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• Bipolar Disorder Symptoms and Traits

What Causes Bipolar Disorder?

• Is Bipolar Hereditary?
• How to Diagnose Bipolar Disorder
• Bipolar Disorder Treatments to Manage Symptoms
• When Your Loved One Has Bipolar Disorder

Bipolar Disorder Explained: Everything You Need to Know

What is bipolar disorder, living with bipolar disorder.

• Next in Bipolar Disorder Guide Bipolar Disorder Symptoms and Traits

Bipolar disorder refers to a group of mental health conditions characterized by sudden, dramatic changes in mood, energy, and behavior. Formerly known as manic depression, this condition causes mood episodes lasting days or weeks at a time and hinder day-to-day functioning, school or work performance, and relationships.

This article describes the symptoms , causes, and treatments for bipolar disorder and discusses how to cope if you’re diagnosed with this mental health condition.

FG Trade / Getty Images

Estimated to affect 4.4% of U.S. adults at some point in their lives, bipolar disorder causes distinct periods of extreme emotional states or episodes that can last for days or weeks. Episodes are characterized by manic or depressive behavior.

Manic Episodes

A manic episode is a phase of a week or more during which you have an elevated mood and energy most of the time for most days. In this phase, you may feel abnormally happy, agitated, restless, and don’t need much sleep.

In rare and severe cases, people experience hallucinations and delusions during manic episodes. In addition, some people experience hypomanic episodes—less severe manic episodes lasting four or more days.    

Everything You Should Know About Bipolar Disorder

Major depressive episodes.

A major depressive episode is a period of two or more weeks of depressive symptoms, such as sadness, hopelessness, lethargy (lack of energy), and apathy. These episodes can become severe, leading to suicidal thoughts. As with manic episodes, severe depressive episodes can lead to hallucinations or delusions.

What Are the Types of Bipolar Disorder?

Healthcare providers break down bipolar disorder into four primary types : bipolar 1, bipolar 2, cyclothymic disorder, and unspecified bipolar disorder.

Bipolar 1 Disorder

With bipolar 1 disorder, manic episodes last a week or become so severe that you require hospitalization. In most cases, bipolar 1 also causes depressive episodes. Some people have “mixed” episodes that feature both manic and depressive symptoms at the same time. Neutral periods—neither manic nor depressive—are also common with this type.

Bipolar 2 Disorder

Bipolar 2 disorder occurs when you experience one depressive episode and at least one hypomanic episode (milder manic episodes that last four or more days). In between these are symptom-free periods. Those with bipolar 2 disorder often have other mental health conditions, such as anxiety or depression.

Cyclothymic Disorder (Cyclothymia)

Cyclothymic disorder is a milder type of bipolar disorder that causes regular mood swings. Ranging between those of mild depression and hypomania, the symptoms aren’t severe enough to be considered clinically depressive or hypomanic episodes.

Unspecified Bipolar Disorder

Unspecified bipolar disorder is when you have extreme mood fluctuations, but the symptoms aren’t as bad as those of bipolar 1 or 2. Still, with this type, the symptoms are significant enough to affect daily functioning, relationships, and work or school.

Bipolar Disorder Symptoms

Dramatic and intense changes in your mood, emotions, behaviors, and activity level are the primary signs of bipolar disorder. These shifts tend to be noticeable to others and impact your relationships, performance at work or school, or daily functioning.

The symptoms you experience depend on whether you’re having a manic or depressive episode.

Manic Episode Symptoms

During manic episodes, emotion and activity levels are elevated. Manic episode symptoms include the following:

• Abnormal giddiness or happiness 
• Changing topics when speaking 
• Distractibility
• Feeling energetic despite insufficient sleep
• Increased irritability or agitation
• Racing, uncontrollable thoughts
• Recklessness or risky, impulsive behaviors
• Restlessness, increased activity
• Talking faster or more often

Major Depressive Episode Symptoms

In contrast to manic episodes, during a depressive episode, you feel “low” in terms of energy, mood, and emotion. Symptoms of this type include combinations of the following:

• Despair, thoughts about death or suicide
• Difficulty falling or staying asleep or sleeping excessively
• Difficulty with routine tasks
• Feeling sad, hopeless, or anxious
• Forgetfulness, slowed speech, not knowing what to say
• Loss of energy or motivation 
• Loss of interest in activities
• Restlessness

When to Call 911

If you have bipolar disorder, go to an emergency room (ER) if you experience:

• Suicidal thoughts 
• Thoughts about hurting yourself or others
• Hallucinations or delusions
• Lithium toxicity symptoms: nausea, vomiting, dizziness, changes in vision, and slurred speech

Researchers don’t know what exactly causes bipolar disorder. The consensus is that genetic factors, brain chemistry and structure, and environmental factors all play a role in this condition.  

Genetic Factors

Though more work is needed, researchers have linked genetics with an increased risk of developing bipolar disorder. This condition is heritable, making family history a risk factor; people with a parent or sibling with the condition are more likely to have it.

Brain Chemistry and Structure

Using imaging techniques, researchers have found differences between the brains of those with and without bipolar disorder. Some research shows that people with bipolar disorder have smaller subcortical structures (associated with mood and cognition) and a thinner cortex (the outer layer of the brain).

In addition, researchers have linked imbalances in certain neurotransmitters (brain chemicals), particularly dopamine and serotonin, to bipolar disorder.

Environmental Factors

Stressful or traumatic life events and certain behaviors can also raise your risk of developing bipolar disorder. Examples of traumatic events found to trigger attacks include childbirth, losing a job or a loved one, divorce, misusing or overusing drugs or alcohol, or traumatic head injuries.

How Is Bipolar Disorder Diagnosed?

