalances in systems associated with monoaminergic neurotransmitters, particularly dopamine and serotonin, and intracellular signaling systems that regulate mood are thought to be involved. However, no singular dysfunction of these neurotransmitter systems has been identified. [8]

• History and Physical

Because bipolar disorder is a clinical diagnosis, making the correct diagnosis requires a comprehensive clinical assessment, including the directed patient interview, preferably supplemented by interviews of their relatives and the longitudinal course of their condition. Currently, there is no biomarker or neuroimaging study to aid in making the diagnosis.

Most patients with bipolar disorder are not correctly diagnosed until approximately 6 to 10 years after first contact with a healthcare provider, despite the presence of clinical characteristics of the condition. [17]  Notably, misdiagnosing BD after first contact differs from not recognizing the transition from major depressive disorder (MDD), the most common index presentation, to BD. Estimates of patients transitioning to BD within three years of an MDD diagnosis range from 20-30%; therefore, clinicians must maintain an awareness of the potential for this transition when caring for patients with MDD who initially screened negative for BD. [18] Also, subthreshold hypomanic symptoms can occur in as many as 40% of patients with MDD. [19]

Although not highly sensitive and specific, self-report screening tools for BD may aid clinicians in making an accurate diagnosis. The most studied screening tools are the Mood Disorders Questionnaire (sensitivity 80%, specificity 70%) and the Hypomania Checklist 32 (sensitivity 82%, specificity 57%). [20]  Positive results should motivate the clinician to conduct a thorough clinical assessment for bipolar disorder.

A significant diagnostic challenge is distinguishing between unipolar and bipolar depression because episodes of unipolar major depression and bipolar depression have the same general diagnostic criteria. Clinicians must inquire about past manic, hypomanic, and depressive episodes in patients presenting with symptoms of a depressive episode. Inquiry into past hypomanic or manic episodes is particularly important for patients with early onset of their first depressive episode (ie, in patients younger than 25 years), a high number of lifetime depressive episodes (5 or more episodes), and a family history of bipolar disorder. These findings in the patient’s history have been shown to increase the likelihood of a bipolar rather than a unipolar diagnosis. [21]  

Other factors increasing the likelihood of a diagnostic change from MDD to BD include the presence of psychosis, unresponsiveness to antidepressants, the induction of manic or hypomanic symptoms by antidepressant drug treatment, and polymorbidity, defined as 3 or more comorbid conditions. [18] [22]

General DSM-5 Diagnostic Criteria for Bipolar and Related Disorders (American Psychiatric Association. Diagnostic and StatisticalManual of Mental Disorders 5th edition (DSM-5). Arlington, VA: American Psychiatric Publishing; 2013)

BD-I : Criteria met for at least one manic episode, which might have been preceded or followed by a hypomanic episode or major depressive episode (hypomanic or major depressive episodes are not required for the diagnosis).

BD-II : Criteria met for at least one current or past hypomanic episode and a major depressive episode; no manic episodes.

Cyclothymic disorder : Hypomanic symptoms that do not meet the criteria for hypomanic episodes and depressive symptoms that do not meet the criteria for major depressive episodes in numerousperiods (at least half the time) for at least 2 years (1 year in those aged ≤18 years); criteria for major depressive, manic, or hypomanic episodes have never been met.

Specified bipolar and related disorders : Bipolar-like phenomena that do not meet the criteria for BD-I, BD-II, or cyclothymic disorder due to insufficient duration or severity, ie, 1) short-duration hypomanic episodes and major depressive disorder, 2) hypomanic episodes with insufficient symptoms and major depressive episode, 3) hypomanic episode without a prior major depressive episode, and 4) short-duration cyclothymia.

Unspecified bipolar and related disorders : Characteristic symptoms of bipolar and related disorders that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning but do not meet the full criteria for any category previously mentioned.

The symptoms and episodes used to diagnose these disorders must not be related to the physiological effects of a substance or general medical condition.

BD-I and BD-II can be further specified as rapid cycling or seasonal patterns and whether the episodes have psychotic features, catatonia, anxious distress, melancholic features, or peripartum onset. Rapid cycling refers to 4 or more distinct mood episodes during a 12-month period. 

Mood-congruent delusions may be present in either a depressive or manic episode, including delusions of guilt or grandiose delusions of power and wealth. Psychotic features, by definition, are absent in hypomanic episodes. 

To better account for "mixed features," the current diagnostic criteria implements specifiers. Manic or hypomanic episodes with mixed features meet the full criteria for mania or hypomania and have at least 3 of the following signs or symptoms: depressed mood, anhedonia, psychomotor retardation, fatigue, excessive guilt, or recurrent thoughts of death. Major depressive episodes with mixed features meet the full criteria for a major depressive episode and have at least 3 of the following signs or symptoms: expansive mood, grandiosity, increased talkativeness, flight of ideas, increased goal-directed activity, indulgence in activities with a high potential for "painful consequences," and decreased need for sleep. The mixed features must be present during "most days."

DSM-5 Diagnostic Criteria for Bipolar I Disorder

For a diagnosis of BD-I, it is necessary to meet the following criteria for a manic episode. The manic episode may have been preceded by and may be followed by hypomanic or major depressive episodes (hypomanic or major depressive episodes are not required for the diagnosis).

A manic episode is defined as a distinct period of persistently elevated or irritable mood with increased activity or energy lasting for at least 7 consecutive days or requiring hospitalization. The presence of 3 or more of the following is required to qualify as a manic episode. If the mood is irritable, at least 4 of the following must be present:

• Inflated self-esteem or grandiosity
• Decreased need for sleep
• A compulsion to keep talking or being more talkative than usual
• Flight of ideas or racing thoughts
• High distractibility
• Increased goal-directed activity (socially, at work or school, or sexually) or psychomotor agitation (non-goal-directed activity)
• Excessive involvement in activities that have a high potential for painful consequences, such as engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments

The episode is not attributable to the physiological effects of a substance or general medical condition.

The symptoms of a manic episode are markedly more severe than those of a hypomanic episode and result in impaired social or occupational functioning or require hospitalization.

DSM-5 Diagnostic Criteria for Bipolar II Disorder

For a diagnosis of BD-II, it is necessary to have met the criteria for at least one current or past hypomanic episode and a major depressive episode without a manic episode (see below for major depressive episode criteria).

A hypomanic episode is defined as a distinct period of persistently elevated or irritable mood with increased activity or energy lasting for at least 4 consecutive days. The presence of 3 or more of the following is required to qualify as a hypomanic episode. If the mood is irritable, at least 4 of the following must be present:

The episode is an unequivocal change in functioning, uncharacteristic of the person and observable by others. Also, the episode is not severe enough to cause marked impairment, is not due to the physiological effects of a substance or general medical condition, and there is no psychosis (if present, this is mania by definition).

DSM-5 Diagnostic Criteria for a Major Depressive Episode

The presence of 5 or more of the following symptoms daily or nearly every day for a consecutive 2-week period that is a change from baseline or previous functioning:

• Subjective report of depressed mood most of the day (or depressed mood observed by others)
• Anhedonia most of the day
• Significant weight loss when not dieting or weight gain or decrease or increase in appetite
• Insomnia or hypersomnia
• Psychomotor agitation or retardation
• Fatigue or loss of energy
• Feelings of worthlessness or excessive or inappropriate guilt
• Decreased concentration or indecisiveness
• Recurrent thoughts of death, recurrent suicidal ideation without a specific plan

To meet the criteria, at least one of the symptoms must be depressed mood or anhedonia, the symptoms must not be attributable to a substance or general medical condition, and it causes functional impairment (eg, social or occupational).

Possible Secondary Cause of Bipolar Disorder

The following characteristics may heighten the clinical suspicion for a possible secondary cause in patients with signs and symptoms associated with bipolar disorder: older than 50 at the first onset of symptoms, abnormal vital signs or neurological examination, a recent change in health status or medications temporally associated with symptom onset, unusual response or unresponsiveness to appropriate treatments, and no personal or family history of a psychiatric disorder.

Recommended initial evaluation for a possible secondary cause includes a urine drug screen, complete blood count with blood smear, comprehensive metabolic panel, thyroid function tests, and vitamin B and folate levels.

• Treatment / Management

Although numerous clinical practice guidelines exist for the treatment and management of bipolar disorder, there is not enough consistency to generate a ‘meta-consensus’ model. [23]  Authors of a recent systematic review concluded, “The absence of a uniform language and recommendations in current guidelines may be an additional complicating factor in the implementation of evidence-based treatments in BD.” [24]  The following is an abbreviated synthesis of guidelines published by the National Institute for Health and Care Excellence (NICE), British Association for Psychopharmacology, International College of Neuro-Psychopharmacology (CINP), Canadian Network for Mood and Anxiety Treatments (CANMAT), International Society for Bipolar Disorders (ISBD), and Indian Psychiatric Society (IPS). [25] [26] [27] [28] [29]

Manic Episode

Mania is considered a medical emergency and often requires psychiatric hospitalization. Initial treatment is aimed at stabilization of the potentially or acutely agitated patient to help de-escalate distress, mitigate potentially dangerous behavior, and facilitate the patient assessment and evaluation. When possible, a calming environment with minimal stimuli should be provided. Adjunctive benzodiazepines may be used concomitantly with mood stabilizers and antipsychotic drugs to reduce agitation and promote sleep.

The patient’s current medications must be considered. For example, a second drug is recommended if the patient presents while the condition is already managed with lithium monotherapy. Also, antidepressants are usually tapered and discontinued in a manic phase. First-line monotherapy includes a mood stabilizer, such as lithium or valproate, or an antipsychotic, such as aripiprazole, asenapine, cariprazine, quetiapine, or risperidone.

Add another medication if symptoms are inadequately controlled, or the mania is very severe. Combination treatments include lithium or valproate with either aripiprazole, asenapine, olanzapine, quetiapine, or risperidone. Electroconvulsive therapy (ECT) may be considered as monotherapy or as part of combination therapy in patients whose mania is particularly severe or treatment-resistant and in women with severe mania who are pregnant. 

Valproate should not be used for women of childbearing potential due to the unacceptable risk to the fetus of teratogenesis and impaired intellectual development.

Hypomanic Episodes

By definition, hypomanic episodes are not severe enough to cause marked impairment, and there is no psychosis; therefore, these episodes can be managed in an ambulatory setting. Pharmacotherapy is similar to that for mania, but higher doses may be required for the latter.

Acute Bipolar Depression

Suicidal and self-harm risk has priority in managing patients with bipolar disorder who present with an acute depressive episode because most suicide deaths in patients with BD occur during this phase. Patients may or may not require hospitalization.

For patients not already taking long-term medication for BD, first-line monotherapy includes quetiapine, olanzapine, or lurasidone (has not been studied in acute bipolar mania). Combination treatment with olanzapine-fluoxetine, lithium plus lamotrigine, and lurasidone plus lithium or valproate may also be considered.

Consider cognitive behavioral therapy (CBT) as an add-on to pharmacotherapy. However, never consider CBT as monotherapy because there is minimal evidence to support psychological treatments without pharmacotherapy in treating acute bipolar depression.

Also, consider adding ECT for refractory bipolar depression or as a first-line treatment in the presence of psychotic features and a high risk of suicide.

For patients presenting with a depressive episode while taking long-term medication (breakthrough episode), make sure their current treatments are likely to protect them from a manic relapse (eg, mood stabilizer or antipsychotic). When applicable, check the medication dose, patient adherence, drug-drug interactions, and serum concentrations. Also, inquire about current stressors, alcohol or substance use, and psychosocial intervention adherence.

Generally, treatment options for BD-II depression are similar to those for BD-I depression.

Antidepressant medications should not be used as monotherapy in most patients with bipolar disorder, as available evidence does not support their efficacy, and there is a risk of a switch to mania or mood instability during an episode of bipolar depression. Antidepressants can be administered adjunctively to mood stabilizers (eg, lithium and lamotrigine) and second-generation antipsychotics.

Maintenance Treatment

Most patients with bipolar disorder will require maintenance treatment for many years, possibly lifelong, to prevent recurrent episodes and restore their pre-illness functioning. The current recommendation is for continuous rather than intermittent treatment, with treatments that were effective during the acute phase often continued initially to prevent early relapse. Mood stabilizers and atypical antipsychotics alone or in combination are the mainstays of maintenance pharmacotherapy.

There is substantial evidence showing lithium monotherapy’s effectiveness against manic, depressive, and mixed relapse. Additionally, lithium is associated with a decreased risk of suicide in patients with BD. Monitoring during treatment, including serum lithium concentrations, is a standard of care.

In addition to the individualized pharmacotherapy plan, essential components of maintenance treatment include medication adherence, primary prevention and treatment for psychiatric and medical comorbidities, and psychotherapy when appropriate. Suicidality surveillance is critical throughout the maintenance phase.

