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• Diagnosis and...

Diagnosis and management of bipolar disorders

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

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

Introduction

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

Sources and selection criteria

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

Modern definitions of bipolar disorder

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

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

Epidemiology

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

Causes of bipolar disorder

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

Insights from genetics

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

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

Insights from neuroimaging

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

Environmental risk factors

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

Comorbidity

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

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

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

Precursors and prodromes: who develops bipolar disorder?

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

Screening for bipolar disorder

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

Racial/ethnic disparities

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

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

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

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

FDA approved medications for bipolar disorder

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

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Acute treatment of mania

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

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

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

Pharmacological approaches to bipolar depression

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

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

Antidepressants

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

Pharmacological approaches to prevention of recurrent episodes

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

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

Psychotherapeutic approaches

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

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

Neurostimulation approaches

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

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

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

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

Treatment resistance in bipolar disorder

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

Treatment considerations to reduce suicide in bipolar disorder

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

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

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

Treatment consideration in BD-II and bipolar spectrum conditions

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

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

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

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

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

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

Emerging treatments

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

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

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

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

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

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

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

Questions for future research

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

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

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

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

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

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

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

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

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

Provenance and peer review: Commissioned; externally peer reviewed.

• ↵ . Falret’s discovery: the origin of the concept of bipolar affective illness. Translated by M. J. Sedler and Eric C. Dessain. Am J Psychiatry 1983;140:1127-33. doi: 10.1176/ajp.140.9.1127 OpenUrl CrossRef PubMed Web of Science
• ↵ Kraepelin E. Manic-depressive Insanity and Paranoia. Translated by R. Mary Barclay from the Eighth German. Edition of the ‘Textbook of Psychiatry.’ 1921.
• Merikangas KR ,
• Akiskal HS ,
• Koukopoulos A ,
• Jongsma HE ,
• Kirkbride JB ,
• Rowland TA ,
• Kessler RC ,
• Kazdin AE ,
• Aguilar-Gaxiola S ,
• WHO World Mental Health Survey collaborators
• Bergen SE ,
• Kuja-Halkola R ,
• Larsson H ,
• Lichtenstein P
• Smoller JW ,
• Lichtenstein P ,
• Sjölander A ,
• Mullins N ,
• Forstner AJ ,
• O’Connell KS ,
• Palmer DS ,
• Howrigan DP ,
• Chapman SB ,
• Pirooznia M ,
• Murray GK ,
• McGrath JJ ,
• Hickie IB ,
• ↵ Mostafavi H, Harpak A, Agarwal I, Conley D, Pritchard JK, Przeworski M. Variable prediction accuracy of polygenic scores within an ancestry group. Loos R, Eisen MB, O’Reilly P, eds. eLife 2020;9:e48376. doi: 10.7554/eLife.48376 OpenUrl CrossRef PubMed
• Westlye LT ,
• van Erp TGM ,