To diagnose bipolar disorder, a healthcare provider will ask about your medical history, current medications, symptoms, and your family’s mental health history. You’ll also undergo a physical exam and, in some cases, blood tests to rule out other potential causes of bipolar disorder symptoms, such as hypothyroidism, stroke, and substance use disorder. 

A healthcare provider or a mental health specialist, like a psychiatrist or psychologist , will perform a mental health evaluation. They will diagnose bipolar disorder and identify the type based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).     

Diagnosing Bipolar 1 Disorder

According to the DSM-5, to be diagnosed with bipolar 1 disorder, you must have had at least one manic episode. This may be followed or preceded by a hypomanic or major depressive episode. While hypomanic or major depressive episodes can occur in bipolar 1, they are not required for a diagnosis.

In bipolar 1 disorder, manic episodes last at least one week or are severe enough to require hospitalization. A healthcare provider will look for at least three (or four if you experience irritability) of the following to diagnose you with bipolar 1 disorder:

• An inflated self-esteem or sense of grandiosity
• Difficulty concentrating; being easily distracted
• Increased activities, agitation, toe-tapping, pacing, or other unnecessary movements
• Increased engagement in unusually risky or self-destructive activities    
• Racing thoughts; thoughts in flight
• Reduced need for sleep

Diagnosing Bipolar 2 Disorder

A diagnosis of bipolar 2 disorder is made based on four criteria:  

• A current or past episode of hypomania and at least one major depressive episode 
• Never having a manic episode 
• No other psychological or neurological issues can explain the symptoms
• The mood changes cause impairments in social, personal, and professional life and daily functioning

"Hypomania" is defined as at least four days of manic symptoms that aren’t as severe or numerous as with a full manic episode. Major depressive episodes are defined as having daily or nearly daily symptoms for at least two weeks. According to the DSM-5, these are diagnosed when you display five of the following criteria:

• Agitation, toe-tapping, or pacing
• A lack of interest or enjoyment in life
• Decreased ability to concentrate
• Depression, sadness
• Fatigue, insufficient energy
• Inappropriate guilt or lack of self-worth
• Thinking about suicide without making a concrete plan (suicidal ideation)
• Weight loss without dieting, weight gain, decrease or increase in appetite

Diagnostic Criteria for Cyclothymic Disorder

In the DSM-5, among the criteria for cyclothymic disorder are the following:

• You have neutral, asymptomatic periods for no more than three months at a time.
• Symptoms arise independent of substance use disorder. 
• Symptoms hinder your ability to function and impact your work, school, home, or social life.
• Symptoms are inconsistent with bipolar 1 or 2 or another mental health condition.
• You experience two or more years of hypomania and depressive episodes if an adult and at least one year of symptoms if a child.

Bipolar Disorder Treatment

Treating bipolar disorder typically involves adopting multiple strategies, including medications, counseling, and lifestyle changes.

Medications

Antidepressants, mood stabilizers, and atypical antipsychotics are medication types that healthcare providers consider. A healthcare provider may prescribe selective serotonin reuptake inhibitors (SSRIs), a class of antidepressants, for depression associated with bipolar disorder. However, these can cause what is known as cycling—rapid mood shifts—so healthcare providers prescribe them with caution.

Mood-stabilizing drugs, such as Lithobid (lithium) and Depacon (valproate), are indicated alongside SSRIs and help ease or shorten the length of mood episodes. A provider may also prescribe medications to address insomnia (sleep problems) and anxiety, which often accompany bipolar disorder.

Medication Side Effects

The side effects of medications depend on the type you’re taking. For bipolar disorder, the most common of these are unintended weight gain, sedation, restlessness, and changes in metabolism. 

Psychotherapy and Counseling

Psychotherapy and counseling involve talk therapy with a psychiatrist, therapist, or trained counselor. This work aims to identify and change problematic behaviors, thoughts, or emotions that set off episodes. Another alternative is cognitive behavioral therapy (CBT), which focuses on changing thought patterns.

Lifestyle Changes

Alongside medical treatments or therapy, lifestyle changes can help you manage bipolar disorder, including:

• Relax : Activities like yoga or meditation may help ease anxiety and help with symptoms.
• Stay active : Regular exercise improves sleep and helps with stress, among other benefits.
• Dietary changes : Poor diet is associated with an increased risk for bipolar disorder and a reduced risk of co-occurring conditions. 
• Avoid substances : Drinking alcohol, smoking tobacco, or using recreational drugs can all increase the risk of bipolar symptoms.
• Education : Understand the symptoms of bipolar disorder and keep track of events or things that trigger symptoms; know your medications and their side effects.

Living with bipolar disorder means finding a support system , developing coping mechanisms, and managing the shifts in your mood and behaviors. Strategies that can help include:

• Adding structure to your daily activities
• Enlisting loved ones and/or family members in your care
• Ensuring you’re getting regular exercise and enough sleep
• Making sure to take part in enjoyable activities, staying connected to friends, family, and the local community
• Seeking out social support from online or in-person support groups, social media, or message boards
• Seeking treatment, developing a treatment plan with your healthcare provider
• Tracking and logging your symptoms, medications, and triggers

Bipolar disorder causes dramatic and lasting mood and behavior shifts. People with the condition go through high-energy manic episodes and often also experience depressive episodes. Because of its effects on behavior, bipolar disorder can significantly impact your professional, academic, and/or personal life. If you suspect you or someone you care for has this condition, talk to a healthcare provider for an accurate diagnosis and treatment.

American Psychiatric Association.  What are bipolar disorders?

MedlinePlus. Bipolar disorder .

National Institute of Mental Health. Bipolar disorder: definition . 

National Institute of Mental Health. Bipolar disorder: overview .