• Differential Diagnosis

The differential diagnosis of bipolar disorder includes other conditions characterized by depression, impulsivity, mood lability, anxiety, cognitive dysfunction, and psychosis. The most common differential diagnoses are MDD, schizophrenia, anxiety disorders, substance use disorders, borderline personality disorder, and in the pediatric age group, attention-deficit/hyperactivity disorder and oppositional defiant disorder. [18] [30]

Bipolar disorder is one of the top 10 leading causes of disability worldwide. [31]  A recent meta-analysis showed that patients with BD “experienced reduced life expectancy relative to the general population, with approximately 13 years of potential life lost.” Additionally, patients with bipolar disorder showed a greater reduction in lifespan relative to the general population than patients with common mental health disorders, including anxiety and depressive disorders, and life expectancy was significantly lower in men with BD than in women with BD. [32]  A different meta-analysis showed that all-cause mortality in patients with BD is double that expected in the general population. Natural deaths occurred over 1.5 times greater in BD, comprised of an “almost double risk of deaths from circulatory illnesses (heart attacks, strokes, etc) and 3 times the risk of deaths from respiratory illness (COPD, asthma, etc).” Unnatural deaths occurred approximately 7 times more often than in the general population, with an increased suicide risk of approximately 14 times and an increased risk of other violent deaths of almost 4 times. Deaths by all causes studied were similarly increased in men and women. [33]  A more recent systematic review of the association between completed suicide and bipolar disorder showed an approximately 20- to 30-fold greater suicide rate in bipolar disorder than in the general population. [34]

• Complications

Individuals with bipolar disorder show a markedly increased risk of premature death due to the increased risk of suicide and medical comorbidities, including cardiovascular, respiratory, and endocrine causes. [35]  More than half of patients are overweight or obese, which appears to be independent of treatment with weight-promoting psychotropic medications. [36]  One-third of patients with bipolar disorder also meet the criteria for metabolic syndrome, which increases the risks of heart disease and stroke. [37]  Additionally, attempted suicides are more common among patients with concurrent metabolic syndrome. [37]  Comorbid overweight and obesity are associated with a more severe course, an increased lifetime number of depressive and manic episodes, poorer response to pharmacotherapy, and heightened suicide risk. [22] [38]  Migraine is also associated with bipolar disorder. [39]

Psychiatric comorbidity is present in 50 to 70% of patients with BD. Of those diagnosed with the condition, 70% to 90% meet the criteria for generalized anxiety disorder, social anxiety disorder, or panic disorder, and 30 to 50% for alcohol and other substance use disorders. [40] [41] [42]  Psychiatric comorbidities in patients with bipolar disorder are associated with a more severe course, more frequent depressive and manic episodes, and reduced quality of life. [22]  Up to half of patients with BD have a comorbid personality disorder, particularly borderline personality disorder, and 10 to 20% have a binge eating disorder, leading to more frequent mood episodes and higher rates of suicidality and alcohol and substance use disorders. [43] [44]

• Deterrence and Patient Education

Psychoeducation delivered individually or in a group setting is recommended for patients and family members and may include teaching to detect and manage prodromes of depression and mania, enhance medication adherence, and improve lifestyle choices. Patients are encouraged to avoid stimulants like caffeine, minimize alcohol consumption, exercise regularly, and practice appropriate sleep hygiene. [28]  Providers are encouraged to maximize the therapeutic alliance, convey empathy, allow patients to participate in treatment decisions, and consistently monitor symptoms, which have been shown to reduce suicidal ideation, improve treatment outcomes, and increase patient satisfaction with care. [28] [45]  Patients may also benefit from case management or care coordination services to help connect them to community-based resources, such as support groups, mental health centers, and substance use treatment programs.

• Enhancing Healthcare Team Outcomes

The goal of treatment for patients with bipolar disorder is a full functional recovery (a return to pre-illness baseline functioning). This goal can best be achieved by integrating psychiatric and medical healthcare using an interprofessional team approach to manage BD and comorbid psychiatric and medical conditions. [46]  Interprofessional healthcare teams may consist of any combination of the following: case manager, primary care clinician, psychiatrist, psychiatric nurse practitioner, psychiatric physician assistant, psychiatric nurse specialist, social worker, psychologist, and pharmacist.

Ideally, a consistent long-term alliance will form between the patient, their family, and healthcare team members to provide pharmacotherapy management, psychoeducation, ongoing monitoring, and psychosocial support. [26]  Also, patients with bipolar disorder and co-occurring alcohol or substance use disorders may benefit from the involvement of an addiction specialist, as there is evidence that effective treatment can improve outcomes. [47]  Pharmacists must perform medication reconciliation to ensure there are no drug-drug interactions that could inhibit effective care and report any concerns they have to the prescriber or their nursing staff. Furthermore, collaborative care models have shown efficacy in improving outcomes when used to treat patients with BD. Key elements include patient psychoeducation, using evidence-based treatment guidelines; collaborative decision-making by patients and their healthcare provider(s); and supportive technology to support monitoring and patient follow-up. [46] [48] [49]

An interprofessional approach is a mainstay in treating patients with bipolar disorder. An interprofessional team that provides a holistic and integrated approach to patient care can help achieve the best possible outcomes with the fewest adverse events. [Level 5]

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Disclosure: Ankit Jain declares no relevant financial relationships with ineligible companies.

Disclosure: Paroma Mitra declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

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Special Report: Bipolar Disorder II—Frequently Neglected, Misdiagnosed

• Trisha Suppes , M.D., Ph.D. ,
• Holly A. Swartz , M.D. ,
• Sara Schley

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Unlike its cousin, bipolar I disorder, which has been extensively studied and depicted in popular literature and on screen, bipolar II disorder is poorly understood, underdiagnosed, and insufficiently treated. This has often resulted in an over 10-year delay in diagnosis.

Even experienced clinicians know surprisingly little about bipolar II disorder (BD II), despite its inclusion as a distinct entity in DSM since 1994. An abundance of studies supports conceptualization of BD II as a unique phenotype within the bipolar illness spectrum, although many fail to recognize it as distinct disorder apart from bipolar I disorder (BD I).

Alternatively, BD II is considered a “lesser form” of BD I, despite numerous studies showing comparable illness severity and risk of suicide in these two BD subtypes. Perhaps because of its under-recognition, treatment studies of BD II are limited, and too often results from studies of patients with BD I are simply applied to those with BD II with no direct evidence supporting this practice. BD II is an understudied and unmet treatment challenge in psychiatry.

In this review, we will provide a broad overview of BD II including differential diagnosis, course of illness, comorbidities, and suicide risk. We will summarize treatment studies specific to BD II, identifying gaps in the literature. This review will reveal similarities between BD I and II, including suicide risk and predominance of depression over the course of illness, but also differences between the phenotypes in treatment response, for example to antidepressants.

We highlight the perspective of an expert by experience who discusses her lived experiences of BD II in an accompanying interview ( Interview With an Expert by Lived Experience ).

Diagnosis History

Alternating states of mania and melancholia are among the earliest described human diseases, first noted by ancient Greek physicians, philosophers, and poets. Hippocrates (460-337 B.C.E.), who formulated the first known classification of mental disorders, systematically described bipolar mood states: melancholia, mania, and paranoia. More than two millennia later, Emil Kraepelin, recognized as one of the founders of modern psychiatry, described manic-depressive illness as a singular disease characterized by alternating cycles of mania or melancholia. However, Kraepelin was more focused on mood changes and cycling than the polarity of episodes per se. Thus, his concept included what we now term recurrent major depressive disorder (MDD) . Nevertheless, his and other formulations from this period provide background for our modern concepts of bipolar disorder, differentiating it from unipolar depression (MDD and related disorders).

The hiding in plain sight of patients with BD II was brought to awareness by David L. Dunner, M.D., in the 1960s. When examining a cohort of individuals with mood disorders in a study by the National Institute of Mental Health (NIMH), he identified a subgroup of patients with recurrent episodes of depression who also had a history of at least one period of hypomania and a strong family history of bipolar disorder. This subgroup was found to have a different course of illness compared with those with recurrent depression and a history of mania (BD I). Thanks to this work, BD II was recognized as a distinct disorder, separate from BD I. It finally entered the DSM lexicon in 1994 in DSM-IV and was added to ICD-10 even more recently.

Conceptualization of bipolar disorders continues to evolve as the field learns more; for example, changes were made to the DSM-5 diagnostic criteria for BD such that Criteria A for both mania and hypomania now include increased energy as well as elevated or irritable mood (see Table 1). Thus, BD II is now recognized as a disorder of energy as well as mood.

DSM focuses on categorial diagnoses—that is, thresholds for absence or presence of disease. In parallel to this framework, many have argued for considering bipolar disorders along a continuous spectrum of illness. Thus, the term bipolar spectrum is used to describe both the spectrum of severity across BD symptoms as well as combinations of mood symptoms with manic/hypomanic and depressive components. Some refer to BD II as a part of the bipolar spectrum. These concepts reflect a growing awareness that dimensional descriptions of mood disorders may better map onto continuous biological markers of disease, compared with DSM ’s categorical approach, but the debate about diagnostic boundaries and disease etiology continues. Importantly, conceptualizations of BD as a spectrum condition versus discrete diagnostic categories (that is, BD I or BD II) are not mutually exclusive but rather speak to ongoing efforts to understand and best describe the phenomenology of BD.

Differential Diagnosis

The validity of BD II as a separate disorder has been reified through multiple empirical studies. The clinical diagnosis is reliably separable from BD I, as seen in APA clinical trials preparing for DSM-5 and in careful clinical interviews. In DSM-5 field trials to assess reliability of diagnoses, BD I was among the most recognizable, but BD II fell in the acceptable range and well above MDD as a reliable diagnostic entity. Family studies also support the diagnosis of BD II as an independent entity with distinct familial heritability, according to a 1976 study by Dunner et al. and a 1990 study by J. Raymond DePaulo, M.D., et al., and the authors of this report. Finally, genetic studies have found correlations suggesting the heterogeneity between BD I and BD II is “nonrandom,” supporting the concept of distinct conditions.

BD II diagnosis requires at least one lifetime hypomanic episode and one major depressive episode. Despite clarity of BD II diagnostic criteria, clinicians struggle to accurately identify it in practice. BD II is often either missed or incorrectly diagnosed, resulting in an over 10-year delay in diagnosis. Difficulties in accurate diagnosis arise from several sources. First, DSM-5 criteria for the depressive phase of BD II are identical to those required for a major depressive episode, which make BD II and MDD cross-sectionally indistinguishable. This is particularly notable as MDD diagnoses make up a substantial percent of the incorrect diagnoses for patients with BD II. Second, hypomania, which by definition is a less severe form of mania, may be difficult for patients to distinguish from a “normal” mood state when accompanied by extra energy and good mood. Third, mixed hypomanic mood states are very common in BD II, and in fact more common than euphoric hypomanic states. Mixed mood states are characterized by the presence of symptoms of opposite polarity during a depressive or hypomanic episode. In a mixed hypomania, patients might believe they are simply irritable and angry in the context of depression rather than recognizing the additional hypomanic symptoms warranting a diagnosis of mixed hypomanic state. Finally, patients rarely present for treatment in the midst of a hypomanic episode, a mood state that is either perceived as ego-syntonic or simply not identified as part of their illness during mixed hypomania.

The primary reason patients with BD II seek care is depression. Depression dominates the course of BD II, both in the early and late stages. However, retrospectively identifying episodes of hypomania during a depressive episode can be challenging. Further, many individuals see hypomania (either the euphoric or mixed variant) as part of “normal” mood rather than part of a bipolar spectrum, contributing to misreporting of mood episodes. Especially after unrelenting episodes of depression, it is understandable that many would perceive hypomania as a return to baseline. However, under-recognition of hypomania contributes to incorrect diagnoses. In sum, many individuals with BD II fail to recall, recognize, or report histories of hypomania, leading to an MDD (mis)diagnosis.

In psychiatry, all diagnoses are a one-way road. Individuals who have ever met criteria for a manic episode will continue to carry the diagnosis of BD I—even without further manic episodes. Similarly, patients who have a distant episode of hypomania and at least one prior major depressive episode would be considered to have BD II disorder, even in the absence of additional hypomanic episodes that meet symptom and duration criteria. Thus, accurate diagnosis of BD II relies on careful history taking. To improve diagnostic acumen, it is essential that clinicians systematically screen all patients with MDD for BD and ask careful questions about prior episodes of hypomania.

Course of Illness and Comorbidity

Kraepelin noted before the medication era that the course of illness for patients with BD generally progresses into more persistent and severe depression with aging. While he was primarily referring to manic-depressive illness, which we would call BD I today, the same principle applies to patients with BD II. In the NIMH collaborative study by Lewis Judd, M.D., et al., which included long-term follow-up of up to 20 years, patients with BD II experienced a course of illness characterized by more depressive episodes and fewer well intervals over time.

There is a longstanding debate in the literature whether patients with BD II suffer the same impairments and risks as those with BD I. BD II was previously—and incorrectly—labeled a “less severe” version of BD I. In fact, studies consistently show comparable disease burden in BD I and II. A recent Swedish study by Alina Karanti, M.D., et al. reported higher rates of depressive episodes, illness onset at a younger age, and significantly higher rates of psychiatric comorbidity (anxiety disorders, eating disorders, and ADHD) among patients with BD II compared with those with BD I. In this Swedish sample, (n>8,700) no differences were noted in substance abuse between BD I and BD II. Interestingly, individuals with BD II generally obtained more education and achieved a higher level of independence than those with BD I.

High rates of psychiatric comorbidity in patients with BD II further compound the challenge of differential diagnosis. There is considerable overlap between BD II and anxiety disorders. Attention-deficit/hyperactivity disorder also frequently co-occurs. Approximately 20% of individuals with BD II also meet criteria for borderline personality disorder (BPD), and up to 40% of those with BPD are incorrectly diagnosed as having BD I or II. Tables 2 and 3 show estimated co-occurring psychiatric illnesses for patients with BD II. The diagnosis of BD II requires a careful clinical interview of both past and current symptomatology.

Suicide is a significant risk for all patients with BD, and historically patients with BD I were viewed as having a higher risk than BD II due to the extremities of mania. However, data from a number of sources support that suicide risk is high across all patients with BD, and relatively little difference is found in risk for patients with BD I versus BD II. Older studies have suggested this risk may be higher for patients with BD II than BD I, and, indeed, the Swedish bipolar registry database study recently indicated that the rate of suicide attempts was significantly higher in patients with BD II though no data on completed suicides were provided. Overall, the reports from the International Society for Bipolar Disorders Task Force on Suicide found that the risk for suicide was estimated at 164 of 100,000 per year in patients with BD versus 10 of 100,000 per year in the general population (see the reference by Ayal Schaffer, M.D., at the end of this report).

