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Diagnosis and management of bipolar disorders

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

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

Introduction

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

Sources and selection criteria

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

Modern definitions of bipolar disorder

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

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

Epidemiology

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

Causes of bipolar disorder

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

Insights from genetics

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

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

Insights from neuroimaging

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

Environmental risk factors

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

Comorbidity

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

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

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

Precursors and prodromes: who develops bipolar disorder?

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

Screening for bipolar disorder

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

Racial/ethnic disparities

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

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

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

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

FDA approved medications for bipolar disorder

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Fig 1

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

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Acute treatment of mania

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

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

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

Pharmacological approaches to bipolar depression

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

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

Antidepressants

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

Pharmacological approaches to prevention of recurrent episodes

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

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

Psychotherapeutic approaches

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

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

Neurostimulation approaches

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

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

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

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

Treatment resistance in bipolar disorder

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

Treatment considerations to reduce suicide in bipolar disorder

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

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

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

Treatment consideration in BD-II and bipolar spectrum conditions

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

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

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

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

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

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

Emerging treatments

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

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

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

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

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

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

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

Questions for future research

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

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

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

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

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

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

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

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

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

Provenance and peer review: Commissioned; externally peer reviewed.

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Study Finds Lithium Has Advantages Over Other Mood Stabilizers in Youths with Bipolar Disorder

A Way of Predicting if New Psychosis Patients Will or Won’t Respond to Standard Treatment

Posted: August 01, 2019

A Way of Predicting if New Psychosis Patients Will or Won’t Respond to Standard Treatment

A Rarely Studied Brain Structure Provides New Clues About Psychosis

Posted: June 27, 2019

A Rarely Studied Brain Structure Provides New Clues About Psychosis

FDA Approves Cariprazine for Depression in Bipolar I Disorder

Posted: June 20, 2019

FDA Approves Cariprazine for Depression in Bipolar I Disorder

A Medicine That Treats Mania Also Shows Effectiveness in Treating Depression in Bipolar Disorder

Posted: March 19, 2019

A Medicine That Treats Mania Also Shows Effectiveness in Treating Depression in Bipolar Disorder

Long-term Study Reveals How Bipolar Disorder Emerges in High-Risk Youth

Posted: February 25, 2019

Long-term Study Reveals How Bipolar Disorder Emerges in High-Risk Youth

Researchers Train Computers to Identify a Biological Signature of Bipolar Disorder

Posted: October 29, 2018

Researchers Train Computers to Identify a Biological Signature of Bipolar Disorder

A Revealing Genetic Comparison of Schizophrenia and Bipolar Disorder

Posted: October 17, 2018

A Revealing Genetic Comparison of Schizophrenia and Bipolar Disorder

A New Understanding of Risk for Bipolar Disorder

Posted: September 17, 2018

A New Understanding of Risk for Bipolar Disorder

Evidence Links White Matter Patterns to Cognitive Performance in Bipolar Disorder

Posted: August 02, 2018

Evidence Links White Matter Patterns to Cognitive Performance in Bipolar Disorder

Certain Patterns of Brain Activity May Protect Against Bipolar Disorder

Posted: April 10, 2018

Certain Patterns of Brain Activity May Protect Against Bipolar Disorder

Large Gene Expression Study Sheds Light on Causal Factors in Five Brain Disorders

Posted: April 03, 2018

Large Gene Expression Study Sheds Light on Causal Factors in Five Brain Disorders

Molecular Picture Points the Way to Better Antipsychotic Medications

Posted: March 20, 2018

Molecular Picture Points the Way to Better Antipsychotic Medications

NAC Medication Improves Working Memory in Schizophrenia and Bipolar Patients with Psychosis

Posted: March 12, 2018

NAC Medication Improves Working Memory in Schizophrenia and Bipolar Patients with Psychosis