National Alliance on Mental Illness (NAMI). Bipolar disorder .

MedlinePlus. Lithium toxicity . 

Rowland TA, Marwaha S. Epidemiology and risk factors for bipolar disorder . Ther Adv Psychopharmacol . 2018 26;8(9):251-269. doi:10.1177/2045125318769235.

Abé C, Liberg B, Klahn AL, Petrovic P, Landén M. Mania-related effects on structural brain changes in bipolar disorder – a narrative review of the evidence.  Mol Psychiatry . 2023;28(7):2674-2682. doi:10.1038/s41380-023-02073-4

Lee JG, Woo YS, Park SW, Seog DH, Seo MK, Bahk WM. Neuromolecular etiology of bipolar disorder: possible therapeutic targets of mood stabilizers .  Clin Psychopharmacol Neurosci . 2022;20(2):228-239. doi:10.9758/cpn.2022.20.2.228

Substance Abuse and Mental Health Services Administration. DSM-5 changes: implications for child serious emotional disturbance . Substance Abuse and Mental Health Services Administration; 2016. Table 12, DSM-IV to DSM-5 Bipolar I Disorder Comparison.

Perugi G, Hantouche E, Vannucchi G.  Diagnosis and treatment of cyclothymia: the "primacy" of temperament .  Curr Neuropharmacol . 2017;15(3):372-379. doi:10.2174/1570159X14666160616120157

Marzani G, Neff AP. Bipolar disorders: evaluation and treatment .  Am Fam Physician.  2021;103(4):227-239

Bauer IE, Gálvez JF, Hamilton JE, et al. Lifestyle interventions targeting dietary habits and exercise in bipolar disorder: A systematic review .  J Psychiatr Res . 2016;74:1-7. doi:10.1016/j.jpsychires.2015.12.006

By Mark Gurarie Gurarie is a freelance writer and editor. He is a writing composition adjunct lecturer at George Washington University.  

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Diagnosis and management of bipolar disorders

• Related content
• 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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• Review Article
• Published: 15 April 2021

A unified model of the pathophysiology of bipolar disorder

• Paola Magioncalda   ORCID: orcid.org/0000-0003-4985-4819 1 , 2 , 3   na1 &
• Matteo Martino   ORCID: orcid.org/0000-0002-3783-707X 1 , 2   na1  

Molecular Psychiatry volume  27 ,  pages 202–211 ( 2022 ) Cite this article

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• Bipolar disorder
• Neuroscience

This work provides an overview of the most consistent alterations in bipolar disorder (BD), attempting to unify them in an internally coherent working model of the pathophysiology of BD. Data on immune-inflammatory changes, structural brain abnormalities (in gray and white matter), and functional brain alterations (from neurotransmitter signaling to intrinsic brain activity) in BD were reviewed. Based on the reported data, (1) we hypothesized that the core pathological alteration in BD is a damage of the limbic network that results in alterations of neurotransmitter signaling. Although heterogeneous conditions can lead to such damage, we supposed that the main pathophysiological mechanism is traceable to an immune/inflammatory-mediated alteration of white matter involving the limbic network connections, which destabilizes the neurotransmitter signaling, such as dopamine and serotonin signaling. Then, (2) we suggested that changes in such neurotransmitter signaling (potentially triggered by heterogeneous stressors onto a structurally-damaged limbic network) lead to phasic (and often recurrent) reconfigurations of intrinsic brain activity, from abnormal subcortical–cortical coupling to changes in network activity. We suggested that the resulting dysbalance between networks, such as sensorimotor networks, salience network, and default-mode network, clinically manifest in combined alterations of psychomotricity, affectivity, and thought during the manic and depressive phases of BD. Finally, (3) we supposed that an additional contribution of gray matter alterations and related cognitive deterioration characterize a clinical–biological subgroup of BD. This model may provide a general framework for integrating the current data on BD and suggests novel specific hypotheses, prompting for a better understanding of the pathophysiology of BD.

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Magioncalda, P., Martino, M. A unified model of the pathophysiology of bipolar disorder. Mol Psychiatry 27 , 202–211 (2022). https://doi.org/10.1038/s41380-021-01091-4

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• Published: 06 November 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

Study on research needs

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

Study on care needs

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

Participants and data collection

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

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

Data analysis

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

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

Ethical considerations

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

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

Characteristics of the participants

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Generic care needs

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

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

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

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

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

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

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

Strengths, limitations and future research

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

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

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

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Authors’ contributions

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Study samples’ characteristics

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

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

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

Data collection

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

Data analysis

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

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

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

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

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

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

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

Theme one: knowledge about the disorder

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

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

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

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

Theme two: information about the medications

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

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

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

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

Theme three: information about the treatment

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

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

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

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

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

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

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

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

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

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

Theme five: reasons for pharmacological treatment non-adherence

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Availability of data and materials

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

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Acknowledgements

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

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

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

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Zahra Taherifar

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

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

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

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DOI : https://doi.org/10.1186/s12888-020-03008-x

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Diagnosis and treatment of patients with bipolar disorder: A review for advanced practice nurses

Ursula mccormick.

1 Medical Services, Centerstone of Indiana, Bloomington, Indiana

Bethany Murray

2 Indiana University School of Nursing, Columbus, Indiana

Brittany McNew

This review article provides an overview of the frequency, burden of illness, diagnosis, and treatment of bipolar disorder (BD) from the perspective of the advanced practice nurses (APNs).

Data sources

PubMed searches were conducted using the following keywords: “bipolar disorder and primary care,” restricted to dates 2000 to present; “bipolar disorder and nurse practitioner”; and “bipolar disorder and clinical nurse specialist.” Selected articles were relevant to adult outpatient care in the United States, with a prioritization of articles written by APNs or published in nursing journals.