Treatment of BD II

Treatment guidelines for bipolar disorder often give only a passing nod to distinguishing appropriate treatments for BD I versus BD II. The combined guidelines by the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) were unusual in making a point of distinguishing the evidence base for BD I versus BD II. They are reported in a 2018 paper by Lakshmi N. Yatham, M.D., et al. (see reference at end of article).

These guidelines have a separate section devoted to BD II, and they clearly state that one cannot directly apply studies on patients with BD I to management of patients with BD II. The conclusion of these guidelines is that there are too few controlled studies in patients with BD II to make detailed evidence-based recommendations or develop evidence-based treatment algorithms. Below is a brief overview of our current knowledge of treatments for patients with BD II with medication and/or psychotherapy.

Antidepressants

It is worth highlighting that, while monotherapy antidepressants would be viewed as an inappropriate practice for patients with BD I depression, studies suggest that the risks and benefits may be different for those with BD I and BD II. In at least one study, risk of switching to hypomania was no greater with lithium than with sertraline monotherapy. Other studies have shown antidepressant monotherapy to be an efficacious monotherapy for BD II. Meta-analyses on risk of antidepressant-induced switches are inconclusive, though the risk of treatment-emergent (hypo)mania due to medication appears to be less in patients with BD II than in patients with BD I depression receiving monotherapy antidepressants. Absent conclusive data on antidepressant switch rates, without a past record of good response to antidepressant monotherapy, current treatment guidelines suggest starting with lithium or a mood stabilizer before adding or switching to antidepressant monotherapy. Additionally, it is important to note that antidepressants in some patients may worsen the overall course of illness and may not be efficacious in some patients with BD II. Any patient who experiences hypomania or mania (which must be distinguished from transient activation symptoms) while on antidepressant medication should be presumed to be on the bipolar spectrum.

Antipsychotics

Most atypical antipsychotics have not been studied for the treatment of both BD I and BD II depression, with two notable exceptions. Quetiapine registration trials included individuals with BD II, with post-hoc analyses demonstrating efficacy of quetiapine monotherapy for BD II depression. Lumateperone is the first antipsychotic formally studied for depression response in patients with BD II since quetiapine trials in the early 2000s. Lumateperone, in randomized, controlled trials, performed as well or better for BD II than BD I, according to a 2021 study by Joseph R. Calabrese, M.D., et al. Cariprazine and lurasidone, while both FDA approved to treat bipolar depression, were never formally studied in patients with BD II. There have been case series supporting their use in BD II depression, but no randomized, controlled trials have been carried out. FDA approval to treat patients with BD II depression with lumateperone came in 2021, 15 years after quetiapine was approved. This glacial rate of accruing new FDA-approved compounds for BD II speaks to the need for more studies in this population.

Lithium and Anticonvulsants

While we might expect lithium to be the frontrunner treatment for managing BD II, study results are varied. Certainly, for hypomania and maintenance treatment of patients with BD II, lithium is a top choice. Lithium has a disappointingly poor track record for treating BD II depression with little indication that response rates are superior to those of antidepressants and atypical antipsychotics. Lamotrigine has good evidence for preventing new depression episodes in the context of BD (both BD II and I). The evidence, however, is less robust for treating acute depression in patients with BD II. In clinical practice, many clinicians prescribe lamotrigine, especially as an adjunctive treatment, for BD II depression, but our ability to make firm recommendations with confidence about lamotrigine is limited.

Other Therapies

Rapid-acting therapies are on the rise across all treatments for depression. There has been a recent surge of clinical work and research examining transcranial magnetic stimulation (TMS), ketamine, and psychedelics and related compounds. More work is needed specifically focused on BD II depression before firm conclusions may be drawn.

There is limited evidence supporting the use of TMS for BD II depression. This evidence base is developing, and more information is forthcoming on the utility of TMS for BD II depression.

Ketamine and Psychedelic Studies

Racemic ketamine has been in use for many years as an anesthetic and more recently was approved by the FDA as intranasal esketamine (the s-enantiomer of racemic ketamine) as a treatment for MDD. Three small studies of racemic ketamine suggest that it is effective for BD II depression. A 2022 observational study by Farhan Fancy et al. assessing patients with BD I versus BD II treated with racemic ketamine included more than 60 patients (n=35 BD II). In this largest open observational study to date involving ketamine and BD, patients with BD II demonstrated a more robust response than those with BD I. More studies are in development exploring this new use of an old drug; to date, there is no information on the role of esketamine for bipolar depression, let alone BD II.

Recently, it’s been difficult to pick up a journal or look at other media without seeing something about psychedelics and related compounds. There is a surge of interest in psychedelics for MDD, although evidence about their effectiveness is still early and with rare exceptions involves small samples. There is one report on treatment of depression with psilocybin in patients with BD II. In this pilot study, 15 patients with BD II were given a one-time dose of psilocybin (25 mg) and provided preparatory, dosing, and integration therapy consistent with psilocybin studies in MDD. In this small open study by Scott Aaronson, M.D., et al., the rate of response at 3 and 12 weeks was more robust than has been observed in MDD studies. An ongoing study is assessing the durability of patients’ response to psilocybin administered one time for patients with BD II depression. While no notable adverse events or increased mood lability were noted in this small sample to date, further study is needed to assess benefits and harms.

Psychotherapy

Most information about psychotherapy for BD II is derived from trials of interventions for BD in general that also included a subset of individuals with BD II. A recent systematic review of psychotherapies for BD II identified over 1,000 individuals with BD II who participated in randomized, controlled trials testing psychosocial interventions to treat depression or prevent recurrence of mood symptoms. However, relatively few of these trials—only eight of 27—examined outcomes in those with BD II separately. From this review, we concluded that there is preliminary evidence supporting the efficacy of several evidence-based psychotherapies for BD II: cognitive-behavioral therapy, psychoeducation, family focused therapy, interpersonal and social rhythm therapy (IPSRT), and functional remediation. None of these psychotherapies have undergone rigorous testing in randomized, controlled trials focused specifically on BD II depression, with the exception of IPSRT, pointing to the need for additional research in this area. To our knowledge, no meta-analysis of psychotherapy for BD II has been published.

IPSRT, the only psychosocial intervention to be tested in a randomized, controlled trial consisting of participants with BD II only (rather than a mixed patient population of BD I and II), focuses on helping individuals develop more regular routines to stabilize underlying disturbances in circadian rhythms. Because abnormalities in circadian biology have been implicated in the genesis of bipolar disorders, including BD II, a chronobiologic behavioral approach may be especially helpful to mitigate BD II symptoms.

Conclusions

BD II is a relatively common disorder affecting approximately 0.4% of the population. Its prevalence, morbidity, and mortality are comparable to that of BD I. Evidence supports conceptualizing BD II as a distinct phenotype, separable from both BD I and MDD. Compared with BD I and MDD, far less is known about BD II and how to treat it. Further, despite being reliably diagnosed in DSM-5 field trials, BD II is frequently misdiagnosed in practice, resulting in a decade-long lag between onset of symptoms and appropriate diagnosis. A neglected condition, BD II causes unnecessary suffering in those who are misdiagnosed or for whom appropriate treatments are unclear. More research is urgently needed to improve identification and treatments for BD II. ■

David L. Dunner, M.D., et al. “ Heritable Factors in the Severity of Affective Illness ,” Biological Psychiatry , February 1976.

J. Raymond DePaulo, M.D., et al. “ Bipolar II Disorder in Six Sisters ,” Journal of Affective Disorders , August 1990.

Lewis Judd, M.D., et al. “ Long-Term Symptomatic Status of Bipolar I vs. Bipolar II Disorders ,” International Journal of Neuropsychopharmacology, June 2003.

Alina Karanti, Ph.D., et al. “ Characteristics of Bipolar I and II Disorder: A Study of 8766 Individuals ,” Bipolar Disorders , June 2020.

Ayal Schaffer, M.D., et al. “ A Review of Factors Associated With Greater Likelihood of Suicide Attempts and Suicide Deaths in Bipolar Disorder: Part II of a Report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder ,” Australian & New Zealand Journal of Psychiatry , November 2015.

Lakshmi N. Yatham, M.D., et al. “ Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 Guidelines for the Management of Patients With Bipolar Disorder ,” Bipolar Disorders , March 2018.

Joseph R. Calabrese, M.D., et al. “ Efficacy and Safety of Lumateperone for Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder: A Phase 3 Randomized Placebo-Controlled Trial ,” American Journal of Psychiatry , December 2021.

Farhan Fancy, et al. “ Real-World Effectiveness of Repeated Ketamine Infusions for Treatment-Resistant Bipolar Depression ,” Bipolar Disorders , December 14, 2022.

Scott Aaronson, M.D., et al. “ COMP360 Psilocybin Therapy Shows Potential in Open-Label Study in Type II Bipolar Disorder ,” Global Newswire, December 8, 2022.

Trisha Suppes, M.D., Ph.D., is a professor of psychiatry, staff psychiatrist at the VA Palo Alto, and director of the Exploratory Therapeutics Laboratory at Stanford University.

Holly A. Swartz, M.D., is a professor of psychiatry at the University of Pittsburgh School of Medicine and director of the Center for Advanced Psychotherapy at Western Psychiatric Hospital.

They are co-editors of Bipolar II Disorder: Recognition, Understanding, and Treatment from APA Publishing. APA members may purchase the book at a discount.

Sara Schley is the author of Brainstorm: From Broken to Blessed on the Bipolar Spectrum (Seed Systems, 2022). She is the founder of a consulting business and has worked with hundreds of renowned companies worldwide.

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Genomic Data From More Than 41,000 People Shed New Light on Bipolar Disorder

September 29, 2021 • Research Highlight

In the largest genome-wide association study of bipolar disorder to date, researchers found about twice as many genetic locations associated with bipolar disorder as reported in previous studies. These and other genome-wide findings help improve our understanding of the biological origins of bipolar disorder and suggest some promising genes for further research.

The study, led by the Psychiatric Genomics Consortium   bipolar disorder working group, is published in Nature Genetics   . The Psychiatric Genomics Consortium is a global collaborative effort consisting of more than 800 investigators, including researchers in the National Institute of Mental Health (NIMH) Intramural Research Program and extramural scientists conducting NIMH-supported research.

Bipolar disorder is a mental illness characterized by episodes of mania and depression that can seriously impair day-to-day functioning. Affecting up to 50 million people worldwide, bipolar disorder is a major public health concern. Although evidence suggests that genes play an important role in the development of bipolar disorder, researchers still do not have a clear understanding of the disorder’s specific biological causes. Examining common genetic variations in the genomes  (or complete set of DNA) of people with bipolar disorder is a way that scientists can home in on the genetic factors that are likely to play a causal role in the disorder.

For this study, the researchers analyzed genomic data from 57 groups of participants across Europe, North America, and Australia. These cohorts included individuals receiving clinical care for bipolar disorder and individuals classified as having bipolar disorder based on data from health registries, electronic health records, or repositories. The total combined sample included 41,917 individuals with bipolar disorder and 371,549 individuals without bipolar disorder.

The researchers used an approach known as a genome-wide association study (GWAS)  , which allowed them to identify common genetic variations that are more likely to occur in people with bipolar disorder. Identifying these variations can provide important clues about the biological pathways and processes that are likely to be involved in the disorder.

According to the GWAS results, a total of 64 genomic locations, or risk loci  , were associated with bipolar disorder even after accounting for all the variations studied across the genome. These 64 risk loci included 33 that had not been reported in previous bipolar disorder studies. Among the novel loci, the researchers found that bipolar disorder was associated with the major histocompatibility complex, which is a large group of genes involved in immune function. They also found a correlation between bipolar disorder and loci linked to other psychiatric disorders, including schizophrenia, major depression, and childhood-onset disorders such as attention-deficit/hyperactivity disorder (ADHD).

The study findings also revealed genome-wide genetic overlaps, or correlations, between bipolar disorder and certain traits. For example, the results showed a genetic correlation between bipolar disorder and both alcohol use and smoking, as well as genetic correlations with some aspects of sleep (daytime sleepiness, insomnia, and sleep duration).

The researchers also compared genetic overlap between the two types of bipolar disorder: bipolar I disorder (which includes manic episodes and, typically, depressive episodes) and bipolar II disorder (which includes depressive episodes and hypomanic episodes). As expected, the results indicated a substantial but incomplete genetic overlap between the two types. Comparing the two types and their associations with other psychiatric disorders, the researchers found that bipolar I disorder showed a stronger genetic correlation with schizophrenia, whereas bipolar II disorder was more closely correlated with major depression. Additional studies with detailed trait data for large cohorts will be essential for further understanding the genetic components of these bipolar disorder types.

Drawing from the GWAS results, the researchers found that the 64 risk loci contained at least 161 individual genes. Some of these genes play a role in how neurons signal to each other in the brain. Some of these genes are also known to be targets for certain types of drugs currently used to treat bipolar disorder, such as antipsychotics, mood stabilizers, and antiepileptics. And some genes are known to be targets for other drug types, including calcium channel blockers (typically used to treat high blood pressure) and certain anesthetics.

The researchers then used an analytic technique called “fine-mapping” to connect risk loci with specific genes that are most likely to play a causal role in bipolar disorder. This technique identified 15 genes with the strongest evidence, which suggests they are promising candidates for further study.