• Costa Rica/Colombia Consortium for Genetic Investigation of Bipolar Endophenotypes
• Pauling M ,
• ENIGMA Bipolar Disorder Working Group
• Schnack HG ,
• Ching CRK ,
• ENIGMA Bipolar Disorders Working Group
• Goltermann J ,
• Hermesdorf M ,
• Dannlowski U
• Gurholt TP ,
• Suckling J ,
• Lennox BR ,
• Bullmore ET
• Marangoni C ,
• Hernandez M ,
• Achtyes ED ,
• Agnew-Blais J ,
• Gilman SE ,
• Upthegrove R ,
• ↵ Etain B, Aas M. Childhood Maltreatment in Bipolar Disorders. In: Young AH, Juruena MF, eds. Bipolar Disorder: From Neuroscience to Treatment . Vol 48. Current Topics in Behavioral Neurosciences. Springer International Publishing; 2020:277-301. doi: 10.1007/7854_2020_149
• Johnson SL ,
• Weinberg BZS
• Stinson FS ,
• Costello CG
• Klein & Riso LP DN
• Sandstrom A ,
• Perroud N ,
• de Jonge P ,
• Bunting B ,
• Nierenberg AA
• Hantouche E ,
• Vannucchi G
• Zimmerman M ,
• Ruggero CJ ,
• Chelminski I ,
• Leverich GS ,
• McElroy S ,
• Mignogna KM ,
• Balling C ,
• Dalrymple K
• Kappelmann N ,
• Stokes PRA ,
• Jokinen T ,
• Baldessarini RJ ,
• Faedda GL ,
• Offidani E ,
• Viktorin A ,
• Launders N ,
• Osborn DPJ ,
• Roshanaei-Moghaddam B ,
• De Hert M ,
• Detraux J ,
• van Winkel R ,
• Lomholt LH ,
• Andersen DV ,
• Sejrsgaard-Jacobsen C ,
• Skjelstad DV ,
• Gregersen M ,
• Søndergaard A ,
• Brandt JM ,
• Van Meter AR ,
• Youngstrom EA ,
• Taylor RH ,
• Ulrichsen A ,
• Strawbridge R
• Hafeman DM ,
• Merranko J ,
• Hirschfeld RM ,
• Williams JB ,
• Spitzer RL ,
• Adolfsson R ,
• Benazzi F ,
• Regier DA ,
• Johnson KR ,
• Akinhanmi MO ,
• Biernacka JM ,
• Strakowski SM ,
• Goldberg JF ,
• Schettler PJ ,
• Coryell W ,
• Scheftner W ,
• Endicott J ,
• Zarate CA Jr . ,
• Matsuda Y ,
• Fountoulakis KN ,
• Zarate CA Jr .
• Bowden CL ,
• Brugger AM ,
• The Depakote Mania Study Group
• Calabrese JR ,
• Depakote ER Mania Study Group
• Weisler RH ,
• Kalali AH ,
• Ketter TA ,
• SPD417 Study Group
• Keck PE Jr . ,
• Cutler AJ ,
• Caffey EM Jr . ,
• Grossman F ,
• Eerdekens M ,
• Jacobs TG ,
• Grundy SL ,
• The Olanzipine HGGW Study Group
• Versiani M ,
• Ziprasidone in Mania Study Group
• Sanchez R ,
• Aripiprazole Study Group
• McIntyre RS ,
• Panagides J
• Calabrese J ,
• McElroy SL ,
• EMBOLDEN I (Trial 001) Investigators
• EMBOLDEN II (Trial D1447C00134) Investigators
• Lamictal 606 Study Group
• Lamictal 605 Study Group
• Keramatian K ,
• Chakrabarty T ,
• Nestsiarovich A ,
• Gaudiot CES ,
• Neijber A ,
• Hellqvist A ,
• Paulsson B ,
• Trial 144 Study Investigators
• Schwartz JH ,
• Szegedi A ,
• Cipriani A ,
• Salanti G ,
• Dorsey ER ,
• Rabbani A ,
• Gallagher SA ,
• Alexander GC
• Cerqueira RO ,
• Yatham LN ,
• Kennedy SH ,
• Parikh SV ,
• Højlund M ,
• Andersen K ,
• Correll CU ,
• Ostacher M ,
• Schlueter M ,
• Geddes JR ,
• Mojtabai R ,
• Nierenberg AA ,
• Goodwin GM ,
• Agomelatine Study Group
• Vázquez G ,
• Baldessarini RJ
• Altshuler LL ,
• Cuijpers P ,
• Miklowitz DJ ,
• Efthimiou O ,
• Furukawa TA ,
• Strawbridge R ,
• Tsapekos D ,
• Hodsoll J ,
• Vinberg M ,
• Kessing LV ,
• Forman JL ,
• Miskowiak KW
• Lewandowski KE ,
• Sperry SH ,
• Torrent C ,
• Bonnin C del M ,
• Martínez-Arán A ,
• Bonnín CM ,
• Tamura JK ,
• Carvalho IP ,
• Leanna LMW ,
• Karyotaki E ,
• Individual Patient Data Meta-Analyses for Depression (IPDMA-DE) Collaboration
• Vipulananthan V ,
• Hurlemann R ,
• UK ECT Review Group
• Haskett RF ,
• Mulsant B ,
• Trivedi MH ,
• Wisniewski SR ,
• Espinoza RT ,
• Vazquez GH ,
• McClintock SM ,
• Carpenter LL ,
• National Network of Depression Centers rTMS Task Group ,
• American Psychiatric Association Council on Research Task Force on Novel Biomarkers and Treatments
• Levkovitz Y ,
• Isserles M ,
• Padberg F ,
• Blumberger DM ,
• Vila-Rodriguez F ,
• Thorpe KE ,
• Williams NR ,
• Sudheimer KD ,
• Bentzley BS ,
• Konstantinou G ,
• Toscano E ,
• Husain MM ,
• McDonald WM ,
• International Consortium of Research in tDCS (ICRT)
• Sampaio-Junior B ,
• Tortella G ,
• Borrione L ,
• McAllister-Williams RH ,
• Gippert SM ,
• Switala C ,
• Bewernick BH ,
• Hidalgo-Mazzei D ,
• Mariani MG ,
• Fagiolini A ,
• Swartz HA ,
• Benedetti F ,
• Barbini B ,
• Fulgosi MC ,
• Burdick KE ,
• Diazgranados N ,
• Ibrahim L ,
• Brutsche NE ,
• Sinclair J ,
• Gerber-Werder R ,
• Miller JN ,
• Vázquez GH ,
• Franklin JC ,
• Ribeiro JD ,
• Turecki G ,
• Gunnell D ,
• Hansson C ,
• Pålsson E ,
• Runeson B ,
• Pallaskorpi S ,
• Suominen K ,
• Ketokivi M ,
• Hadzi-Pavlovic D ,
• Stanton C ,
• Lewitzka U ,
• Severus E ,
• Müller-Oerlinghausen B ,
• Rogers MP ,
• Li+ plus Investigators
• Manchia M ,
• Michel CA ,
• Auerbach RP
• Altavini CS ,
• Asciutti APR ,
• Solis ACO ,
• Casañas I Comabella C ,
• Riblet NBV ,
• Young-Xu Y ,
• Shortreed SM ,
• Rossom RC ,
• Amsterdam JD ,
• Brunswick DJ
• Gustafsson U ,
• Marangell LB ,
• Bernstein IH ,
• Karanti A ,
• Kardell M ,
• Collins FS ,
• Armstrong K ,
• Concato J ,
• Singer BH ,
• Ziegelstein RC
• ↵ Holmes JH, Beinlich J, Boland MR, et al. Why Is the Electronic Health Record So Challenging for Research and Clinical Care? Methods Inf Med 2021;60(1-02):32-48. doi: 10.1055/s-0041-1731784
• García Rodríguez LA ,
• Cantero OF ,
• Martinotti G ,
• Dell’Osso B ,
• Di Lorenzo G ,
• REAL-ESK Study Group
• Palacios J ,
• DelBello MP ,
• Husain MI ,
• Chaudhry IB ,
• Subramaniapillai M ,
• Jones BDM ,
• Daskalakis ZJ ,
• Carvalho AF ,
• ↵ Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition Recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2016;30:495-553. doi: 10.1177/0269881116636545 OpenUrl CrossRef PubMed
• Verdolini N ,
• Del Matto L ,
• Regeer EJ ,
• Hoogendoorn AW ,
• Harris MG ,
• WHO World Mental Health Survey Collaborators