Conclusions

BD has a substantial lifetime prevalence in the population at 4%. Because the manic or depressive symptoms of BD tend to be severe and recurrent over a patient's lifetime, the condition is associated with significant burden to the individual, caregivers, and society. Clinician awareness that BD may be present increases the likelihood of successful recognition and appropriate treatment. A number of pharmacological and nonpharmacological treatments are available for acute and maintenance treatments, with the prospect of achieving reduced symptom burden and increased functioning for many patients.

Implications for practice

Awareness of the disease burden, diagnostic issues, and management choices in BD has the potential to enhance outcome in substantial proportions of patients.

Introduction

Bipolar disorder (BD) is a chronic illness associated with severely debilitating symptoms that can have profound effects on both patients and their caregivers (Miller, 2006 ). BD typically begins in adolescence or early adulthood and can have life‐long adverse effects on the patient's mental and physical health, educational and occupational functioning, and interpersonal relationships (Valente & Kennedy, 2010 ). Although not as common as major depressive disorder (MDD), the lifetime prevalence of BD in the United States is substantial (estimated at approximately 4%), with similar rates regardless of race, ethnicity, and gender (Ketter, 2010 ; Merikangas et al., 2007 ). Long‐term outcomes are persistently suboptimal (Geddes & Miklowitz, 2013 ). The economic burden of BD to society is enormous, totaling almost $120 billion in the United States in 2009. These costs include the direct costs of treatment and indirect costs from reduced employment, productivity, and functioning (Dilsaver, 2011 ). Given the burden of illness to the individual and to society, there is an urgent need to improve the care of patients with BD.

There is a growing recognition of the substantial contribution that advanced practice nurses (APNs) such as nurse practitioners (NPs) and clinical nurse specialists (CNSs) can make in the recognition and care of patients with BD (Culpepper, 2010 ; Miller, 2006 ). Most patients with BD present initially to primary care providers, but—through a lack of resources or expertise—many do not receive an adequate evaluation for possible bipolar diagnosis (Manning, 2010 ). Early recognition can lead to earlier initiation of effective therapy, with beneficial effects on both the short‐term outcome and the long‐term course of the illness (Geddes & Miklowitz, 2013 ; Manning, 2010 ). Patients with BD are also likely to have other psychiatric and medical comorbidities, and, therefore, rely on their primary care provider for holistic care (Kilbourne et al., 2004 ; Krishnan, 2005 ). Finally, the importance of collaborative, team‐based care is increasingly recognized in managing BD. APNs, by their training and experience, are well suited to facilitate optimal patient care in collaboration with the other healthcare team members (Bauer et al., 2006 ; Chung et al., 2007 ). An especially important role for APNs within primary care lies in the care of the patient, while specialists manage the bipolar illness. It is essential that these two specialties collaborate in order to stay abreast of each other's current phase of treatment.

This review provides an up‐to‐date discussion of the principles and practices of managing BD in the primary care setting. Our emphasis is on holistic, team‐oriented, multimodal approaches to care, which is compatible with the experience and therapeutic orientation of APNs.

Diagnosis of BD

Definitions in bd.

Patients with BD experience recurrent episodes of pathologic mood states, characterized by manic or depressive symptoms, which are interspersed by periods of relatively normal mood (euthymia; Figure ​ Figure1; 1 ; Vieta & Goikolea, 2005 ). Formal definitions of manic and depressive symptoms are included in the recently updated Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ( DSM‐5 ; American Psychiatric Association, 2013 ). Notably, the depressive episodes of BD are defined by the same criteria as MDD in the DSM‐5 , so that distinguishing BD from MDD frequently depends on identifying a history of manic or hypomanic symptoms (Table 1 ).

Mood range and associated mood diagnosis (Vieta & Goikolea, 2005 ).

Diagnostic criteria for BD diagnoses: Overview of DSM‐5

Adapted from DSM‐5 (American Psychiatric Association, 2013 ). Readers are referred to the full DSM‐5 criteria published by the American Psychiatric Association ( 2013 ) for establishing a bipolar diagnosis.

There are two major types of BD. Bipolar I disorder (BD I) is defined by the presence of at least one episode of mania, whereas bipolar II disorder (BD II) is characterized by at least one episode of hypomania and depression. The main distinction between mania and hypomania is the severity of the manic symptoms: mania results in severe functional impairment, it may manifest as psychotic symptoms, and often requires hospitalization; hypomania does not meet these criteria (American Psychiatric Association, 2013 ).

The duration of mood episodes is highly variable, both between patients and in an individual patient over time, but, in general, a hypomanic episode may last days to weeks, a manic episode lasts weeks to months, and a depressive episode may last months to years (Benazzi, 2007 ; Manning, 2010 ; Valente & Kennedy, 2010 ). Although a history of depressive episodes is not required to make a diagnosis of BD I by the DSM‐5 criteria, in practice most patients do experience depressive episodes; however, depressive episodes are required for a diagnosis of BD II. Long‐term studies show that patients with BD, regardless of the subtype, experience symptomatic episodes of depression more frequently and for longer durations than manic or hypomanic episodes (Baldessarini et al., 2010 ; Geddes & Miklowitz, 2013 ; Judd et al., 2003 ; Valente & Kennedy, 2010 ).

While a mood episode may consist solely of manic or depressive symptoms, it may also include a combination of these symptoms. Such episodes are newly defined in DSM‐5 as either a manic or hypomanic episode with mixed features or a depressive episode with mixed features, depending on which symptoms are predominant (American Psychiatric Association, 2013 ; Table 1 ).

Rapid cycling is a term describing the occurrence of at least four mood episodes within 1 year. Identification of rapid cycling is important, because these patients are less responsive to treatment. Rapid cycling should be considered a “red flag” that indicates the need for referral to specialist care.