Overall, the study findings confirmed many of the risk loci and genetic correlations reported in previous studies. But the study also represents an advance for the field, as a 1.5-fold increase in the number of participants effectively doubled the number of loci identified as associated with bipolar disorder. According to the researchers, this marks an “inflection point” in discovery because it indicates that the number of loci identified will continue to increase rapidly with the addition of new cohorts.

Taken together, these findings establish a more detailed picture of the genetic factors that underlie bipolar disorder and suggest possible biological targets for new treatments.

Mullins, N., Forstner, A. J., O’Connell, K. S., Coombes, B., Coleman, J. R., Qiao, Z., Als, T. D., Bigdeli, T. B., Børte, S., Bryois, J., Charney, A. W., Drange, O. K., Gandal, M. J., Hagenaars, S. P., Ikeda, M., Kamitaki, N., Kim, M., Krebs, K., Panagiotaropoulou, G.,…Andreassen, O.A. (2021). Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.  Nature Genetics, 53, 817–829. https://doi.org/10.1038/s41588-021-00857-4  

MH109528  , MH094421  , MH085520 

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Bipolar II Disorder: Understudied and Underdiagnosed

• Holly A. Swartz , M.D. , and
• Trisha Suppes , M.D., Ph.D.

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Despite its inclusion as a distinct entity in APA’s Diagnostic and Statistical Manual of Mental Disorders since 1994, bipolar II disorder remains a surprisingly neglected psychiatric condition. Understudied and underrecognized, bipolar II disorder is often misdiagnosed and misunderstood, even by experienced clinicians. As a result, patients typically experience symptoms for more than 10 years before receiving the correct diagnosis. Incorrect diagnosis leads to incorrect treatment, including overuse of monoaminergic antidepressant medications, with resultant declines in functioning and worse quality of life. Perhaps because of its underrecognition, treatment studies of bipolar II disorder are limited, and, too often, results of bipolar I disorder studies are applied to bipolar II disorder, with no direct evidence supporting this practice. Bipolar II disorder is an understudied and unmet treatment challenge in psychiatry. In this review, the authors provide a broad overview of bipolar II disorder, including differential diagnosis, course of illness, comorbid conditions, and suicide risk. The authors summarize treatment studies specific to bipolar II disorder, identifying gaps in the literature. This review reveals similarities between bipolar I and bipolar II disorders, including risks of suicide and predominance of depression over the course of illness, but also differences between the phenotypes in treatment response, for example, to antidepressant medications.

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Behavioral lateralization in bipolar disorders: a systematic review

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High lithium concentration at delivery is a potential risk factor for adverse outcomes in breastfed infants: a retrospective cohort study

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Rates and associations of relapse over 5 years of 2649 people with bipolar disorder: a retrospective UK cohort study

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Exploratory study of ultraviolet B (UVB) radiation and age of onset of bipolar disorder

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Clinicians’ preferences and attitudes towards the use of lithium in the maintenance treatment of bipolar disorders around the world: a survey from the ISBD Lithium task force

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Phenotype fingerprinting of bipolar disorder prodrome

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Predictors of adherence to electronic self-monitoring in patients with bipolar disorder: a contactless study using Growth Mixture Models

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Stigma in people living with bipolar disorder and their families: a systematic review

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Long-term lithium therapy and risk of chronic kidney disease, hyperparathyroidism and hypercalcemia: a cohort study

Lithium is well recognized as the first-line maintenance treatment for bipolar disorder (BD). However, besides therapeutic benefits attributed to lithium therapy, the associated side effects including endocrin...

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Clinical Trials

Bipolar disorder.

Displaying 18 studies

The purpose of this biobank is to develop a research resource for bipolar disorder. Patients, and close genetic relatives, will provide samples of blood, complete interviews, complete health questionnaires, and allow access to medical records. Participants will also agree to be followed into the future by linking to medical records, along with occasional follow-up health surveys or collection of additional biologic specimens. The biobank serves as a source for researchers instead of having to look for volunteers for each new project.

The purpose of this study is to obtain input from people with bipolar disorder to choose the preferred measure for monitoring bipolar disorder symptoms that is understandable, acceptable, and helpful in informing when to change treatment.

The purpose of this study is to determine if interpersonal and social rhythm therapy for patients who have bipolar disorder can be delivered in the formal program group psychotherapy format of the outpatient mood program.

This study uses an MRI scan called an MR Spectroscopy to measure brain chemicals before and after treatment with lamotrigine or fluoxetine in patients with bipolar depression. This better understanding of therapy impact on brain function may help individualize future treatment for bipolar depression.

The purpose of this study is to explore whether Medibio’s system can provide objective measures of response to standard medication treatment for unipolar depression and bipolar depression, and to see if the system can tell these two conditions apart.

Medibio’s system uses software to analyse a person’s heart rate, activity, and posture to provide objective measures of a person’s autonomic nervous system, sleep, and other daily patterns.

Transcranial Magnetic Stimulation (TMS) is an increasingly accepted neurostimulation- based treatment for major depressive disorder. While there is a growing anecdotal database supporting its use in bipolar depression the investigators propose to collect open label efficacy and safety data in a small population of patients with clinically verified bipolar disorder.

The purpose of this study is to assess the effectiveness and safety of MYDAYIS® as an augmentation agent for bipolar depression.

Quetiapine, a second generation antipsychotic, is only available as oral tablets. However, topical and rectal formulations have been produced in compounding pharmacies. There is no data available suggesting that topical or rectal formulations provide serum levels similar to oral medication. In the clinical setting, when oral administration of quetiapine is not possible (for example, when a patient is extremely ill physically or mentally or both), clinicians and pharmacists have collaborated in such cases and have at times had to administer quetiapine compounded in other dosage formulations such as rectal or topical formulations. Despite clinical effectiveness of these "other" formulations, there ...

The purposes of this study are to summarize clinician evaluations of the NNDC battery in the single clinic where the adult battery is currently being administered to adolescents, to determine patient and clinician level of interest in using the NNDC battery in clinics where the adult battery is not currently being administered to adolescent patients (n=14), to measure change in evaluation 3 months post-implementation for any sites that begin administering the NNDC battery to adolescents, and to generate potential new Child and Adolescent Mood Disorders Interest Group (CAMDIG) research protocols for future consideration.

The purpose of this research study is to find out if the medication known as ketamine can help the symptoms of depression. This drug is approved by the Food and Drug Administration (FDA) but the investigators will use it for a non-FDA approved reason (depression).

The purpose of this study is to find out if some patients with mood symptoms have antibodies (part of the immune system) that affect the brain, and could possibly play a role in the development of mood symptoms. We also want to find out if these immune markers change once your mood normalizes.

The FLAME Study is a 16-week clinical trial to study treatment with lamotrigine or fluoxetine in bipolar I, II and bipolar schizoaffective depressed adults. The purpose of the trial is to have a better understanding of whether individuals with a particular gene type and other inherited biological markers will have a good response to fluoxetine or lamotrigine, or alternatively, would be more likely to have side effects to this medication.

This study will compare glutamate and other neurometabolites measured by proton magnetic resonance spectroscopy (1H-MRS) in bipolar I and II patients currently depressed with age-matched healthy controls. The study will also compare 1H-MRS of bipolar I and II patients before and after taking a 12-week course of lamotrigine. This study requires 8 visits over a 12 week period. These visits need to occur at Mayo Clinic in Rochester, MN.

The goal of this proposed study is to examine the genetic signature of the validated proteomic signature (model) based on a panel of serum proteomic markers that discriminates different mood disorders.

The purpose of this research study is to compare the antidepressant effect of lithium versus placebo in adults receiving ketamine. Lithium is available commercially for depression; ketamine is available commercially and can help the symptoms of depression; however, it has not been approved by the U.S. Food and Drug Administration (FDA) for this use. The FDA has allowed the use of this drug in this research study.

In an effort to understand the effects of evidence-based interventions on children and adolescents, the aims of this study are to 1) evaluate the feasibility of utilizing wearable devices to track health information (i.e., sleep, physical activity); 2) evaluate the effectiveness of evidence-based intervention components on emotional and interpersonal functioning, family engagement, and sleep and physical activity level outcomes.

The overall goal is to better understand the underlying pathophysiology of mood disorders and bipolar disorders in particular. We aim to investigate whether the subclinical atherosclerotic and inflammatory markers differ between patients with bipolar disorder, major depressive disorder, and psychiatric non-mood disorders and healthy subjects.

The purpose of this study is to evaluate the clinical and neurocognitive correlates of COVID-19 in patients with bipolar disorder (BD). 

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• Published: 18 April 2024

A bibliometric and visual analysis of cognitive function in bipolar disorder from 2012 to 2022

• Xiaohong Cui 4 , 5   na1 ,
• Tailian Xue 1   na1 ,
• Zhiyong Zhang 1 ,
• Hong Yang 2 &
• Yan Ren 3  

Annals of General Psychiatry volume  23 , Article number:  13 ( 2024 ) Cite this article

215 Accesses

Metrics details

Introduction

Bipolar disorder (BD) is a chronic psychiatric disorder that combines hypomania or mania and depression. The study aims to investigate the research areas associated with cognitive function in bipolar disorder and identify current research hotspots and frontier areas in this field.

Methodology

Publications related to cognitive function in BD from 2012 to 2022 were searched on the Web of Science Core Collection (WoSCC) database. VOSviewer, CiteSpace, and Scimago Graphica were used to conduct this bibliometric analysis.

A total of 989 articles on cognitive function in BD were included in this review. These articles were mainly from the United States, China, Canada, Spain and the United Kingdom. Our results showed that the journal “ Journal of Affective Disorders ” published the most articles. Apart from “Biploar disorder” and “cognitive function”, the terms “Schizophrenia”, “Meta analysis”, “Rating scale” were also the most frequently used keywords. The research on cognitive function in bipolar disorder primarily focused on the following aspects: subgroup, individual, validation and pathophysiology.

Conclusions

The current concerns and hotspots in the filed are: “neurocognitive impairment”, “subgroup”, “1st degree relative”, “mania”, “individual” and “validation”. Future research is likely to focus on the following four themes: “Studies of the bipolar disorder and cognitive subgroups”, “intra-individual variability”, “Validation of cognitive function tool” and “Combined with pathology or other fields”.

Bipolar disorder presents a complex clinical presentation. It is characterized by alternating episodes of mania and depression, and is a serious mental health problem with a high rate of disability and difficult to cure [ 1 ]. The phenotypic manifestations of BD include not only core abnormalities in mood regulation, but also cognitive impairments, sleep/wake disturbances, and a high prevalence of comorbidities in both internal medicine and psychiatry. Cognitive function, also known as neurocognitive function, refers to the ability of the human brain to process information, including memory, executive function, space, time, language comprehension and expression. The current cognitive dysfunction in patients with bipolar disorder primarily affects memory, attention, executive function and so on [ 2 ].

In recent years, there has been increasing attention on cognitive functioning in patients with bipolar disorder. For example, a study has shown that individuals with bipolar disorder experience cognitive impairments during periods of remission as well as during acute episodes of depression or mania. Cognitive impairment is associated with multiple factors, including age of onset, duration of remission, and cognitive impairment, which are also intrinsic phenotypes of the disease [ 3 ]. Different diseases cause varying degrees of cognitive impairment. Patients with schizophrenia exhibit comprehensive cognitive decline, while those with bipolar disorder primarily experience impairment in memory, attention, and executive function, especially during acute episodes. The classification of bipolar disorder also corresponds to different areas of cognitive impairment. The impact of medication treatment on the cognitive function of bipolar disorder patients is contradictory, requiring a combined approach with other therapeutic methods to improve patient cognition [ 4 ]. The assessment of cognitive function is also a research prominent topic in this field. The assessment of cognitive function in bipolar disorder includes both objective and subjective aspects. Various neuropsychological tests, such as the Rey Auditory Verbal Learning Test (RAVLT) and Rapid Visual Information Processing (RVP) test, are used to assess objective cognitive function in individuals with bipolar disorder. Subjective cognitive function assessment can be performed using the Cognitive and Physical Functioning Questionnaire (CPFQ) [ 5 ]. In addition to the above assessment tools, the results of another study showed: for patients with BD in partial or full remission, the Screen for Cognitive Impairment in Psychiatry (SCIP) and the Cognitive Complaints in Bipolar Disorder Rating Scale (COBRA) are effective tools for screening objective and subjective cognitive impairments, respectively [ 6 ]. These findings indicate that we need to assess different aspects of cognitive impairment in patients using various scales. This will help us better understand their cognitive performance and provide assistance for clinical treatment.

Bibliometrics is the analysis of published information (books, journal articles, datasets, blogs) and associated metadata (abstracts, keywords, citations). It describes or shows the relationship between published works by using statistical data [ 7 ]. The characteristics of publications and the relationships between publications can be described by qualitative and quantitative analysis. Cognitive function is currently a hot topic of research in bipolar disorder, but there are no bibliometric articles yet, although there are many articles on cognitive function in bipolar disorder.

In this article, we use CiteSpace and VOSviewer software to review the research of cognitive function in bipolar disorder in the past 12 years (from 2012 to 2022) to learn the status of international research, the shift in research hotspots and emerging trends in this field.

Research methodology

Data sources and search strategy.

This study searched the related literature of cognitive function in bipolar disorder from the Web of Science (core collection) database, The reason for choosing WoSCC is that it is a high-quality digital literature resources database, suitable for the quantitative analysis of literature. The retrieval formula is TS="bipolar disorder” OR “bipolar affective disorder” OR “bipolar depressive disorder” OR “bipolar spectrum disorder” OR “biphasic disorder” AND TS = cognition OR “cognitive impairment” OR “cognitive decline” OR “cognitive function” OR “cognitive dysfunction” OR cognitive, selected over a period of 2012–2022, analyzed the type of literature as articles and reviews, and included the studies without regard to language. Through the analysis of the titles, abstracts and keywords of the article, a total of 4939 articles were searched, 1005 articles were preliminarily screened out, 989 articles were obtained (865 articles, 124 reviews) (Fig.  1 ).