Social Impairment Levels Remain Stable in Patients with Psychotic Disorders

Posted: February 26, 2018

Social Impairment Levels Remain Stable in Patients with Psychotic Disorders

Strategy for Developing New Bipolar Disorder Treatments

Posted: January 23, 2018

Animal Studies Suggest a Strategy for Developing New Bipolar Disorder Treatments

Visual Processing Is Disrupted in People with Bipolar Disorder

Posted: January 18, 2018

Brain Imaging Suggests Visual Processing Is Disrupted in People with Bipolar Disorder

research on bipolar disorder

Posted: October 16, 2017

Study Shows Exposure to Bright Light at Midday Reduces Depression in Patients with Bipolar Disorder

Lithium Reduces Mania in Bipolar Disorder Opens Research Path to More Effective Treatments

Posted: September 07, 2017

New Knowledge about How Lithium Reduces Mania in Bipolar Disorder Opens Research Path to More Effective Treatments

Large Study Showed Lithium Lowered Suicide Risk in Patients with Bipolar Disorder

Posted: August 21, 2017

Large Study Showed Lithium Lowered Suicide Risk in Patients with Bipolar Disorder

Sex and other human activities

Posted: July 11, 2017

Brain Structure Study in Children Suggests Biological Overlaps in Disorders Usually Considered Distinct

man with suicidal thoughts, bipolar disorder and depression

Posted: June 19, 2017

Trial Finds Rapid Reduction in Suicidal Thoughts after Ketamine Treatment in Patients with Bipolar Disorder

Deep Transcranial Magnetic Stimulation (dTMS)

Posted: April 26, 2017

Deep Transcranial Magnetic Stimulation (dTMS) Could Help Treat Bipolar Depression

Study Compares 3 Different Treatments for Bipolar II Disorder

Posted: April 17, 2017

Study Compares 3 Different Treatments for Bipolar II Disorder

Creative image of brain neurons

Posted: March 03, 2017

Combinations of Genetic Risks are Linked with Abnormal Processing of Emotional Information in Bipolar Disorder

Wireframe of the human brain

Posted: February 28, 2017

Parts of the Brain’s Hippocampus are Diminished in Size in People with Bipolar Disorder

Suicidal Behavior in Young People with Bipolar Disorder

Posted: February 21, 2017

Brain Abnormalities Linked to Suicidal Behavior in Young People with Bipolar Disorder

Adolescents With Bipolar Disorder Not More Likely to be Overweight

Posted: January 20, 2017

Adolescents With Bipolar Disorder Not More Likely to be Overweight or Obese

Brain’s White Matter

Posted: December 02, 2016

Emotional Disorders Share Disruptions to Brain’s White Matter, Imaging Reveals

Researchers Pinpoint Neurons That Cause and Maintain Wakefulness

Posted: November 02, 2016

Researchers Pinpoint Neurons That Cause and Maintain Wakefulness

A Breakthrough in the Effort to Develop a Fast-Acting Antidepressant

Posted: September 30, 2016

A Breakthrough in the Effort to Develop a Fast-Acting Antidepressant

Abstract Creative Concept of the Human Brain

Posted: August 30, 2016

Study Finds Some Autism and Schizophrenia Related Genes May Also Be Involved in Bipolar Disorder

Suicidal Behavior in Young People with Bipolar Disorder

Posted: August 19, 2016

New Tool Calculates Patients’ Personal Psychosis Risk

Shrinking of Hippocampus in Bipolar Disorder Patients

Posted: August 09, 2016

Long-term Lithium Treatment May Prevent Shrinking of Hippocampus in Bipolar Disorder Patients

some people who suffer from major depression may benefit from the diagnosis and treatment of metabolic deficiencies

Posted: August 01, 2016

Study Identifies Separate Brain Network Disturbances in Bipolar Disorder States

Exercise May Treat Cognitive Symptoms in Bipolar Disorder

Posted: June 23, 2016

Exercise May Treat Cognitive Symptoms in Bipolar Disorder By Restoring Brain Activation Patterns

Blood Markers Indicate High Inflammation Levels

Posted: May 16, 2016

Blood Markers Indicate High Inflammation Levels in People with Schizophrenia, Bipolar Disorder and Depression