Bipolar disorders

Affiliations.

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

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

Copyright © 2020 Elsevier Ltd. All rights reserved.

Publication types

• Research Support, Non-U.S. Gov't
• Anticonvulsants / therapeutic use
• Antidepressive Agents / therapeutic use
• Antimanic Agents / therapeutic use
• Antipsychotic Agents / therapeutic use
• Bipolar Disorder / classification*
• Bipolar Disorder / drug therapy*
• Bipolar Disorder / genetics
• Bipolar Disorder / psychology
• Carbamazepine / therapeutic use
• Cardiovascular Diseases / complications
• Cardiovascular Diseases / mortality
• Child Abuse / psychology
• Comorbidity
• Depressive Disorder, Major / drug therapy*
• Depressive Disorder, Major / genetics
• Depressive Disorder, Major / psychology
• Environmental Exposure / adverse effects
• Lamotrigine / therapeutic use
• Lithium / therapeutic use
• Mania / drug therapy
• Mania / psychology
• Suicide / psychology
• Suicide Prevention*
• Valproic Acid / therapeutic use
• Young Adult
• Anticonvulsants
• Antidepressive Agents
• Antimanic Agents
• Antipsychotic Agents
• Carbamazepine
• Valproic Acid
• Lamotrigine

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• Ther Adv Psychopharmacol
• v.8(9); 2018 Sep

Epidemiology and risk factors for bipolar disorder

Tobias a. rowland.

Unit of Mental Health and Wellbeing, Division of Health Sciences, University of Warwick, Coventry, CV4 7AL, UK

Steven Marwaha

Division of Health Sciences, University of Warwick, Coventry, UK

Coventry and Warwick-shire Partnership Trust, The Caludon Centre, Coventry, UK

Bipolar disorder is a multifactorial illness with uncertain aetiology. Knowledge of potential risk factors enables clinicians to identify patients who are more likely to develop bipolar disorder, which directs further investigation, follow up and caution when prescribing. Ideally, identifying directly causative factors for bipolar disorder would enable intervention on an individual or population level to prevent the development of the illness, and improve outcomes through earlier treatment. This article reviews the epidemiology of bipolar disorder, along with putative demographic, genetic and environmental risk factors, while assessing the strength of these associations and to what extent they might be said to be ‘causative’. While numerous genetic and environmental risk factors have been identified, the attributable risk of individual factors is often small, and most are not specific to bipolar disorder but are associated with several mental illnesses. Therefore, while some genetic and environmental factors have strong evidence supporting their association with bipolar disorder, fewer have sufficient evidence to establish causality. There is increasing interest in the role of specific gene–environment interactions, as well as the mechanisms by which risk factors interact to lead to bipolar disorder.

Introduction

Bipolar affective disorder (bipolar) is a multicomponent illness involving episodes of severe mood disturbance, neuropsychological deficits, immunological and physiological changes, and disturbances in functioning. 1 It is one of the leading causes of disability worldwide 2 and is associated with high rates of premature mortality from both suicide and medical comorbidities. 3 , 4

The aetiology of bipolar is not well understood and research into the disorder lags behind disorders such as psychosis. However, the last decade has seen an expanding evidence into the genetics of the disorder, underlying developmental pathways, risks and vulnerability factors, gene–environment interactions and the putative features of the bipolar prodrome.