Diagnostic criteria for BD

Successful assessment and treatment by the healthcare team requires knowledge of the episodic nature of BD. Diagnosis of a full‐blown manic episode may be relatively straightforward. If presenting to primary care, these patients may require immediate referral to specialist hospital care because of the risk of harm to self or others. However, more common in the primary care setting is the presentation of patients with depressive symptoms, who require a differentiation between BD and MDD (Cerimele, Chwastiak, Chan, Harrison, & Unutzer, 2013 ; Sasdelli et al., 2013 ). For this reason, all patients presenting with depressive symptoms should be assessed for a history of manic or hypomanic symptoms (Cerimele et al., 2013 ; Sasdelli et al., 2013 ; Valente & Kennedy, 2010 ).

Use of a bipolar screening tool is a time‐efficient first step in diagnosis, to be followed by a confirmatory clinical interview. The Mood Disorder Questionnaire (MDQ, Table 2 ) and the Composite International Diagnostic Interview, version 3.0 (CIDI 3.0), are commonly used screening tools in which scores above specific cut‐off values raise a suspicion of BD (Hirschfeld et al., 2000 ; Kessler & Ustun, 2004 ). Web‐based and electronic screening tools are also being developed with the aim of greater time efficiency (Gaynes et al., 2010 ; Gill, Chen, Grimes, & Klinkman, 2012 ). A comprehensive recent review of the screening tools in BD is provided by Hoyle, Elliott, and Comer ( 2015 ). While screening tools can help to recognize patients likely to have BD and can improve the efficiency of the clinical interview, it is important to note that case‐finding tools are not infallible and cannot replace the interview.

The Mood Disorder Questionnaire

Adapted from Hirschfeld et al. ( 2000 ).

The clinical interview should aim to establish the following (Manning, 2010 ; Price & Marzani‐Nissen, 2012 ):

• ▪ The presence of past or current episodes of manic or depressive symptoms, as described in DSM‐5
• ▪ The duration and severity of these episodes, including the presence of suicidal or homicidal ideation
• ▪ The impact of mood episodes on functioning in work, social, and family roles
• ▪ The presence of comorbidities (such as substance abuse, personality disorder, and anxiety disorder including posttraumatic stress disorder)
• ▪ The history of treatments administered and the response to treatments
• ▪ The family history.

In cases of continued diagnostic uncertainty, a formal diagnosis of BD may require a consultation with an experienced primary care physician, psychiatrist, psychologist, or APN to confirm the presence of DSM‐5 criteria, as well as to categorize the bipolar subtype that is present. The clinical interview, besides establishing the bipolar diagnosis, represents an important element in treatment planning, by helping to select the optimal medication(s) and the optimal site of treatment—either within primary care or by involving specialist psychiatric support. Finally, continued interviews over the course of treatment will help establish rapport and trust with the patient that encourages communication and enhances treatment adherence (Zolnierek & Dimatteo, 2009 ). Open dialogue between the healthcare worker and patient represents an essential element of patient interviews.

Other elements of the patient interview should include a physical examination and laboratory tests, with the particular aim to exclude disorders that can mimic bipolar symptoms, for example, hypothyroidism or hyperthyroidism, infection, and substance misuse (Krishnan, 2005 ). Psychiatric disorders (e.g., panic disorder, posttraumatic stress disorder) other than MDD can also mimic symptoms of BD and these should be considered in the differential diagnosis (Goldberg, 2010 ).

In establishing a BD diagnosis, it can be very informative to ask family members or close friends to provide a description of the patient's symptoms (with, of course, the patient's consent). Lack of insight is a characteristic of patients with BD, and hypomanic symptoms, in particular, may not be considered a manifestation of the illness by the patient. This is also an opportunity to assess the burden that family or friends may be experiencing as well as their current relationships with the patient (National Collaborating Centre for Mental Health [UK], 2006 ).

Misdiagnosis and underdiagnosis

Because MDD is more common than BD, and because MDD and BD have similar symptoms, it is very common for BD to be misdiagnosed as MDD (Manning, 2010 ; Miller, 2006 ). In one study, over 60% of patients who were eventually diagnosed with BD had previously been misdiagnosed with MDD.

A number of adverse consequences can result from the misdiagnosis and underdiagnosis of BD (Hirschfeld, 2007 ; Manning, 2010 ; McCombs, Ahn, Tencer, & Shi, 2007 ). Most importantly, patients with BD who are misdiagnosed with MDD may be treated with conventional antidepressant monotherapy. Compared with appropriately treated patients, such patients are less likely to respond, are at increased risk of a switch to mania, and may experience an acceleration of mood cycling (Manning, 2010 ; Miller, 2006 ; Sidor & Macqueen, 2011 ; Vieta & Valenti, 2013 ).

Sharing the diagnosis

Discussing the diagnosis with the patient is critical to laying a foundation for effective treatment. The acceptance of a BD diagnosis may be difficult and often occurs over time. The initial diagnosis is frequently provisional, and requires additional observations or confirmatory historical information. It can also be expected that patients will show resistance to the diagnosis, possibly because of the social stigma of having a mental illness. One of the best tools to facilitate acceptance of the diagnosis is motivational interviewing, which is a form of counseling that elicits and strengthens the patient's motivation for change through a process of collaboration and rapport. Motivational interviewing was developed for patients with an alcohol or drug problem, but has been applied more broadly in recent years (Laakso, 2012 ). Having patience and persistence in helping patients to “own” their BD, and take responsibility for managing it, is an important objective in motivational interviewing (Laakso, 2012 ).