New Biotypes Classify Psychosis Cases

Posted: May 01, 2016

New Biotypes Classify Psychosis Cases According to Measurable Biological Features

Immune Activity During Pregnancy Tied to Neuronal Defects, Anxiety, and Cognitive Impairments

Posted: April 05, 2016

Immune Activity During Pregnancy Tied to Neuronal Defects, Anxiety, and Cognitive Impairments

Large Study Ties Genes to Variable Lithium Response in Bipolar Disorder

Posted: March 22, 2016

Large Study Ties Genes to Variable Lithium Response in Bipolar Disorder

Muscle Relaxant May Help in Treating Some Aspects of Alcohol Dependence in Anxious People

Posted: February 22, 2016

Enhanced Brain Plasticity May Help Overcome Predisposition to Bipolar Disorder

Posted: November 19, 2015

Antipsychotic Treatment for Bipolar Disorder Not Always Effective After Six Months

Posted: October 06, 2015

Measuring Gene Activity in the Blood Could Help Diagnose Bipolar Disorder

Posted: July 31, 2015

Genes Linked to Abnormal Brain Waves in Schizophrenia, Psychotic Bipolar Disorder

Posted: June 22, 2015

D-Serine, A Potential Schizophrenia Treatment, May Guide Some Early Brain Development

Posted: June 11, 2015

Parent’s History of Suicide Attempts Helps Predict Suicide Attempts In Children

research on bipolar disorder

Looking For Clues in Reward Circuits of Bipolar and Depressed Patients

Large-Scale Gene Mutation

Posted: June 01, 2015

Large-Scale Gene Mutation Disrupts Brain Development During Key Period

Posted: March 03, 2015

Lithium Linked to Lower Incidence of Dementia in Older People with Bipolar Disorder

Posted: February 17, 2015

For Children and Adolescents with Bipolar Disorder, a New Antidepressant Combination Treatment

Posted: February 03, 2015

In Bipolar Disorder, a Chemical Signal of Abnormal Metabolism

Posted: January 30, 2015

Multiple Psychiatric illnesses Share the Same Perturbed Biological Pathways

Posted: December 23, 2014

New Approach Provides Path Toward Functional Recovery in Bipolar Disorder

Posted: October 23, 2014

What Causes the Placebo Effect in Clinical Trials of Antipsychotic Medications?

Fast-Acting Antidepressant Restores Ability to Experience Pleasure in People with Bipolar Disorder

Posted: October 15, 2014

Fast-Acting Antidepressant Restores Ability to Experience Pleasure in People with Bipolar Disorder

Posted: September 29, 2014

International Collaborative Effort Develops the Beginnings of a Blood Test for Psychosis

Posted: September 09, 2014

Mother Discusses Why She Raises Money for Mental Health Research

Upcoming keynote at foundation’s dc event featured in forbes article.

With New Technology, Researchers See How Faulty Human Brain Cells Develop

Posted: August 21, 2014

With New Technology, Researchers See How Faulty Human Brain Cells Develop

Posted: June 19, 2014

Gene Linked to Bipolar Disorder, Schizophrenia Plays Key Role in Brain Development

Posted: March 05, 2014

Making the Impossible Possible: The Challenges of Practicing Evidence-Based Psychiatry with a Focus on Bipolar Depression*

Posted: November 04, 2013

Watch Dr. Boris Birmaher’s Video: 2013 Colvin Prize for Outstanding Achievement in Mood Disorders Research

Watch dr. andrew nierenberg’s video: 2013 colvin prize for outstanding achievement in mood disorders research.