This article summarizes the research into demographic, genetic and environmental risk factors for the development of bipolar, with a focus on recent updates and the role of environmental triggers. To identify relevant literature, searches were conducted in PubMed and PsycINFO using the terms ‘Bipolar Disorder’, combined with ‘risk factors’ or ‘epidemiology’. Results were reviewed with a focus on the most recent evidence and systematic reviews or large prospective studies, and further individual searches were then expanded for each risk factor category identified. A summary of the included studies relating to specific risk factors for bipolar are included in Table 1 .

Studies investigating specific risk factors for bipolar disorder.

ADHD, attention deficit hyperactivity disorder; BDNF, brain-derived neurotrophic factor; bipolar, bipolar disorder; CI, confidence interval; COMT, Catechol- O -methyltransferase; 5-HTTL, serotonin system gene; 5-HTTLPR, serotonin-transporter-linked polymorphic region; GWAS, genome-wide association study; HR, hazard ratio; MDD, major depressive disorder; mRNA, messenger ribonucleic acid; OR, odds ratio; SNP, single nucleotide polymorphism; TLR2, toll-like receptor 2.

Epidemiology of bipolar disorder

Epidemiological studies have suggested a lifetime prevalence of around 1% for bipolar type I in the general population. 54 , 55 A large cross-sectional survey of 11 countries found the overall lifetime prevalence of bipolar spectrum disorders was 2.4%, with a prevalence of 0.6% for bipolar type I and 0.4% for bipolar type II. 56 Although findings varied across different countries, this suggested a lower prevalence of bipolar type I and II than previous studies, 55 , 57 while the prevalence of bipolar type I in USA was found to be 1%, slightly higher than the other countries. It is unclear whether differences were due to more stringent diagnostic criteria used in this study, or true differences in rates of bipolar across countries and ethnic groups. In one of the very few epidemiological investigations in England, the recent Adult Psychiatric Morbidity Survey 2014 found lifetime prevalence of likely bipolar was 2%. The measurement method suggests that this was an underestimate, but the study did not distinguish bipolar subtypes. 58 A recent meta-analysis of 25 studies found a pooled lifetime prevalence of 1.06% and 1.57% for bipolar type I and II, respectively, although the majority of the included studies were from North or South America. 59 Nevertheless, a similar prevalence has been found in the UK, Germany and Italy, 60 and a lifetime prevalence between 0.1–1.83% was found in a systematic review of studies from African countries. 61

The reason for international variations in the prevalence of bipolar is not entirely clear, and ethnicity, 49 cultural factors 62 and variations in diagnostic criteria and study methodology 59 may each have an impact. The evidence for differing rates of bipolar in different ethnicities is conflicting, with some studies showing higher rates in Caucasians 63 , 64 and others in nonwhite populations. 65 A systematic review found no clear evidence for differences across ethnic groups, and suggested individual study differences may be related to cultural factors, migration and higher rates of misdiagnosis of black ethnic groups as having schizophrenia rather than bipolar. 49 With regards to sex, several studies report equal distribution in bipolar, 49 while others have identified a higher prevalence of manic episodes and bipolar type I in males and higher rates of bipolar type II in females. 56 Overall, the evidence is not sufficiently strong to deviate from the view that bipolar appears to have a roughly equal distribution across sex and ethnicity.

The mean age of onset for bipolar appears to be in the early twenties, 56 although findings vary between 20–30 years. 55 A bimodal distribution of the incidence of bipolar has been suggested, 66 supported by a large population-based cohort study, which found two peaks in age of onset at 15–24 years and at 45–54 years. 67 However, age of onset estimates are very difficult to define accurately for bipolar, given the long periods of untreated illness, when symptoms can be nascent or apparent without individuals accessing services, which is often used as the measure of onset in many studies. 68 Moreover, there appear to be differences in the presentation and clinical course of bipolar depending on age of onset, 69 with higher rates of psychiatric and medical comorbidities such as suicidality and vascular disease in later-onset mania. 70

A number of studies have investigated rates of bipolar according to sociodemographic variables, with generally inconsistent findings. 49 There is some evidence of higher rates in low income, unemployed and unmarried groups, 49 although the social disruption caused by severe mental illness giving rise to such associations cannot be ruled out. 54 Conversely, an interesting finding among some studies is that higher socioeconomic status and higher occupational level, as well as creativity, 54 , 71 are associated with increased risk of bipolar, 72 , 73 which is opposite to that of unipolar depression and schizophrenia. 54 However, these studies are limited by small sample sizes and a lack of replication. 74 Explanations for this association include the possibility of referral bias for those with higher socioeconomic status, while some have suggested that those with high-functioning creative traits may confer a genetic risk of bipolar. 54

There is also emerging evidence for an association between urban environments and increased rates of bipolar. 49 While the evidence is stronger for schizophrenia, where there have been multiple suggested explanations, 75 the reason for the association between urbanization and bipolar is less clear. However, a cohort study found that there was a strong association between urban residence and the incidence of psychotic bipolar, but no association for bipolar without psychosis. 76 This may suggest that urban residence is a transdiagnostic risk factor for psychotic illness rather than bipolar per se .