Pharmacotherapy

Pharmacological treatment is fundamental for successfully managing patients with BD. For acute episodes, the objective is symptom reduction, with the ultimate goal of full remission. For maintenance treatment, the goal is to prevent the recurrences of mood episodes. Medications used in the treatment of BD include mood stabilizers (e.g., lithium, valproate, lamotrigine, and carbamazepine), atypical antipsychotics, and conventional antidepressants (Geddes & Miklowitz, 2013 ; Hirschfeld, Bowden, & Gitlin, 2002 ). Table 3 lists the medications that are approved by the U.S. Food and Drug Administration (FDA) in treating the different phases of BD.

Medications with FDA indication for treatment of BD

*Also used adjunctively but not FDA indicated.

A, adjunctive to a mood stabilizer; C, combination therapy with another mood stabilizer, antipsychotic, or antidepressant; M, monotherapy; RLAI risperidone long‐acting injectable; X, recommended in guidelines but not FDA indicated.

Mood stabilizers

Lithium was the first agent to be used in the treatment of BD. Although it has many limitations, including a delayed onset of action in the treatment of acute mania, limited efficacy in the treatment of bipolar depression, and a narrow therapeutic window, lithium still has an important role today (Geddes, Burgess, Hawton, Jamison, & Goodwin, 2004 ; Hirschfeld et al., 2002 ). In particular, lithium has shown efficacy in preventing recurrence of manic episodes and it is the only medication correlated with a reduced risk of suicide in BD. A study that reduced the lithium dosage (to increase its tolerability) reported no benefit from using lithium plus optimized personalized treatment when compared to optimized personalized treatment alone (Nierenberg et al., 2013 ).

Sodium valproate is the most commonly used mood stabilizer. It has a more rapid onset of action than lithium for the acute treatment of mania, and was superior to placebo as an acute therapy in the largest study performed to date (Bowden et al., 1994 ), but the evidence for its efficacy as a maintenance treatment for mania is not so robust (Geddes et al., 2010 ; Kessing, Hellmund, Geddes, Goodwin, & Andersen, 2011 ). Placebo‐controlled studies of carbamazepine describe significant efficacy in acute mania (Weisler, Kalali, & Ketter, 2004 ; Weisler et al., 2005 ). In the absence of long‐term controlled studies, a naturalistic study over an average of 10 years reported that carbamazepine is efficacious in most patients (Chen & Lin, 2012 ). Lamotrigine, in contrast to the other mood stabilizers, is more effective for preventing the recurrence of depressive than manic episodes of BD (Vieta & Valenti, 2013 ). Lamotrigine has also been investigated for the treatment of acute bipolar depression, but the evidence for efficacy is less convincing (Geddes, Calabrese, & Goodwin, 2009 ). A study of lamotrigine in acute mania reported no significant difference from placebo (Frye et al., 2000 ).

There are a number of safety and tolerability concerns with mood stabilizers that impact their long‐term use. Lithium requires regular monitoring of blood levels, because the therapeutic window is narrow. Lithium can cause progressive renal insufficiency and thyroid toxicity. After initial assessment of renal and thyroid functions, repeat monitoring of renal and thyroid functions every 6 months is recommended to ensure normal functioning (Price & Heninger, 1994 ). The most common adverse events associated with lithium include tremors as well as gastrointestinal problems such as nausea, vomiting, and diarrhea. Hepatotoxicity is the most common serious adverse event associated with valproate (risk: 1/20,000); other adverse effects include nausea, dizziness, somnolence, lethargy, infection, tinnitus, and cognitive impairment. Monitoring is required for hematologic abnormalities including low platelet count, low white blood count, and, in some cases, bone marrow suppression during valproate therapy (Martinez, Russell, & Hirschfeld, 1998 ). Carbamazepine is associated with reduced tolerability during rapid dose titration and its potential for interaction with other psychiatric and nonpsychiatric medications further limits its use (Grunze et al., 2009 ). Carbamazepine has an FDA boxed warning for agranulocytosis and aplastic anemia and is associated in approximately 10% of patients with the formation of a benign rash. Lamotrigine, which is overall the best‐tolerated medication in this class, can cause a rash like the Stevens–Johnson rash. Lamotrigine has been studied specifically in relation to fetal cleft palate formation; however, the evidence remains unconvincing. Fetal exposure to valproate, carbamazepine, and lithium can be teratogenic (Connolly & Thase, 2011 ; Dodd & Berk, 2004 ; Geddes & Miklowitz, 2013 ; Hirschfeld et al., 2002 ; Tatum, 2006 ).

Atypical antipsychotics

The atypical antipsychotics were developed in the modern era of psychopharmacology; all agents in this class have been studied by randomized controlled trials in the treatment of BD (Derry & Moore, 2007 ; Yatham et al., 2013 ). For the treatment of acute bipolar mania, all approved atypical antipsychotics (also called “second‐generation” antipsychotics) demonstrate efficacy and acceptable safety. For acute bipolar depression, however, few atypical antipsychotics have demonstrated efficacy. Only quetiapine (immediate‐release [IR] and extended‐release [XR] formulations) has proven efficacy as monotherapy for treating acute depressive episodes of BD I or BD II (Table 3 ; Calabrese et al., 2005 ; Suppes et al., 2010 ; Thase et al., 2006 ). A fixed‐dose combination of olanzapine and fluoxetine has demonstrated efficacy for treating acute depressive episodes of BD I (Tohen et al., 2003 ) and lurasidone has recently received FDA approval as monotherapy or adjunctive therapy (with either lithium or valproate) in BD I but not BD II (Loebel et al., 2014a , 2014b ).