Flow chart of scientometric analysis

Research tools

In this study, VOSviewer software (version 1.6.18) on WoSCC database is applied to conduct co-occurrence analysis, combined with Scimago Graphica software to achieve a country map visualization analysis. Using CiteSpace (version of 6.1.R6) software for the database author co-operation analysis, keyword cluster analysis, literature co-citations and keyword mutation analysis. VOSviewer application developed by Nees Jan van Eck and Ludo Waltman (Leiden University) in 2010, can be used for a variety of network analysis, including collaborative analysis, keyword co-occurrence analysis, citation and co-citation analysis, and bibliographic coupling. It can be used to conduct co-authorship analysis, keyword co-occurrence analysis, citation and co-citation analysis, and bibliographic coupling [ 8 ]. Citespace is a software developed by Professor Chaomei Chen of Drexel University (Philadelphia, USA) for the visual analysis of scientific references. With the software, we can generate a series of visual knowledge atlases to understand the research hotspots in the field, delve into the forefront of its development, and ascertain emerging trends [ 9 ].

The parameters used for co-occurrence analysis using VOSviewer are the default parameters for the software, and the parameters used in CiteSpace are as follows: time slices (2012–2022), number of years per slice (1), node types (author collaborations, co-citations, and keywords), pruning (pathfinder, pruning sliced network, pruning the merged network), g-index (k = 25, literature co-citations are k = 15).

Analysis of publication years

Distribution of publication from 2012 to 2022

There are a total of 989 articles were used in this study from 57 countries. Figure  2 shows the distribution of publication years for articles in the field of cognitive function in bipolar disorder. Overall, the volume of articles in this field is relatively balanced, with more than 60 articles published annually starting from 2012. The number of articles published in 2018–2020 remained relatively stable. The highest volume of articles was in 2021, with 129 articles published. The annual cumulative volume model aligns with the annual growth data y = 91.188e 0.244x (R 2 = 0.8956). This also shows that the field of cognitive function in bipolar disorder has garnered significant attention from scholars, with the development of society and technology, the study of cognition in the context of bipolar disorder has become an important and hot topic.

Analysis of author

By analyzing the authors of the literature cited in this paper, we aimed to gain insights into the prominent scholars and core strength within this research area. Famous scholar Price pointed out that, in the same subject, half of the papers are written by a group of high-productivity authors, and the number of authors in this group is approximately equal to the square root of the total number of authors [ 10 ].

According to the Price’s Law, the minimum number of core authors in the field is m = 4.79, so authors with 5 or more posts (including 5) are positioned as core authors in the field, where they are active professionals. Table  1 shows the top five productivity authors with contributions in this area. Top of the list was Vieta E, professor and chair of psychiatry at the University of Barcelona, with the highest number of published articles (41). He spearheads research focused on investigating cognitive function, cognitive impairment, and clinical manifestations associated with bipolar disorder, leading the Bipolar Disorder and Depression Project in Barcelona, Catalonia, Spain.

We then analyzed the author’s cooperation relationship. These studies published between 2012 and 2022, the year per slice for analysis is 1 year. The author cooperation network is shown in Fig.  3 (N = 419, E = 862). The circle size of the node represents the number of publications.

The centrality indicates that an author has a close cooperation relationship with other authors. According to Table  1 , the centrality of Vieta E is 0.14 (centrality > 0.1), indicating that the author has cooperation with multiple authors in the field, while the centrality of Vinberg M is 0.02. The author’s cooperation network graph also shows that Vinberg M is far away from other high-yielding authors, indicating that the author has less cooperation with other high-yielding authors in the research of cognitive function in bipolar disorder.

Author collaboration network analysis. The shorter the distance between two nodes the thicker the connection, indicating a higher level of collaboration between the two authors. Green nodes represent earlier published studies, while yellow nodes represent more recent studies

Analysis of the most productive journals

The analysis of the journals in literature shows that journals published in this field belong to the medical field except a few comprehensive journals in the past ten years. The top 10 most publication journals have shown in Table  2 . Journals with more than 60 published articles were Journal of Affective Disorders , Psychiatry Research and Bipolar Disorders , with 185, 72, and 66 articles, respectively. Among them, PLOS ONE is an open-source journal, with 20 citations, ranking 10th in the number of published journals.

Analyzing of journal citation founds that (Table  2 ) the most cited journals are the top medical journal “ Acta Psychiatrica Scandinavica ”, with a total of 27 articles cited up to 47 times. It indicates that the journal publishes high-quality articles and is of widespread interest in the field of cognitive function in bipolar disorder. The contents published in this journal include: empirical studies, factor studies, and the influence of variable indicators on cognitive function in patients with bipolar disorder.

Furthermore, a visual analysis of the journal co-citation network reveals the presence of three clusters (Fig.  4 , in supplementary material). According to the subject of the co-citation literature clustering, it divided into three different themes. The top 3 most cited journals are Journal of Affective Disorders (3807 citations),  Bipolar Disorders (2186 citations), and American Journal of Psychiatry (1284 citations). All three of these journals are in the JCR1. The most cited journal, Journal of Affective Disorders , which includes articles on affective disorder. It covers a wide range of subjects, including neuroimaging, cognitive neuroscience, genetics, molecular biology, etc. This is in line with the research focus on cognitive function in bipolar disorder.

Co-citation resource

Analysis of the most productive countries/regions

In 2012–2022, a total of 57 countries have published articles on cognitive function in bipolar disorder. To gain an understanding of the countries that have made significant contributions to this field, the study utilized VOSviewer to visualize the countries with 5 or more articles, a total of 33 countries met this criterion. The data was then exported in HTML format and imported into Scimago Graphica for visual analysis to generate map. The result is shown in the Fig.  5 .

As we can see, most of articles are written by scholars from a few countries. Other countries such as Chile, Ireland, Colombia, etc. They have published fewer articles related to cognitive function in bipolar disorder in 2012–2022.

The visual map of countries. ( A ) The size of each node represents the number of publications from that country. ( B ) The number displayed below each country indicates the total number of publications

A further analysis of high-productivity countries in the field is presented in Table  3 , showing the Top 5 countries in the field. According to the data in Table  3 , American scholars have contributed the most research articles (287 articles published), accounting for 29% of the total number of articles published in this field. The second largest country is China, with 123 articles. The USA and the United Kingdom with a centrality value above 0.1, with centrality ratios of 0.25 and 0.36, respectively, indicating that these countries work closely with other countries in the study of cognitive function in bipolar disorder.

Analysis of keywords

We can classify keywords according to their frequency of occurrence and point out the links between high-frequency keywords. The analysis of keywords can help us understand the academic structure of a field and reveal the frontiers of research in the discipline. Figure  6 ( in supplementary material) presents the network and density of keywords that are referenced in the top 50. Keywords that are close to each other are classified into the same cluster, providing an overview of the main topics related to cognitive function in bipolar disorder.

Co-occurrence analysis of keywords. ( A ) The size of the node represets the frequency of the keyword. ( B ) The distance between two node represets the strength of their association

In terms of co-occurrence frequency, the most frequent keyword was “Biploar disorder” with 712 citation times, followed by “Schizophrenia”, “Cognition”, “Meta analysis”, “Rating scale”, “Impairment”, “Euthymic patients”, “Deficits”, “Depression” and “Cognitive impairment” (Table  4 ). These high-frequency keywords reflect the hot spots of cognitive function in bipolar disorder.

In CiteSpace, the LLR method was used to cluster the keywords (N = 473, E = 947) (Fig.  7 , in supplementary material). All keywords were divided into 15 clusters with co-citation relationship, including the largest cluster “cognitive function” (#0), followed by “Alzheimer disease” (#1), “cognitive control” (#2) and “executive function” (#3). Clustering results point to clinical symptoms (including #0 cognitive function, #1 Alzheimer disease, #2 cognitive control, #3 executive function, #15 affective response inhibition) and diagnostic and intervention strategies (#5 psychological testing, #10 clinical staging model, #11 antipsychotic).

The cluster map of keywords

Generally, Q = 0.6638 (Q > 0.3) means that the clustering structure is significant. Silhouette: S value is the average contour value of clustering, it is generally believed that S > 0.5 clustering is reasonable, and S = 0.8425 (S > 0.7) means clustering is convincing (Fig.  7 ).

Analysis of reference co-citation

The CiteSpace software analysis was used to analyze studies published between 2012 and 2022, with 1-year time slice for analysis. The network diagram of the document is shown in Fig.  8 , which consists of 216 nodes and 235 connections. The more times a document is cited, the greater the circle of the node. A circle with a purple outer ring indicates the document of intermediary centrality, meaning it is cited by several documents simultaneously. The color of the circle corresponds directly to the time slice, with yellow representing the earlier year and green representing more recent years. For example, light yellow represents co-cited studies in 2012, while dark green represents more recent co-references.

Co-occurrence analysis of references. ( A ) The nodes represent references. ( B ) The lines represent the relationships between the references and the common references of the collected studies

Table  5 shows the top 10 references, the most frequently cited is “Bourne C (2013)”, and the title of the article is “Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis”, with 104 citations. This article is a meta-analysis describing reliable measures of cognitive impairment in bipolar patients: VLT, Digit Span, and TMT. Among the top ten cited articles, the highest centrality is “Bora E (2017)”, with the title “Meta-analysis of longitudinal studies of cognition in bipolar disorder: comparison with healthy controls and schizophrenia”, with a centrality of 0.22, which indicates that the article has important reference value in cognitive research of bipolar disorder.

Burst analysis of keywords

Burst words are the keywords that are frequently quoted and regarded as frontier topic indicators in a certain period. Figure  9 shows the top 25 keywords which are the most burst between 2012 and 2022. The most recent keywords are “pathophysiology”, “subgroup”, “individual”, “cognitive control” and “cluster analysis”. The keyword “neurocognitive impairment”, shows the reference burst to 5.55 began in 2012.

As can be seen from the figure, the research hotspots can be divided into the following three stages. The first stage was from 2012 to 2016. Focused on exploring cognitive impairment in patients with bipolar disorder, with keywords such as “neurocognitive impairment”, “cognitive impairment”, and“internal phenotype”,. The second stage was from 2016 to 2019, the keywords include “cognitive control”, “executive function”, “task”, and “risk factors”. This stage focused on investigating specific cognitive domains affected in bipolar disorder, utilizing cognitive task procedures and further integrating cognition with neurology. In the third stage, from 2019 to 2022, the keywords with bursts include “subgroup”、 “individual”、 “validation”、 “pathophysiology”. This stage emphasized the study of the neurocognitive subgroup within bipolar disorder, validating the scale for measuring cognitive function, and combining with pathophysiology. These studies provide practical evidence for the treatment of bipolar disorder.

Top 25 Keyword with the strongest citation. The blue and white squares in each row on the right side of the figure correspond to the year of hotspot. Red squares represent the year of hotspot, and blue squares represent non-hotspot year. The recent successive red squares represent the research hotspots in recent wears

This is the first bibliometric analysis of cognitive function in bipolar disorder. Our investigation covered 989 publications from WoSCC, most of them are original articles, and a few are review articles. The results show that during 2012–2022, the number of related publications increased significantly.

From the perspective of the authors. Vieta E, McIntyre RS, Vinberg M, and Miskowiak KW have published 20 or more articles. The articles published by Professor Eduard focus on cognitive dysfunction of schizophrenia and bipolar disorder. One of these articles points out that there is a widespread cognitive impairment in the first episode of mania, and its severity is lower than that of individuals with schizophrenia in their first episode. BD patients performed better than schizophrenia patients in verbal working memory, mental speed, executive control, and immediate verbal memory [ 11 ]. Both diseases have cognitive impairments, albeit with varying degrees of severity. Exploring the comorbidities between the two can lead to the development of more treatment options. In McIntyre RS’s articles, two of them examined the impact of obesity on the cognitive function of BD patients. The result shows that overweight/obese BD patients have significant cognitive defects and experience more severe cognitive impairment than normal-weight BD patients [ 12 , 13 ]. Approved for obesity treatment, Liraglutide, a GLP-1R agonist, has shown promise in enhancing objective measures of cognitive function in adults diagnosed with mood disorders. This research suggests that Liraglutide could potentially serve as a therapeutic intervention to improve cognitive function in individuals with mood disorders [ 14 ]. This research finding highlights the possibility of investigating factors like obesity, which contribute to cognitive abnormalities in patients, as potential avenues for developing interventions to enhance cognitive function.