Genetics and gene environment interactions

The contribution of genetic factors to bipolar has long been identified, with evidence from twin studies suggesting monozygotic concordance of between 40–70%, and lifetime risk in first-degree relatives is 5–10%; around seven times higher than the general population risk. 5 However, relatives of patients with bipolar are more likely to develop unipolar depression than bipolar themselves, suggesting the genetic risk transcends diagnostic categories. 5 There is also evidence of shared genetic risk between bipolar, schizophrenia and autism. 77 , 78 Nonetheless, bipolar clearly does not follow a Mendelian pattern of inheritance, and linkage studies have not identified individual genes with a strong association with the disorder. 79 The genetic risk for bipolar in part is likely due to multiple single nucleotide polymorphisms, which are highly prevalent in the general population and confer a very small increased risk individually. 80 Technological advances have allowed for genome-wide association studies that have pooled data and identified multiple genetic loci associated with bipolar patients, suggesting aggregated polygenic risk. 6

Whilst many important genetic loci have been identified, how these translate to risk of illness is a second frontier of discovery. Studies have identified polymorphisms in genes coding for brain-derived neurotrophic factor (BDNF) to be associated with bipolar. 7 BDNF is suspected to be involved in the pathogenesis of bipolar as well as being a potential biomarker of disease activity. 81 Associations with catechol- O -methyl transferase (COMT) and monoamine transporters have also been observed. 8 , 82 Genes for voltage-gated calcium channel subunits such as CACNA1C are located near to single nucleotide polymorphisms that have an association with bipolar, as well as proteins involved in cell signalling such as ODZ4, 6 and genes encoding for gamma-aminobutyric acid (GABA) receptor subunits. 83 The fact that many of the medications used as prophylactic agents in bipolar act on calcium channels or GABA receptors 84 suggests these proteins may be involved in the neurobiology of the disorder, and this evidence is guiding the search for new therapeutic targets. 85

However, it is clear that the effect size of each single nucleotide polymorphism is very small. For example, the odds of having bipolar in those with the polymorphism around CACNA1C is 1.14, and the majority of those with this polymorphism do not go on to develop the disorder. 6 , 80 There has therefore been increasing interest in the role of how gene–environment interactions contribute to the onset of bipolar, although this remains an under-researched area, compared with schizophrenia. 86 , 87 Nevertheless, interaction between childhood abuse and BDNF gene polymorphisms have been shown in several studies, 9 , 86 while toll-like receptor 2 polymorphisms may interact with stressful life events and Toxoplasma gondii infection to increase the risk of bipolar. 10 , 11 A COMT polymorphism has been found to interact with stressful life events for bipolar depressive episodes, 12 while serotonin transporter genes have interactions with cannabis use on the presence of psychotic symptoms in bipolar. 13 With the increasing ability of genome-wide association studies to identify polymorphisms conferring a very small increased risk, further study of how these genes interact with environmental factors to trigger bipolar is required.

Environmental risk factors

Prenatal and perinatal factors.

Prenatal viral infections have been implicated in a number of mental illnesses, including bipolar. 88 – 90 A recent review by Barichello and colleagues 14 investigated associations between bipolar and 10 infectious agents. Findings between studies were generally inconsistent, and no association was found for Epstein-Barr virus, human herpesvirus 6 or varicella zoster virus. Five of the eleven studies investigating cytomegalovirus found an association between antibody levels and bipolar, while two studies found an association between maternal influenza infection and bipolar with psychosis, 91 , 92 although other studies found no association. 93 – 95 None of these studies were prospective or longitudinal and it is uncertain whether these infections occurred during pregnancy or subsequently. Therefore, the evidence for maternal viral infection as a risk factor for bipolar remains weak, overall.

However, there is stronger evidence for an association between bipolar and seropositivity for T. gondii infection, demonstrated in two recent meta-analyses. 15 , 16 The first included 11 studies and demonstrated overall increased odds of having bipolar in those with immunoglobulin G (IgG) to T. gondii , with an odds ratio of 1.52 (95% confidence interval 1.06–2.18). 15 A second meta-analysis of eight studies also found a significant association between bipolar and T. gondii seropositivity, with an odds ratio of 1.26 (95% confidence interval 1.08–1.47). 16 However, the included studies were not prospective and it remains uncertain when T. gondii exposure occurred. Notwithstanding, there is preclinical evidence suggestive of a relationship between T. gondii and development of mental illness, with studies showing behavioural changes in mice 96 and humans. 97 , 98 Moreover, there is evidence that infection with T. gondii causes changes in dopamine metabolism leading to increased dopamine production, 99 similar to that suggested as a potential mechanism for manic episodes in bipolar. 100 Furthermore, there is evidence that following T. gondii infection, the local inflammatory response leads to alteration in cytokines, 101 such as IL-6, 102 which have been implicated in mental illness and bipolar specifically, 103 and may be related to cognitive deterioration in this patient group. 102