For the maintenance treatment of BD I, FDA‐approved atypical antipsychotics include aripiprazole, olanzapine, quetiapine (IR and XR), risperidone long‐acting injection (LAI), and ziprasidone; these agents are approved either as monotherapy or as adjunctive therapy in combination with a mood stabilizer. A recent meta‐analysis of trials of the atypical antipsychotics in maintenance treatment concluded that aripiprazole, olanzapine, quetiapine (IR or XR), and risperidone LAI monotherapy were statistically superior to placebo for treating manic or mixed episodes, while quetiapine alone was also significantly effective against recurrence of depressive episodes (Vieta et al., 2011 ).

The safety and tolerability profiles of the atypical antipsychotics have been well characterized in patients with BD. A number of safety issues are associated with these drugs as a class, including sedation/somnolence, metabolic effects (e.g., weight gain, hyperglycemia, and dyslipidemia), and extrapyramidal side effects (EPS). The relative risk of these effects differs between individual atypical antipsychotics. For example, the risk of adverse metabolic effects is reported to be greatest with olanzapine and lowest with ziprasidone, and intermediate with quetiapine and risperidone (Perlis, 2007 ). Adjunctive therapies that include atypical antipsychotics in combination with other agents (usually mood stabilizers) are also associated with a greater risk of adverse events than monotherapies (Smith, Cornelius, Warnock, Tacchi, & Taylor, 2007 ). Given the propensity of atypical antipsychotics to adversely affect weight, lipid levels, and other metabolic parameters, it is important to monitor patients regularly (Hirschfeld et al., 2002 ; The Management of Bipolar Disorder Working Group, 2010 ).

Conventional antidepressants

The proper use of conventional antidepressants is an area of controversy in the treatment of BD (Pacchiarotti et al., 2013 ). The main concern in using antidepressants as monotherapy in patients with bipolar depression is the risk of precipitating a switch to mania/hypomania, which is estimated to occur in between 3% and 15% of cases (Pacchiarotti et al., 2013 ; Tondo, Baldessarini, Vazquez, Lepri, & Visioli, 2013 ; Vazquez, Tondo, & Baldessarini, 2011 ). Another unresolved issue is whether maintenance treatment that includes antidepressants is effective for the prevention of recurrence (Pacchiarotti et al., 2013 ; Vazquez et al., 2011 ). If conventional antidepressants are used, it is recommended to combine them with a mood stabilizer or an atypical antipsychotic, and to taper the antidepressant dose following remission of the episode (Amit & Weizman, 2012 ; Connolly & Thase, 2011 ; Hirschfeld et al., 2002 ; Yatham et al., 2013 ). Contemporary guidelines recommend selective serotonin reuptake inhibitors (SSRIs) or bupropion rather than selective serotonin‐norepinephrine reuptake inhibitors (SNRIs) or tricyclics, as SSRIs and bupropion are less likely to cause manic switch. While full consensus is currently absent, there is wide agreement that antidepressant monotherapy should be avoided in patients with BD I and patients with BD II with two or more concomitant core manic symptoms, while antidepressants should be avoided entirely in patients with rapid cycling or those being treated for a mixed episode (Pacchiarotti et al., 2013 ).

Psychosocial treatments

Psychosocial treatments, including individual psychotherapies as well as educational and supportive group therapies, are increasingly considered an integral part of the treatment of BD (Connolly & Thase, 2011 ; Geddes & Miklowitz, 2013 ). Common components of psychosocial treatments are education about the disease and a focus on treatment adherence and self‐care. Interestingly, among the psychosocial treatments, the strongest evidence for effectiveness is for group psychoeducation of patients and caregivers (Colom et al., 2009 ; Reinares et al., 2008 ). Long‐term benefits of this approach include a reduction in days with symptoms and in days hospitalized (Colom et al., 2009 ).

Two other psychotherapies with evidence to support their effectiveness are BD‐specific cognitive behavioral psychotherapy (Jones et al., 2012 ) and interpersonal and social rhythm therapy (Frank et al., 2005 ). Interpersonal and social rhythm therapy is an intervention designed to increase the regularity of patients’ daily routines, based on the concept that disruption of circadian rhythms is a underlying feature of mood disorders (Frank, Swartz, & Boland, 2007 ). These therapies can help patients improve adherence to their medication, enhance their ability to recognize triggers to mood episodes, and develop strategies for early intervention. Combining BD‐specific adjunctive psychotherapies with pharmacological therapy has been shown to significantly reduce relapse rates (Scott, Colom, & Vieta, 2007 ).

Peer support

BD impacts all aspects of a person's life, causing severe disruption to relationships, employment, and education. Peer support can be very helpful in dealing with the consequences of these effects through sharing of experiences, where patients can discover that others have had similar experiences and can have hope for recovery, stability, and a satisfying life. Support groups, sponsored by national organizations, may be available locally or regionally. There is also a wealth of resources available online (Table 4 ).

Web resources for BD

Major challenges in the management of patients with BD

A number of commonly encountered challenges can contribute to suboptimal outcomes in BD. An awareness of these challenges and the implementation of proactive strategies can help to maximize adherence to care and the benefits of treatment.

Nonadherence

Medication nonadherence is a significant problem in primary care medicine generally, and in patients with BD in particular. Experience from other areas of medicine suggests that nonadherence may be widely unrecognized (Ho, Bryson, & Rumsfeld, 2009 ). Validated scales for gauging nonadherence include the Morisky Adherence Scale, although this is not widely adopted in clinical practice (Morisky, Ang, Krousel‐Wood, & Ward, 2008 ). Reasons for nonadherence among patients with BD include the following: a denial of the diagnosis, especially in those with predominant mania; a lack of belief that the medications being offered are necessary or effective; and a wish to avoid the real or imagined adverse effects of medications (Devulapalli et al., 2010 ). Additional practical factors, including poor access to health care and limited resources to support treatment costs, can also affect adherence (Kardas, Lewek, & Matyjaszczyk, 2013 ).