According to the analysis of centrality and author’s cooperative relationship, it can be known that Miskowiak KW cooperated with two productive authors, Vieta E and Vinberg M. The five articles, produced in collaboration with Vieta E, are systematic reviews or meta-analyses. Two of them focus on cognitive dysfunction in patients with bipolar disorder across different age groups. Euthymic youths with BD exhibit significant cognitive dysfunction in verbal learning and memory, working memory, visual learning, and memory domains. Further research has shown that euthymic adults with BD have more widespread cognitive impairment [ 15 ]. Euthymic older adults with BD have important deficits in almost all cognitive domains, particularly in the memory domain [ 16 ]. The impact of the disease varies among different age groups, with cognitive decline typically occurring as individuals grow older, resulting in irreversible damage. Treatment options can only enhance cognitive performance in patients to a certain extent. One article explores the effects of various medications on cognitive function of BD patients. The efficacy of N-acetyl cysteine, pregnenolone, ketamine, and pramipexole did not demonstrate any cognitive benefits, while mifepristone, galantamine, and insulin were shown to improve different areas of cognition [ 17 ]. In addition, they also conducted a functional magnetic resonance imaging study on individuals with BD, and the results showed that the neural basis of cognitive impairment in BD patients was a failure to recruit key regions in the CCN and to suppress task-irrelevant DMN activity during cognitive performance [ 18 ]. Miskowiak KW has published eight articles with Vinberg M, one of which is meta-analysis. From the perspective of the ‘cold’ and ‘hot’ cognition and neuroimaging, they found that the most promising specific endophenotypic marker for BD is the abnormalities within ‘hot’ cognition, which is represented by impairments in emotion processing and regulation and reward processing [ 19 ]. The remaining seven articles are experimental studies. There are four articles related to cognitive remediation. They first conducted erythropoietin (EPO) trials, which showed that EPO effectively promotes cognitive recovery in patients [ 20 ]. Then based on the above research, they conducted a study on Action-Based Cognitive Remediation (ABCR). The result showed that the ABCR can improve executive function and subjective cognitive functioning in BD patients [ 21 , 22 ]. In another study, cognitive remediation (CR) was shown to improve subjective sharpness/mental acuity, verbal fluency and psychological quality of life in BD patients [ 23 ].

Most of the research on cognitive functioning in bipolar disorder was published in Journal of Affective Disorders (IF = 6.533, Q1), indicating it is currently the most popular journal in this research field. Among these journals, the journal with the highest impact factor is Psychiatry Research (IF = 11.225, Q1), followed by Psychological Medicine (IF = 10.592, Q1). Besides, PLOS ONE , which ranks 10th in terms of the number of published articles, is an open-source journal. This indicates that the presence of open-source journals has also promoted the development of this field, and it can obtain full-text documents for free, which facilitates knowledge dissemination and allows researchers to stay updated with the latest findings in the field of cognitive function in bipolar disorder. Through the co-citation analysis of journals, it can be found that the top cited journals are Q1 journals, which provide support for the study of cognitive function in bipolar disorder. More importantly, the most of research on cognitive function in bipolar disorder is published in clinical journals, which indicates that current research is in the clinical research stage.

In this bibliometric analysis, the majority of the related articles were published by authors from the United States, China, Canada, Spain, and Britain. According to the centrality, the United States and Britain had more cooperation with other countries, indicating their higher level of international cooperation. Although the number of articles published by China ranks second, showed that it had made extensive development in this field. However, due to a lack of collaboration with other productive countries, its influence is relatively low. Therefore, more international cooperation is needed in China. Spain ranks third in the number of articles published and had a significant presence due to the most active scholar, “Vieta E”, from the University of Barcelona. Vieta E set up a group to study bipolar disorder and depression, through experimental design and clinical trials, research on medication treatments, psychological therapy, and biophysical therapy, investigate the clinical development and progression of these disorders.

Keywords can be regarded as the core content of a specific article. Thus, keyword frequencies provide important clues about major trends in a research area [ 24 ]. Through the co-occurrence analysis of keywords, it can be found that apart from bipolar disorder and cognition, schizophrenia is also a high-frequency cited keyword, which indicates that one direction of research in this field is a comparative study of schizophrenia and bipolar disorder. This study compares the evolution of cognitive functioning in the same intervention mode and explores the fields of cognitive impairment. The research has shown that people with schizophrenia also perform significantly worse than people with bipolar disorder on social cognitive tasks such as theory of mind (ToM) and emotion recognition [ 25 ]. The keyword “Rating Scale” is also frequently cited, reflecting that a research topic in this research field is the analysis and measurement of cognitive scale for bipolar disorder, such as evaluating the degree of cognitive impairment in patients with bipolar disorder using different scales. Through cluster analysis, it can be found that the research mainly focuses on the cognitive impairments, diagnosis, and treatment of bipolar affective disorder in clinical settings.

Highly co-cited references are those that are frequently cited together by other articles, and thus, can be regarded as knowledge bases in a particular field [ 26 ]. In this article, the top ten cited literature are listed. The total number of citations can be regarded as an important indicator of interest in a specific research field. Nine of the articles in the top 10 co-cited references are meta-analyses. The tenth article is an empirical study published by Torrent Carla in 2012. This study points out the changes in cognitive impairment in BD patients during a longitudinal study: except for a worsening of executive function and slight improvement of attention, other cognitive fields remained stable [ 27 ]. The most frequently cited documents have been mentioned before and will not be explained here. The second most cited article is a meta-analysis published by Bora E in 2009. The results of this analysis show that response inhibition, set- shifting, verbal memory, and target detection impairments are potential candidate endophenotypes for BD. Euthymic patients may be associated with the medication they are taking and can also be influenced by disease-related factors [ 28 ]. The top 10 co-cited references focus on the following topics: meta-analysis, cognitive impairment, endophenotype, memory, executive function, neuropsychological test, and neurocognition. These are the research bases of cognitive function in bipolar disorder.

The burst detection analysis can show the interests of the research field and the changes in research hotspots over time. If a keyword is a high-frequency cited burst word, it indicates that the keyword has been actively discussed or used in a certain period [ 29 ]. From the citation bursts, we can conclude that the research on cognitive function in bipolar disorder mainly focuses on the following aspects: subgroup, individual, validation, and pathophysiology.

“subgroup”. There are three neurocognitive subgroups of BD. The “cognitively intact group” does not differ from HCs. The “Selective cognitive impairment group” has a lower cognitive score compared to HCs and one or two cognitive fields are damaged. The “Global cognitive impairment group” shows overall cognitive impairment [ 30 , 31 , 32 ]. There are differences in cognitive performance between subgroups of BD. BD-I performs significantly worse than BD-II in some cognitive performance, such as verbal memory, and processing speed [ 33 ]. However, BD-II has larger impairments in inhibition [ 34 ]. The study of cognitive subgroups and the varying impairments of the cognitive function in different subtypes of bipolar disorder will emerge as a prominent research focus in this field.

“individual”. Bipolar patients demonstrate increased intra-individual variability in cognitive processing, which can be observed through dispersion across tests within a single testing session or relative variability compared to their average performance over time [ 35 , 36 ]. In the future, we can study the intra-individual variability of cognitive ability of BD patients and its clinical significance。.

“validation”. The related content is the validation of cognitive assessment for bipolar disorder. The effectiveness of a cognitive assessment tool may vary among different individuals or regions, so it is necessary to verify its validity when applied in new situations. ICAT, an internet-based cognitive assessment tool, has been found to be feasible for large-scale assessment and monitoring of cognition in the clinical management of bipolar disorder [ 37 ]. The reliability and validity of the new cognitive assessment tools may be verified in future research. By utilizing existing cognitive assessment tools, we can determine the extent of cognitive impairment in BD patients, which can help identify therapeutic targets. For instance, a study has shown that many patients with BD have sleep problems, which can impact the process of cognitive testing and the accuracy of test results. It indicates that sleep maybe a potential target for treating cognitive disturbances in BD [ 38 ].

“pathophysiology”, major depressive disorder (MDD) and BD exhibit similar microstructural abnormalities in anterior callosal fibers, which can be considered as a basis for the neuropathy physiology of these two disorder [ 39 ]. Additionally, some evidence indicates that there is a connection between the dysfunction of the the hypothalamic-pituitary-adrenal (HPA) axis and impairments in neurocognitive function in BD. Dopamine neurotransmission is also believed to play an important role in the pathophysiology of BD [ 40 ]. By incorporating these findings into a coherent pathophysiological model, future research can generate testable hypotheses.

Strengths and limitations

Firstly, this study analyzes the research on the cognitive function of bipolar disorder using a bibliometrics system for the first time, providing valuable guidance for scholars interested in related research. Secondly, this article uses two bibliometrics tools, VOSviewer and CiteSpace, which have been widely used in the field of bibliometrics, ensuring an objective data analysis process.

At the same time, there are certain limitations. The data of this study only comes from the WoSCC database, other databases are ignored, and language restriction to English may result in the omission of relevant studies. Additionally, the time span considered in this study is from 2012 to 2022, excluding the year 2023 due to insufficient data.

Cognitive function has important research value and promising prospects for application in bipolar disorder. In general, the number of research papers is increasing, and there is a need for stronger collaboration among countries. Each journal has its scope, and researchers can choose an appropriate journal based on their article. On the one hand, the study of the neurocognitive subgroup of bipolar disorder helps us determine cognitive domains that are impaired in individuals with the disorder. This knowledge is valuable for diagnosing the disease process of bipolar disorder. On the other hand, with the development of society, the cognitive function assessment tools of bipolar disorder are also constantly updated, and these tools can help us understand the general situation of the patient before formal treatment. Therefore, it is of great application value to continuously verify the reliability and validity of new cognitive assessment tools. In addition, more treatment options can be explored in combination with other areas.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

We thank all authors who participated in the study.

The study was supported by the Research Project Supported by Shanxi Scholarship Council of China (2021 − 167) and the Scientific Research Project of Health Commission of Shanxi Province (2019007).

Author information

Xiaohong Cui and Tailian Xue contributed equally to this work.

Authors and Affiliations

Department of Psychology, School of Humanities and Social Sciences, Shanxi Medical University, Taiyuan, Shanxi, China

Tailian Xue & Zhiyong Zhang

Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China

Department of Psychiatry, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences,Tongji Shanxi Hospital, Taiyuan, 030032, China

Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China

Xiaohong Cui

Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

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Study design: YR, HY; data collection, analysis, and interpretation: TLX, XHC, YZZ; drafting of the manuscript: TLX; critical revision of the manuscript: XHC. All authors contributed to the article and approved the submitted version.

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Correspondence to Zhiyong Zhang or Yan Ren .

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Cui, X., Xue, T., Zhang, Z. et al. A bibliometric and visual analysis of cognitive function in bipolar disorder from 2012 to 2022. Ann Gen Psychiatry 23 , 13 (2024). https://doi.org/10.1186/s12991-024-00498-x

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• Bipolar disorder
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• Patient Care & Health Information
• Diseases & Conditions
• Bipolar disorder

To determine if you have bipolar disorder, your evaluation may include:

• Physical exam. Your doctor may do a physical exam and lab tests to identify any medical problems that could be causing your symptoms.
• Psychiatric assessment. Your doctor may refer you to a psychiatrist, who will talk to you about your thoughts, feelings and behavior patterns. You may also fill out a psychological self-assessment or questionnaire. With your permission, family members or close friends may be asked to provide information about your symptoms.
• Mood charting. You may be asked to keep a daily record of your moods, sleep patterns or other factors that could help with diagnosis and finding the right treatment.
• Criteria for bipolar disorder. Your psychiatrist may compare your symptoms with the criteria for bipolar and related disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published by the American Psychiatric Association.

Diagnosis in children

Although diagnosis of children and teenagers with bipolar disorder includes the same criteria that are used for adults, symptoms in children and teens often have different patterns and may not fit neatly into the diagnostic categories.

Also, children who have bipolar disorder are frequently also diagnosed with other mental health conditions such as attention-deficit/hyperactivity disorder (ADHD) or behavior problems, which can make diagnosis more complicated. Referral to a child psychiatrist with experience in bipolar disorder is recommended.

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• Bipolar disorder in children: Is it possible?

Treatment is best guided by a medical doctor who specializes in diagnosing and treating mental health conditions (psychiatrist) who is skilled in treating bipolar and related disorders. You may have a treatment team that also includes a psychologist, social worker and psychiatric nurse.

Bipolar disorder is a lifelong condition. Treatment is directed at managing symptoms. Depending on your needs, treatment may include:

• Medications. Often, you'll need to start taking medications to balance your moods right away.
• Continued treatment. Bipolar disorder requires lifelong treatment with medications, even during periods when you feel better. People who skip maintenance treatment are at high risk of a relapse of symptoms or having minor mood changes turn into full-blown mania or depression.
• Day treatment programs. Your doctor may recommend a day treatment program. These programs provide the support and counseling you need while you get symptoms under control.
• Substance abuse treatment. If you have problems with alcohol or drugs, you'll also need substance abuse treatment. Otherwise, it can be very difficult to manage bipolar disorder.
• Hospitalization. Your doctor may recommend hospitalization if you're behaving dangerously, you feel suicidal or you become detached from reality (psychotic). Getting psychiatric treatment at a hospital can help keep you calm and safe and stabilize your mood, whether you're having a manic or major depressive episode.

The primary treatments for bipolar disorder include medications and psychological counseling (psychotherapy) to control symptoms, and also may include education and support groups.

Medications

A number of medications are used to treat bipolar disorder. The types and doses of medications prescribed are based on your particular symptoms.

Medications may include:

• Mood stabilizers. You'll typically need mood-stabilizing medication to control manic or hypomanic episodes. Examples of mood stabilizers include lithium (Lithobid), valproic acid (Depakene), divalproex sodium (Depakote), carbamazepine (Tegretol, Equetro, others) and lamotrigine (Lamictal).
• Antipsychotics. If symptoms of depression or mania persist in spite of treatment with other medications, adding an antipsychotic drug such as olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), aripiprazole (Abilify), ziprasidone (Geodon), lurasidone (Latuda) or asenapine (Saphris) may help. Your doctor may prescribe some of these medications alone or along with a mood stabilizer.
• Antidepressants. Your doctor may add an antidepressant to help manage depression. Because an antidepressant can sometimes trigger a manic episode, it's usually prescribed along with a mood stabilizer or antipsychotic.
• Antidepressant-antipsychotic. The medication Symbyax combines the antidepressant fluoxetine and the antipsychotic olanzapine. It works as a depression treatment and a mood stabilizer.
• Anti-anxiety medications. Benzodiazepines may help with anxiety and improve sleep, but are usually used on a short-term basis.

Finding the right medication

Finding the right medication or medications for you will likely take some trial and error. If one doesn't work well for you, there are several others to try.