Evidence regarding other prenatal exposures such as maternal smoking and severe psychological stressors are inconsistent, with only a small number of studies investigating these factors. 50 Obstetric complications have generated interest as a risk factor for later development of bipolar, 104 but a meta-analysis found no significant evidence for this association, 17 and bipolar patients were less likely to have experienced obstetric complications than those with schizophrenia. A systematic review by Marangoni and colleagues 50 identified prospective studies which suggested extreme prematurity (less than 32 weeks’ gestation) conferred a significant risk of developing bipolar.

In general, the evidence for prenatal and perinatal factors as an independent risk factor for developing bipolar is relatively weak and inconsistent, and such factors appear to confer greater risk for developing other mental disorders, such as schizophrenia. 17 The evidence for T. gondii infection is more substantial, while maternal CMV and influenza infection warrant further investigation as to their associations with bipolar.

Postnatal factors

Childhood maltreatment.

Childhood maltreatment is a well-studied environmental risk factor with high-quality evidence that it confers a risk for later development of bipolar, 51 although it is also associated with behavioural problems and other mental illnesses. 105 , 106 When investigating specific subtypes of abuse, several studies have identified a link between emotional abuse or emotional neglect and the later the development of bipolar, 18 , 19 while emotional abuse appears to be the most frequent subtype of abuse experienced in bipolar patients. 20 A recent high quality meta-analysis of childhood adversity in bipolar patients compared with healthy controls found significant associations between development of bipolar and prior physical, sexual and emotional abuse, and physical and emotional neglect. 21 The largest association was for emotional abuse which was four times more likely to have occurred in bipolar patients than in controls. 21 Moreover, higher rates of childhood adversity were found in patients with bipolar compared with unipolar depression, although rates were similar to schizophrenia. 21 Gilman and colleagues 52 also found that a history of childhood abuse increased the risk of transitioning to bipolar following a depressive episode. This suggests that abuse and neglect during childhood confer some specific risk to more severe forms of mental illness.

As well a risk factor, childhood maltreatment appears to be associated with poorer clinical outcomes in bipolar, with more severe and more frequent mood episodes, 22 earlier onset, increased risk of suicide and comorbid substance misuse. 23 The relationship between childhood abuse and the severity of bipolar adds further weight to its position as a potential causative factor for the disorder. Notwithstanding, childhood maltreatment does not appear to be specifically related to psychotic symptoms or a diagnosis of bipolar type I over type II. 21 , 24

Whilst it seems likely that childhood traumatic events increase the risk of bipolar, why or how they do this remains unclear but is the focus of ongoing research. Traumatic events are linked to increased levels of affective instability or emotional dysregulation more generally in people with bipolar and this represents one possible mechanism of action. 107 Other dimensions of psychopathology such as hostility and impulsivity, along with affective instability have been shown to mediate the association between childhood maltreatment and outcomes in bipolar, 108 while alterations in the hypothalamic–pituitary–adrenal (HPA) axis, 109 increased levels of BDNF and inflammatory cytokines 110 and reduced limbic grey matter volume 111 represent possible neurobiological underpinnings of the effect of childhood trauma and how this may lead to later psychopathology and bipolar, in particular.

It should be noted that there is difficulty in determining to what extent childhood maltreatment is a cause or consequence of the predisposition to develop bipolar, as parental psychopathology may confer a genetic risk of the disorder, as well as increased risk of childhood maltreatment. 112 The retrospective nature of these studies introduces the possibility of recall bias with regard to childhood adversity, and at present, there are few prospective studies investigating the association between childhood maltreatment and bipolar.

Psychological stressors

Recent stressful life events are known to affect the course of bipolar, 113 although their relationship with the onset of the disorder has been less extensively investigated compared with unipolar depression. 49 A systematic review by Tsuchiya and colleagues 49 identified four studies investigating stressful life events prior to the onset of bipolar, the three largest of which found an increased risk of onset within 6 months of such events. A meta-analysis found that patients experience more life events prior to relapses into either manic or depressive episodes than during euthymic periods, although the rate of significant life events prior to the onset of bipolar was similar to unipolar depression. 25 Other studies have supported the association between life events and the onset of bipolar, including a large case-control study which found that stressful life events were associated with a first hospitalization for a manic episode, particularly suicide of a first-degree relative, but also recent marriage, divorce, disability or unemployment. 26 There are a number of confounders to these associations, particularly with regard to suicide of a first-degree relative, where genetic factors play a significant role, as death due to other causes was not associated with hospitalization. 26 A bidirectional relationship has also been suggested for stressful life events in bipolar, as there is evidence that these events occur both prior to and following mood episodes. 27