Nonadherence is probably the most significant factor contributing to poor treatment outcome in BD (Hassan & Lage, 2009 ; Lew, Chang, Rajagopalan, & Knoth, 2006 ), which leads to increased emergency room visits and hospitalization (Hassan & Lage, 2009 ; Lage & Hassan, 2009 ; Lew et al., 2006 ; Rascati et al., 2011 ). Investing more time and resources to work with patients during symptom‐free periods is likely to be cost saving by reducing the utilization of these high‐cost resources (Zeber et al., 2008 ).

Comorbid psychiatric disorders

The complexity in treating patients with BD is increased by the high rates of cooccurring psychiatric disorders, in particular anxiety disorders and substance use disorders (Grant et al., 2005 ; Krishnan, 2005 ). The importance of these cooccurring conditions cannot be overstated; they are associated with both exacerbations of BD and poor treatment outcomes (Grant et al., 2005 ; Kessler et al., 1996 ). Although it may be prudent to refer such patients to specialist care, the first critical step is to make a correct diagnosis and to help these patients to accept the problem and the need for treatment.

Comorbid medical disorders

Patients with BD have an elevated prevalence of medical morbidities, including obesity, diabetes, cardiovascular disease, and hepatitis (Kilbourne et al., 2004 ; Krishnan, 2005 ). A comorbidity of increasingly recognized importance is obstructive sleep apnea (OSA), which causes sleep disturbance that can trigger mood episodes (Soreca, Levenson, Lotz, Frank, & Kupfer, 2012 ). A recent study reported OSA in over 20% of patients with BD, which the authors mention may be an underestimate of the true prevalence (Kelly, Douglas, Denmark, Brasuell, & Lieberman, 2013 ). The authors concluded that unrecognized OSA may play a major role in the mortality and morbidity of BDs. All patients diagnosed with a BD should be screened with an OSA questionnaire.

The burden of medical disorders may be increased by the adverse effects of BD treatment, by cooccurring substance misuse or by decrements in self‐care secondary to BD itself (McIntyre, 2009 ). For example, depression typically deprives patients of the motivation and energy to engage in treatment for chronic medical conditions. Early recognition and treatment of medical disorders in patients with BD has been shown to have a major beneficial effect on all‐cause mortality (Crump, Sundquist, Winkleby, & Sundquist, 2013 ).

Women of childbearing age

Women are at high risk of BD recurrence during pregnancy, especially if medications are discontinued, as well as during the postpartum period. Balancing the risk of medications against the need to prevent a mood episode requires active collaboration between the healthcare providers and the patient (McKenna et al., 2005 ). Teratogenicity is a potential risk with most of the mood stabilizers; lamotrigine may be an exception, but there are no well‐controlled studies in humans to confirm this. Atypical antipsychotics, with the exception of lurasidone, are rated FDA pregnancy category C, meaning that they have not been shown to be either safe or unsafe for use during pregnancy; lurasidone is classed in pregnancy category B based on current data.

Suicide rates in BD are the highest among the psychiatric disorders (Chen & Dilsaver, 1996 ; Tondo, Isacsson, & Baldessarini, 2003 ). The lifetime incidence of at least one suicide attempt was reported in one study to be 29% in patients with BD, compared to 16% for MDD (Chen & Dilsaver, 1996 ). Other studies have reported even higher rates of suicide attempts of 25%–60% during the course of BD, with suicide completion rates of 14%–60% (Sublette et al., 2009). The primary healthcare team should monitor all patients with BD for suicidality, especially those with persistent depressive or mixed‐mood symptoms, and immediately refer any patient at high‐risk for suicide to specialist care (Tondo et al., 2003 ).

Alcohol abuse in patients with BD is associated with further elevation in the risk of suicide, particularly in the presence of concurrent drug use disorders. A study that investigated this association concluded that higher suicide attempt rates in patients with BD I and alcoholism were mostly explained by higher aggression scores, while the higher rates of attempted suicide associated with other drug use disorders appeared to be the result of higher impulsiveness, hostility, and aggression (Sublette et al., 2009). This study, similar to previous reports, found that earlier age of bipolar onset increased the likelihood that alcohol use disorder would be associated with suicide attempts. Effective clinical management of substance use disorders has the potential to reduce the risk of suicidal behavior in these patients with BD.

BD continues to represent a substantial burden to patients, their care providers, and society. Management of BD poses a challenge to all healthcare providers, including the APNs. A suspicion of BD increases the likelihood of successful diagnosis. Emphasis should be placed on accurately identifying manic, hypomanic, and depressive episodes. A number of pharmacological and nonpharmacological treatments are available for acute and maintenance treatments. Healthcare providers should be aware of the efficacy and safety profiles of each of these agents, with the aim to achieve the most effective utilization of the approaches available in the management of patients with BD. An awareness of these aspects in BD—disease burden, diagnostic issues, and management choices—can enhance outcome in substantial proportions of patients. In summary, Table 5 provides a useful overview of the principles to consider when providing care for patients with BD.

Principles of providing care for patients with BD

Red flags indicating need for specialist involvement:

▪ Suicidality

▪ Pregnancy and postpartum

▪ Severe psychiatric comorbidity (e.g., substance dependence, anxiety)

▪ History of treatment resistance (e.g., multiple hospitalizations)

▪ Rapid‐cycling pattern.

Adapted from Culpepper ( 2010 ).

Funding Editorial support was provided by Bill Wolvey of PAREXEL, funded by AstraZeneca.

Disclosure Ursula McCormick has received personal fees from AstraZeneca and Sunovian. Bethany Murray and Brittany McNew report no conflicts of interest.

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