This process requires patience, as some medications need weeks to months to take full effect. Generally only one medication is changed at a time so that your doctor can identify which medications work to relieve your symptoms with the least bothersome side effects. Medications also may need to be adjusted as your symptoms change.

Side effects

Mild side effects often improve as you find the right medications and doses that work for you, and your body adjusts to the medications. Talk to your doctor or mental health professional if you have bothersome side effects.

Don't make changes or stop taking your medications. If you stop your medication, you may experience withdrawal effects or your symptoms may worsen or return. You may become very depressed, feel suicidal, or go into a manic or hypomanic episode. If you think you need to make a change, call your doctor.

Medications and pregnancy

A number of medications for bipolar disorder can be associated with birth defects and can pass through breast milk to your baby. Certain medications, such as valproic acid and divalproex sodium, should not be used during pregnancy. Also, birth control medications may lose effectiveness when taken along with certain bipolar disorder medications.

Discuss treatment options with your doctor before you become pregnant, if possible. If you're taking medication to treat your bipolar disorder and think you may be pregnant, talk to your doctor right away.

• Psychotherapy

Psychotherapy is a vital part of bipolar disorder treatment and can be provided in individual, family or group settings. Several types of therapy may be helpful. These include:

• Interpersonal and social rhythm therapy (IPSRT). IPSRT focuses on the stabilization of daily rhythms, such as sleeping, waking and mealtimes. A consistent routine allows for better mood management. People with bipolar disorder may benefit from establishing a daily routine for sleep, diet and exercise.
• Cognitive behavioral therapy (CBT). The focus is identifying unhealthy, negative beliefs and behaviors and replacing them with healthy, positive ones. CBT can help identify what triggers your bipolar episodes. You also learn effective strategies to manage stress and to cope with upsetting situations.
• Psychoeducation. Learning about bipolar disorder (psychoeducation) can help you and your loved ones understand the condition. Knowing what's going on can help you get the best support, identify issues, make a plan to prevent relapse and stick with treatment.
• Family-focused therapy. Family support and communication can help you stick with your treatment plan and help you and your loved ones recognize and manage warning signs of mood swings.

Other treatment options

Depending on your needs, other treatments may be added to your depression therapy.

During electroconvulsive therapy (ECT), electrical currents are passed through the brain, intentionally triggering a brief seizure. ECT seems to cause changes in brain chemistry that can reverse symptoms of certain mental illnesses. ECT may be an option for bipolar treatment if you don't get better with medications, can't take antidepressants for health reasons such as pregnancy or are at high risk of suicide.

Transcranial magnetic stimulation (TMS) is being investigated as an option for those who haven't responded to antidepressants.

Treatment in children and teenagers

Treatments for children and teenagers are generally decided on a case-by-case basis, depending on symptoms, medication side effects and other factors. Generally, treatment includes:

• Medications. Children and teens with bipolar disorder are often prescribed the same types of medications as those used in adults. There's less research on the safety and effectiveness of bipolar medications in children than in adults, so treatment decisions are often based on adult research.
• Psychotherapy. Initial and long-term therapy can help keep symptoms from returning. Psychotherapy can help children and teens manage their routines, develop coping skills, address learning difficulties, resolve social problems, and help strengthen family bonds and communication. And, if needed, it can help treat substance abuse problems common in older children and teens with bipolar disorder.
• Psychoeducation. Psychoeducation can include learning the symptoms of bipolar disorder and how they differ from behavior related to your child's developmental age, the situation and appropriate cultural behavior. Understanding about bipolar disorder can also help you support your child.
• Support. Working with teachers and school counselors and encouraging support from family and friends can help identify services and encourage success.
• Bipolar medications and weight gain
• Bipolar treatment: I vs. II
• Cognitive behavioral therapy
• Electroconvulsive therapy (ECT)
• Transcranial magnetic stimulation

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Lifestyle and home remedies

You'll probably need to make lifestyle changes to stop cycles of behavior that worsen your bipolar disorder. Here are some steps to take:

• Quit drinking or using recreational drugs. One of the biggest concerns with bipolar disorder is the negative consequences of risk-taking behavior and drug or alcohol abuse. Get help if you have trouble quitting on your own.
• Form healthy relationships. Surround yourself with people who are a positive influence. Friends and family members can provide support and help you watch for warning signs of mood shifts.
• Create a healthy routine. Having a regular routine for sleeping, eating and physical activity can help balance your moods. Check with your doctor before starting any exercise program. Eat a healthy diet. If you take lithium, talk with your doctor about appropriate fluid and salt intake. If you have trouble sleeping, talk to your doctor or mental health professional about what you can do.
• Check first before taking other medications. Call the doctor who's treating you for bipolar disorder before you take medications prescribed by another doctor or any over-the-counter supplements or medications. Sometimes other medications trigger episodes of depression or mania or may interfere with medications you're taking for bipolar disorder.
• Consider keeping a mood chart. Keeping a record of your daily moods, treatments, sleep, activities and feelings may help identify triggers, effective treatment options and when treatment needs to be adjusted.

Alternative medicine

There isn't much research on alternative or complementary medicine — sometimes called integrative medicine — and bipolar disorder. Most of the studies are on major depression, so it isn't clear how these nontraditional approaches work for bipolar disorder.

If you choose to use alternative or complementary medicine in addition to your physician-recommended treatment, take some precautions first:

• Don't stop taking your prescribed medications or skip therapy sessions. Alternative or complementary medicine is not a substitute for regular medical care when it comes to treating bipolar disorder.
• Be honest with your doctors and mental health professionals. Tell them exactly which alternative or complementary treatments you use or would like to try.
• Be aware of potential dangers. Alternative and complementary products aren't regulated the way prescription drugs are. Just because it's natural doesn't mean it's safe. Before using alternative or complementary medicine, talk to your doctor about the risks, including possible serious interactions with medications.

Coping and support

Coping with bipolar disorder can be challenging. Here are some strategies that can help:

• Learn about bipolar disorder. Education about your condition can empower you and motivate you to stick to your treatment plan and recognize mood changes. Help educate your family and friends about what you're going through.
• Stay focused on your goals. Learning to manage bipolar disorder can take time. Stay motivated by keeping your goals in mind and reminding yourself that you can work to repair damaged relationships and other problems caused by your mood swings.
• Join a support group. Support groups for people with bipolar disorder can help you connect to others facing similar challenges and share experiences.
• Find healthy outlets. Explore healthy ways to channel your energy, such as hobbies, exercise and recreational activities.
• Learn ways to relax and manage stress. Yoga, tai chi, massage, meditation or other relaxation techniques can be helpful.

Preparing for your appointment

You may start by seeing your primary care doctor or a psychiatrist. You may want to take a family member or friend along to your appointment, if possible, for support and to help remember information.

What you can do

Before your appointment, make a list of:

• Any symptoms you've had, including any that may seem unrelated to the reason for the appointment
• Key personal information, including any major stresses or recent life changes
• All medications, vitamins, herbs or other supplements you're taking, and the dosages
• Questions to ask your doctor

Some questions to ask your doctor may include:

• Do I have bipolar disorder?
• Are there any other possible causes for my symptoms?
• What kinds of tests will I need?
• What treatments are available? Which do you recommend for me?
• What side effects are possible with that treatment?
• What are the alternatives to the primary approach that you're suggesting?
• I have these other health conditions. How can I best manage these conditions together?
• Should I see a psychiatrist or other mental health professional?
• Is there a generic alternative to the medicine you're prescribing?
• Are there any brochures or other printed material that I can have?
• What websites do you recommend?

Don't hesitate to ask other questions during your appointment.

What to expect from your doctor

Your doctor will likely ask you a number of questions. Be ready to answer them to reserve time to go over any points you want to focus on. Your doctor may ask:

• When did you or your loved ones first begin noticing your symptoms?
• How frequently do your moods change?
• Do you ever have suicidal thoughts when you're feeling down?
• Do your symptoms interfere with your daily life or relationships?
• Do you have any blood relatives with bipolar disorder or depression?
• What other mental or physical health conditions do you have?
• Do you drink alcohol, smoke cigarettes or use recreational drugs?
• How much do you sleep at night? Does it change over time?
• Do you go through periods when you take risks that you wouldn't normally take, such as unsafe sex or unwise, spontaneous financial decisions?
• What, if anything, seems to improve your symptoms?
• What, if anything, appears to worsen your symptoms?
• Reilly-Harrington NA et al. A tool to predict suicidal ideation and behavior in bipolar disorder: The Concise Health Risk Tracking Self-Report. Journal of Affective Disorders. 2016;192:212.
• Bipolar and related disorders. In: Diagnostic and Statistical Manual of Mental Disorders DSM-5. 5th ed. Arlington, Va.: American Psychiatric Association; 2013. http://www.psychiatryonline.org. Accessed Dec. 2, 2016.
• Bipolar disorder. National Institute of Mental Health. https://www.nimh.nih.gov/health/topics/bipolar-disorder/index.shtml. Accessed Dec. 2, 2016.
• Bipolar disorder. National Institute of Mental Health. https://www.nimh.nih.gov/health/publications/bipolar-disorder-tr-15-3679/index.shtml. Accessed Dec. 2, 2016.
• Bipolar disorder in children and teens. National Institute of Mental Health. https://www.nimh.nih.gov/health/publications/bipolar-disorder-in-children-and-teens-qf-15-6380/index.shtml. Accessed Dec. 2, 2016.
• Bipolar disorder. National Alliance on Mental Illness. https://www.nami.org/Learn-More/Mental-Health-Conditions/Bipolar-Disorder. Accessed Dec. 2, 2016.
• AskMayoExpert. Bipolar disorder. Rochester, Minn.: Mayo Foundation for Medical Education and Research; 2016. Accessed Dec. 2, 2016.
• Suppes T, et al. Bipolar disorder in adults: Clinical features. http://www.uptodate.com/home. Accessed Dec. 2, 2016.
• Axelson D, et al. Pediatric bipolar disorder: Overview of choosing treatment. http://www.uptodate.com/home. Accessed Dec. 2, 2016.
• Birmaher B. Pediatric bipolar disorder: Epidemiology, pathogenesis, clinical manifestations, and course. http://www.uptodate.com/home. Accessed Dec. 2, 2016.
• Picardi A, et al. Psychotherapy of mood disorders. Clinical Practice and Epidemiology in Mental Health. 2014;10:140.
• Fountoulakis KN, et al. The International College of Neuro-Psychopharmacology (CINP) treatment guidelines for bipolar disorder in adults (CINP-BP-2017), part 2: Review, grading of the evidence and a precise algorithm. International Journal of Neuropsychopharmacology. In press. http://ijnp.oxfordjournals.org/content/early/2016/11/05/ijnp.pyw100.long. Accessed Dec. 6, 2016.
• Beyer JL, et al. Nutrition and bipolar depression. Psychiatric Clinics of North America. 2016;39:75.
• Qureshi NA, et al. Mood disorders and complementary and alternative medicine: A literature review. Neuropsychiatric Disease and Treatment. 2013;9:639.
• Sansone RA, et al. Getting a knack for NAC: N-acetyl-cysteine. Innovations in Clinical Neuroscience. 2011;8:10.
• Sylvia LG, et al. Nutrient-based therapies for bipolar disorder: A systematic review. Psychotherapy and Psychosomatics. 2013;82:10.
• Hall-Flavin DK (expert opinion). Mayo Clinic, Rochester, Minn. Dec. 27, 2016.
• Krieger CA (expert opinion). Mayo Clinic, Rochester, Minn. Jan. 4, 2017.
• Post RM. Bipolar disorder in adults: Choosing maintenance treatment. http://www.uptodate.com/home. Accessed Jan. 4, 2016.
• Janicak PG. Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects. http://www.uptodate.com/home. Accessed Jan. 4, 2017.
• Stovall J. Bipolar disorder in adults: Pharmacotherapy for acute mania and hypomania. http://www.uptodate.com/home. Accessed Jan. 4, 2017.
• Bipolar disorder and alcoholism: Are they related?

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Bipolar disorder research 2.0: Web technologies for research capacity and knowledge translation

Affiliations.

• 1 Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
• 2 Collaborative Research Team to study psychosocial issues in Bipolar Disorder (CREST.BD), Vancouver, BC, Canada.
• 3 School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.
• 4 Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada.
• 5 Rotman Research Institute, Baycrest, Toronto, Ontario, Canada.
• 6 University of Michigan, Ann Arbor, Michigan, USA.
• 7 University of Toronto, Toronto, Ontario, Canada.
• PMID: 28471066
• DOI: 10.1111/jep.12736

Rationale, aims and objectives: Current Web technologies offer bipolar disorder (BD) researchers many untapped opportunities for conducting research and for promoting knowledge exchange. In the present paper, we document our experiences with a variety of Web 2.0 technologies in the context of an international BD research network: The Collaborative RESearch Team to Study psychosocial issues in BD (CREST.BD).

Methods: Three technologies were used as tools for enabling research within CREST.BD and for encouraging the dissemination of the results of our research: (1) the crestbd.ca website, (2) social networking tools (ie, Facebook, Twitter), and (3) several sorts of file sharing (ie YouTube, FileShare). For each Web technology, we collected quantitative assessments of their effectiveness (in reach, exposure, and engagement) over a 6-year timeframe (2010-2016).

Results: In general, many of our strategies were deemed successful for promoting knowledge exchange and other network goals. We discuss how we applied our Web analytics to inform adaptations and refinements of our Web 2.0 platforms to maximise knowledge exchange with people with BD, their supporters, and health care providers.

Conclusions: We conclude with some general recommendations for other mental health researchers and research networks interested in pursuing Web 2.0 strategies.