There is also evidence for specific life events conferring a risk for bipolar, such as early parental loss and childbirth. The systematic review by Tsuchiya and colleagues 49 found that only 3 of the 10 studies investigating parental loss identified an association with bipolar, although it is noteworthy that one of these was a very large cohort study which adjusted for a number of confounders, including family history of mental illness. 53 A meta-analysis found that childbirth specifically increased the risk of mood episodes in patients with bipolar, more so than relapses in unipolar depression or schizophrenia. 25 Tsuchiya and colleagues 49 identified only three studies investigating onset of bipolar following childbirth, but each found an association with subsequent bipolar diagnosis within 12 months. This is perhaps unsurprising, considering the association between puerperal psychosis and bipolar, 114 but it is unclear whether the reason for the association is genetic, hormonal or related to childbirth as a life event.

However, life events are relatively nonspecific in relation to mental and physical illness, and appear to be associated not only with the onset of bipolar disorder and unipolar depression, but also psychosis, 115 anxiety disorders, 116 ischaemic stroke 117 and circulatory disorders. 118 While gene–environment interactions have been identified between life events and the onset of specific disorders, 12 the use of checklists to identify life events in such studies has been criticized as lacking sufficient detail with regard to the severity and context of such events. 119 These methodological issues make it difficult to establish causation between life events and development of bipolar.

Substance misuse

Bipolar is frequently comorbid with misuse of substances, including cannabis, opioids, cocaine, sedatives and alcohol, 50 , 52 and causality has been suggested in both directions. 120 While the high level of comorbidity is undeniable, causality it much harder to ascertain as there is often difficulty in establishing the temporal relationship between substance misuse and the onset of mental illness. This is compounded by the relative lack of prospective, longitudinal studies examining the relationship between substance misuse and bipolar. 121

There is increasing evidence that cannabis use can act as a risk factor for the development of bipolar as well as psychotic disorders. A recent systematic review by Gibbs and colleagues 28 identified several studies supporting a link between cannabis use and subsequent relapse of manic symptoms. This review also included a meta-analysis of two large prospective cohort studies 29 , 30 which found that cannabis use almost trebled the risk of new-onset subthreshold manic symptoms after adjusting for potential confounding factors. A further large prospective cohort study found cannabis use increased the risk of first episode bipolar by a factor of 5 after adjusting for confounders, and demonstrated evidence of a dose–response relationship. 31 Other studies were more equivocal, finding increased risk of bipolar only in those with weekly to daily cannabis use and no dose–response relationship, 32 or increased risk only in those with a past year episode of depression. 52 Recently, a prospective analysis has demonstrated cannabis use at age 17 is associated with hypomania in young adulthood independent of psychotic symptoms and other important confounders. Further path analysis indicated cannabis use is one mechanism by which childhood abuse translates to increased risk of bipolar symptoms. 33

Other substances of abuse are also important in the risk of bipolar. Prospective studies have linked opioid use to an increased risk of developing bipolar, which is greater than other mood disorders. 34 , 35 A further study found that alcohol and drug abuse or dependence before the age of 25 increased the odds of developing subsequent bipolar, although differences between specific drugs were not examined. 36 Cocaine use has also been implicated, although is less well studied, 37 and as stimulant use can precipitate mania or similar symptoms, 120 this may lead to inappropriate diagnosis of bipolar, 122 rather than act as a causative factor.

There are significant confounding factors to associations between bipolar and substance misuse, which remain despite attempts at adjustment within the studies. It has been suggested that cannabis may serve as self medication for bipolar illness, 123 and therefore may be used by those with subthreshold symptoms prior to the onset of bipolar. Furthermore, there is evidence that shared genetic factors confer risk for developing both substance misuse disorders and bipolar, 124 , 125 while childhood maltreatment is also associated with both disorders. 20 , 22 , 113

Medical comorbidity

Bipolar is known to be comorbid with a number of medical and psychiatric conditions. 51 , 38 , 39 There are multiple reasons for this, including shared genetic and environmental vulnerabilities, consequences of treatment, recognition bias on the part of clinicians as well as the potential for a direct causal relationship in either direction.

There is strong evidence for the association between bipolar and irritable bowel syndrome (IBS) 51 highlighted in a recent large meta-analysis of retrospective cohort studies. 40 However, potentially important confounders, such as antidepressant use, were not adjusted for. There is also evidence that both disorders may share inflammatory 51 , 126 , 127 and stress-related aetiologies, 25 , 128 which could give rise to this association.