Keywords: Web 2.0; bipolar disorder; community-based participatory research; knowledge translation; social media.

© 2017 John Wiley & Sons, Ltd.

• Biomedical Research / methods*
• Bipolar Disorder / therapy*
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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.

• Discovering Self-Love and Acceptance after Tragedy and Mental Illness
• Transcending the Self-Stigma From my Youth

Know the warning signs of mental illness

Learn more about common mental health conditions

NAMI HelpLine is available M-F, 10 a.m. – 10 p.m. ET. Call 800-950-6264 , text “helpline” to 62640 , or chat online. In a crisis, call or text 988 (24/7).

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April 23, 2024

Research in Context: Treating depression

Finding better approaches.

While effective treatments for major depression are available, there is still room for improvement. This special Research in Context feature explores the development of more effective ways to treat depression, including personalized treatment approaches and both old and new drugs.

Everyone has a bad day sometimes. People experience various types of stress in the course of everyday life. These stressors can cause sadness, anxiety, hopelessness, frustration, or guilt. You may not enjoy the activities you usually do. These feelings tend to be only temporary. Once circumstances change, and the source of stress goes away, your mood usually improves. But sometimes, these feelings don’t go away. When these feelings stick around for at least two weeks and interfere with your daily activities, it’s called major depression, or clinical depression.

In 2021, 8.3% of U.S. adults experienced major depression. That’s about 21 million people. Among adolescents, the prevalence was much greater—more than 20%. Major depression can bring decreased energy, difficulty thinking straight, sleep problems, loss of appetite, and even physical pain. People with major depression may become unable to meet their responsibilities at work or home. Depression can also lead people to use alcohol or drugs or engage in high-risk activities. In the most extreme cases, depression can drive people to self-harm or even suicide.

The good news is that effective treatments are available. But current treatments have limitations. That’s why NIH-funded researchers have been working to develop more effective ways to treat depression. These include finding ways to predict whether certain treatments will help a given patient. They're also trying to develop more effective drugs or, in some cases, find new uses for existing drugs.

Finding the right treatments

The most common treatments for depression include psychotherapy, medications, or a combination. Mild depression may be treated with psychotherapy. Moderate to severe depression often requires the addition of medication.

Several types of psychotherapy have been shown to help relieve depression symptoms. For example, cognitive behavioral therapy helps people to recognize harmful ways of thinking and teaches them how to change these. Some researchers are working to develop new therapies to enhance people’s positive emotions. But good psychotherapy can be hard to access due to the cost, scheduling difficulties, or lack of available providers. The recent growth of telehealth services for mental health has improved access in some cases.

There are many antidepressant drugs on the market. Different drugs will work best on different patients. But it can be challenging to predict which drugs will work for a given patient. And it can take anywhere from 6 to 12 weeks to know whether a drug is working. Finding an effective drug can involve a long period of trial and error, with no guarantee of results.

If depression doesn’t improve with psychotherapy or medications, brain stimulation therapies could be used. Electroconvulsive therapy, or ECT, uses electrodes to send electric current into the brain. A newer technique, transcranial magnetic stimulation (TMS), stimulates the brain using magnetic fields. These treatments must be administered by specially trained health professionals.

“A lot of patients, they kind of muddle along, treatment after treatment, with little idea whether something’s going to work,” says psychiatric researcher Dr. Amit Etkin.

One reason it’s difficult to know which antidepressant medications will work is that there are likely different biological mechanisms that can cause depression. Two people with similar symptoms may both be diagnosed with depression, but the causes of their symptoms could be different. As NIH depression researcher Dr. Carlos Zarate explains, “we believe that there’s not one depression, but hundreds of depressions.”

Depression may be due to many factors. Genetics can put certain people at risk for depression. Stressful situations, physical health conditions, and medications may contribute. And depression can also be part of a more complicated mental disorder, such as bipolar disorder. All of these can affect which treatment would be best to use.

Etkin has been developing methods to distinguish patients with different types of depression based on measurable biological features, or biomarkers. The idea is that different types of patients would respond differently to various treatments. Etkin calls this approach “precision psychiatry.”

One such type of biomarker is electrical activity in the brain. A technique called electroencephalography, or EEG, measures electrical activity using electrodes placed on the scalp. When Etkin was at Stanford University, he led a research team that developed a machine-learning algorithm to predict treatment response based on EEG signals. The team applied the algorithm to data from a clinical trial of the antidepressant sertraline (Zoloft) involving more than 300 people.

EEG data for the participants were collected at the outset. Participants were then randomly assigned to take either sertraline or an inactive placebo for eight weeks. The team found a specific set of signals that predicted the participants’ responses to sertraline. The same neural “signature” also predicted which patients with depression responded to medication in a separate group.

Etkin’s team also examined this neural signature in a set of patients who were treated with TMS and psychotherapy. People who were predicted to respond less to sertraline had a greater response to the TMS/psychotherapy combination.

Etkin continues to develop methods for personalized depression treatment through his company, Alto Neuroscience. He notes that EEG has the advantage of being low-cost and accessible; data can even be collected in a patient’s home. That’s important for being able to get personalized treatments to the large number of people they could help. He’s also working on developing antidepressant drugs targeted to specific EEG profiles. Candidate drugs are in clinical trials now.

“It’s not like a pie-in-the-sky future thing, 20-30 years from now,” Etkin explains. “This is something that could be in people's hands within the next five years.”

New tricks for old drugs

While some researchers focus on matching patients with their optimal treatments, others aim to find treatments that can work for many different patients. It turns out that some drugs we’ve known about for decades might be very effective antidepressants, but we didn’t recognize their antidepressant properties until recently.

One such drug is ketamine. Ketamine has been used as an anesthetic for more than 50 years. Around the turn of this century, researchers started to discover its potential as an antidepressant. Zarate and others have found that, unlike traditional antidepressants that can take weeks to take effect, ketamine can improve depression in as little as one day. And a single dose can have an effect for a week or more. In 2019, the FDA approved a form of ketamine for treating depression that is resistant to other treatments.

But ketamine has drawbacks of its own. It’s a dissociative drug, meaning that it can make people feel disconnected from their body and environment. It also has the potential for addiction and misuse. For these reasons, it’s a controlled substance and can only be administered in a doctor’s office or clinic.

Another class of drugs being studied as possible antidepressants are psychedelics. These include lysergic acid diethylamide (LSD) and psilocybin, the active ingredient in magic mushrooms. These drugs can temporarily alter a person’s mood, thoughts, and perceptions of reality. Some have historically been used for religious rituals, but they are also used recreationally.

In clinical studies, psychedelics are typically administered in combination with psychotherapy. This includes several preparatory sessions with a therapist in the weeks before getting the drug, and several sessions in the weeks following to help people process their experiences. The drugs are administered in a controlled setting.

Dr. Stephen Ross, co-director of the New York University Langone Health Center for Psychedelic Medicine, describes a typical session: “It takes place in a living room-like setting. The person is prepared, and they state their intention. They take the drug, they lie supine, they put on eye shades and preselected music, and two therapists monitor them.” Sessions last for as long as the acute effects of the drug last, which is typically several hours. This is a healthcare-intensive intervention given the time and personnel needed.

In 2016, Ross led a clinical trial examining whether psilocybin-assisted therapy could reduce depression and anxiety in people with cancer. According to Ross, as many as 40% of people with cancer have clinically significant anxiety and depression. The study showed that a single psilocybin session led to substantial reductions in anxiety and depression compared with a placebo. These reductions were evident as soon as one day after psilocybin administration. Six months later, 60-80% of participants still had reduced depression and anxiety.

Psychedelic drugs frequently trigger mystical experiences in the people who take them. “People can feel a sense…that their consciousness is part of a greater consciousness or that all energy is one,” Ross explains. “People can have an experience that for them feels more ‘real’ than regular reality. They can feel transported to a different dimension of reality.”

About three out of four participants in Ross’s study said it was among the most meaningful experiences of their lives. And the degree of mystical experience correlated with the drug’s therapeutic effect. A long-term follow-up study found that the effects of the treatment continued more than four years later.

If these results seem too good to be true, Ross is quick to point out that it was a small study, with only 29 participants, although similar studies from other groups have yielded similar results. Psychedelics haven’t yet been shown to be effective in a large, controlled clinical trial. Ross is now conducting a trial with 200 people to see if the results of his earlier study pan out in this larger group. For now, though, psychedelics remain experimental drugs—approved for testing, but not for routine medical use.

Unlike ketamine, psychedelics aren’t considered addictive. But they, too, carry risks, which certain conditions may increase. Psychedelics can cause cardiovascular complications. They can cause psychosis in people who are predisposed to it. In uncontrolled settings, they have the risk of causing anxiety, confusion, and paranoia—a so-called “bad trip”—that can lead the person taking the drug to harm themself or others. This is why psychedelic-assisted therapy takes place in such tightly controlled settings. That increases the cost and complexity of the therapy, which may prevent many people from having access to it.

Better, safer drugs

Despite the promise of ketamine or psychedelics, their drawbacks have led some researchers to look for drugs that work like them but with fewer side effects.

Depression is thought to be caused by the loss of connections between nerve cells, or neurons, in certain regions of the brain. Ketamine and psychedelics both promote the brain’s ability to repair these connections, a quality called plasticity. If we could understand how these drugs encourage plasticity, we might be able to design drugs that can do so without the side effects.

Dr. David Olson at the University of California, Davis studies how psychedelics work at the cellular and molecular levels. The drugs appear to promote plasticity by binding to a receptor in cells called the 5-hydroxytryptamine 2A receptor (5-HT2AR). But many other compounds also bind 5-HT2AR without promoting plasticity. In a recent NIH-funded study, Olson showed that 5-HT2AR can be found both inside and on the surface of the cell. Only compounds that bound to the receptor inside the cells promoted plasticity. This suggests that a drug has to be able to get into the cell to promote plasticity.

Moreover, not all drugs that bind 5-HT2AR have psychedelic effects. Olson’s team has developed a molecular sensor, called psychLight, that can identify which compounds that bind 5-HT2AR have psychedelic effects. Using psychLight, they identified compounds that are not psychedelic but still have rapid and long-lasting antidepressant effects in animal models. He’s founded a company, Delix Therapeutics, to further develop drugs that promote plasticity.

Meanwhile, Zarate and his colleagues have been investigating a compound related to ketamine called hydroxynorketamine (HNK). Ketamine is converted to HNK in the body, and this process appears to be required for ketamine’s antidepressant effects. Administering HNK directly produced antidepressant-like effects in mice. At the same time, it did not cause the dissociative side effects and addiction caused by ketamine. Zarate’s team has already completed phase I trials of HNK in people showing that it’s safe. Phase II trials to find out whether it’s effective are scheduled to begin soon.  

“What [ketamine and psychedelics] are doing for the field is they’re helping us realize that it is possible to move toward a repair model versus a symptom mitigation model,” Olson says. Unlike existing antidepressants, which just relieve the symptoms of depression, these drugs appear to fix the underlying causes. That’s likely why they work faster and produce longer-lasting effects. This research is bringing us closer to having safer antidepressants that only need to be taken once in a while, instead of every day.

—by Brian Doctrow, Ph.D.

Related Links

• How Psychedelic Drugs May Help with Depression
• Biosensor Advances Drug Discovery
• Neural Signature Predicts Antidepressant Response
• How Ketamine Relieves Symptoms of Depression
• Protein Structure Reveals How LSD Affects the Brain
• Predicting The Usefulness of Antidepressants
• Depression Screening and Treatment in Adults
• Serotonin Transporter Structure Revealed
• Placebo Effect in Depression Treatment
• When Sadness Lingers: Understanding and Treating Depression
• Psychedelic and Dissociative Drugs

References:  An electroencephalographic signature predicts antidepressant response in major depression.  Wu W, Zhang Y, Jiang J, Lucas MV, Fonzo GA, Rolle CE, Cooper C, Chin-Fatt C, Krepel N, Cornelssen CA, Wright R, Toll RT, Trivedi HM, Monuszko K, Caudle TL, Sarhadi K, Jha MK, Trombello JM, Deckersbach T, Adams P, McGrath PJ, Weissman MM, Fava M, Pizzagalli DA, Arns M, Trivedi MH, Etkin A.  Nat Biotechnol.  2020 Feb 10. doi: 10.1038/s41587-019-0397-3. Epub 2020 Feb 10. PMID: 32042166. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z, Corby P, Schmidt BL. J Psychopharmacol . 2016 Dec;30(12):1165-1180. doi: 10.1177/0269881116675512. PMID: 27909164. Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. Agin-Liebes GI, Malone T, Yalch MM, Mennenga SE, Ponté KL, Guss J, Bossis AP, Grigsby J, Fischer S, Ross S. J Psychopharmacol . 2020 Feb;34(2):155-166. doi: 10.1177/0269881119897615. Epub 2020 Jan 9. PMID: 31916890. Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors.  Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, Cameron LP, Patel SD, Hennessey JJ, Saeger HN, McCorvy JD, Gray JA, Tian L, Olson DE.  Science . 2023 Feb 17;379(6633):700-706. doi: 10.1126/science.adf0435. Epub 2023 Feb 16. PMID: 36795823. Psychedelic-inspired drug discovery using an engineered biosensor.  Dong C, Ly C, Dunlap LE, Vargas MV, Sun J, Hwang IW, Azinfar A, Oh WC, Wetsel WC, Olson DE, Tian L.  Cell . 2021 Apr 8: S0092-8674(21)00374-3. doi: 10.1016/j.cell.2021.03.043. Epub 2021 Apr 28. PMID: 33915107. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA Jr, Gould TD. Nature . 2016 May 26;533(7604):481-6. doi: 10.1038/nature17998. Epub 2016 May 4. PMID: 27144355.

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