Similarly, recent meta-analyses have shown asthma, 41 obesity, 42 migraine 43 and head injury 44 are associated with bipolar. The evidence for these associations is mediated by the relatively small number of studies included, most of which were cross sectional and lacked data to adjust for confounding factors. However, for asthma, a retrospective cohort 45 and large prospective study 46 also support the association, which may be mediated by shared inflammatory pathways 126 , 127 or the use of corticosteroids during early childhood. 38 , 45 Medication and lifestyle factors significantly confound the association with obesity, for which there are few prospective studies and weak evidence for a directly causal relationship, while the association with traumatic brain injury is potentially confounded by ‘accident proneness’ or physical abuse. 129 There is evidence of increased prevalence of bipolar in patients with multiple sclerosis (MS) 47 , 130 which cannot be completely accounted for by steroid-induced mania, and in some instances, psychiatric symptoms may predate the diagnosis of MS. 131 However, other studies have not supported this association. 38

A meta-analysis reported high lifetime prevalence of anxiety disorders in bipolar patients, 48 while ADHD, conduct disorders, aggression and impulsivity also appeared to increase risk of developing bipolar. 39

Prodromal features and bipolar at-risk criteria

It is becoming increasingly recognised that bipolar, like schizophrenia, has a prodromal phase which can be identified prior to development of the full illness. 132 , 133 However, one issue with research into this area is the potential conflation of the concepts of a prodrome for bipolar, referring to symptoms that can be retrospectively identified as preceding the onset of the disorder, and a ‘risk syndrome’ consisting of clinical features, comorbidities and risk factors which increase the risk of later developing bipolar. 134 At present, neither prodrome nor risk syndrome has been fully defined, although the bipolar at-risk (BAR) assessment tool has demonstrated predictive validity and reliability for identifying those at risk of bipolar, with around 23% of those identified transitioning to mania or hypomania. 135 A study using the BAR assessment tool criteria found that cyclothymia had the best overall clinical utility for case finding and screening when focusing on depressed youths with an early transition to bipolar. The clinical utility profile of subthreshold mania, antidepressant emergent elation, family history of bipolar and atypical depression suggested they were better for screening out noncases. 136 However, other studies have questioned the associations between clinical characteristics of depression and transition to bipolar. 52

The low positive predictive value of these precursors reduces their usefulness, and of the significant proportion of those ‘at risk’ who do not go on to develop bipolar there is limited understanding of what factors are protective against this transition, or how this group differs from those who do develop bipolar. 134 Future research should focus on identifying differences in this group, while continuing to refine screening tools for prodromal identification and risk syndromes in prospective studies. Focusing on transition to first-episode mania may have greater reliability in identifying cases. 134

First-episode bipolar mania has an annual incidence of around 5 per 100,000 of population, 137 and peak incidence occurs between 21–25 years. 138 Although the incidence of first-episode mania is equal between males and females, 137 studies have found that age of onset is around 5 years earlier for men. 139 A meta-analysis of longitudinal studies of first-episode mania found that 87.5% of patients achieve syndromal recovery within the first year, meaning they no longer meet criteria for diagnosis. However, the symptomatic recovery rates (essentially defined as being symptom free) were 62.1% within the first year, while 41% experience a recurrence of a manic, mixed or depressed episode over the same period. 140 Considering the relatively poor outcome in such patients, the potential to identify a risk syndrome or prodromal phase of bipolar in those presenting with a depressive illness offers the opportunity to intervene at an earlier stage, leading to improved outcomes. 68

Risk factors for bipolar are numerous, both genetic and environmental, but low attributable risk, inconsistency of results, inability to identify the temporality of the relationship, lack of a clear biological mechanism and the nonspecific nature of many risk factors means that causation is difficult to assign in an individual patient. Studies of environmental risk were also unable to completely adjust for confounding. However, there is evidence that severity of bipolar is related to childhood emotional abuse and the degree of cannabis misuse, suggesting a dose–response relationship. The association with T. gondii is also strong, with some evidence of biological plausibility, although concerns remain about temporality. Bipolar is associated with medical comorbidities such as IBS and asthma, which may point towards shared inflammatory pathophysiology of the disorders, while other psychiatric disorders and clinical features that predate the onset of bipolar may point towards an identifiable ‘risk syndrome’. Future research into these risk factors should focus on establishing temporality, whether the severity of bipolar is linked to the risk factor, and identifying potential neurobiological and environmental mechanisms to explain the associations. Finally, research into gene–environment interactions is required to link existing evidence on genetic and environmental risks.

Funding: TR is partly funded through the National Institute of Health Research as an academic clinical fellow. The authors received no financial support for the research, authorship, or publication of this article.

Conflict of interest statement: The authors declare that there is no conflict of interest.

Contributor Information

Tobias A. Rowland, Unit of Mental Health and Wellbeing, Division of Health Sciences, University of Warwick, Coventry, CV4 7AL, UK.

Steven Marwaha, Division of Health Sciences, University of Warwick, Coventry, UK. Coventry and Warwick-shire Partnership Trust, The Caludon Centre, Coventry, UK.