Posted: November 01, 2013

New Insight for Difficult-to-Treat Mania in Bipolar Disorder

Posted: October 24, 2013

Electrical Stimulation Can Improve Cognitive Performance―May Help in Schizophrenia, Bipolar Disorder

Posted: October 22, 2013

State of MD Supports Foundation Scientific Council Member’s Early Intervention in Psychosis Program

research on bipolar disorder

Posted: October 08, 2013

Defining Psychotic Disorders―Mood Disorders and Schizophrenia―by Symptom Course and Long-Term Outcome

Posted: October 04, 2013

Pre-Term Birth Associated with Higher Risk of Mental Illness, But Also for Siblings

Posted: August 26, 2013

NARSAD Grant-Funded Study Identifies Disrupted Brain Communication in Schizophrenia and Bipolar Disorder

Posted: August 20, 2013

Using Brain Imaging, NARSAD Grantee Identifies Predictor of Psychosis Treatment Effectiveness

Posted: July 31, 2013

Linking Brain Imaging With Genetics Helps Identify New Risk Profile for Depression

Posted: March 12, 2013

NARSAD Grantee Discovers Predictor of Psychosis in Bipolar Disorder, Schizophrenia

Posted: March 01, 2013

Current Progress in Developing More Effective Treatments for Bipolar Disorder

Posted: January 17, 2013

NARSAD Grantees Make New Discoveries About the Brain Circuitry of Bipolar Disorder

Posted: December 03, 2012

Karen Dineen Wagner Wins 2012 Colvin Prize for Mood Disorders Research

Posted: November 06, 2012

Eduard Vieta is Recognized for Outstanding Achievement in Mood Disorders Research

Posted: September 24, 2012

Premature Birth Heightens Risk for Mental Illness

Posted: August 22, 2012

NARSAD Grant-Funded Research Furthers Understanding of Causes of Bipolar Disorder

Posted: August 07, 2012

Addressing the Major Public Health Issue of Vascular Disease in Mood Disorders

Creating a new window to study synaptic (dys)function in brain and behavior disorders.

Posted: July 05, 2012

NARSAD Grant-funded Research Finds Links Between Schizophrenia, Bipolar and Autism

Posted: July 03, 2012

NARSAD Grantee Discusses Innovative Work to Understand and Better Treat Mental Illnesses

Posted: June 04, 2012

NARSAD Grant-Funded Research Finds Premature Birth Increases Risk for Mental Illness

Posted: April 18, 2012

Off-Balance Circadian Clocks and the Risk of Mood Disorders

Building careers, changing lives; q&a with david j. miklowitz, ph.d..

Posted: April 03, 2012

NARSAD Grantees Learning to Predict Likelihood of Mental Illness in Teenagers

Posted: January 23, 2012

Research News Update – Deep Brain Stimulation

Posted: January 11, 2012

NARSAD Grants Fund Breakthrough Bipolar & Depression Treatment

Posted: January 06, 2012

Foundation-funded Discovery: Early Childhood Immigration Linked to Psychotic Disorders

Posted: December 30, 2011

Basic Research and Novel Therapeutic Treatments Pave the Road to Cures for Mental Illness

Posted: November 22, 2011

VIDEO: 2011 Gloria Neidorf Memorial Lecture on Bipolar Disorder

Posted: November 15, 2011

The Challenge of Co-Morbidity: How to Treat Patients with Multiple Brain and Behavior Disorders

Posted: September 26, 2011

Understanding Why Identical Twins Are Not Carbon Copies in Mental Illness

Posted: September 22, 2011

Foundation Honors Scientists For Outstanding Achievements in Mental Illness Research

Posted: August 26, 2011

New Approach Leads Toward More Effective Bipolar Treatments

Using other disorders with similar symptoms to help unravel the genetic code of bipolar disorder, an overview of treatment options for bipolar disorder, the diagnostic challenge: is it depression or bipolar disorder.

Posted: July 14, 2011

Sharing Knowledge as We Unlock the Mysteries of Mental Illness

Posted: March 11, 2011

The NARSAD Feed: NARSAD Researchers in the News, Research Finds Bipolar Disorder is Under-Diagnosed in Some Countries, Talk Therapy Doesn’t Pay

Posted: February 01, 2011

New York Times Profiles NARSAD Investigator as ‘Master Virus Hunter’

Posted: December 09, 2010

The Most Avant-Garde Bipolar Disorder Researcher Found in Denmark … the NARSAD Outstanding Achievement in Mood Disorder Research Awarded to Dr. Lars Kessing

Posted: December 01, 2010

Understanding the Brain Physiology of Bipolar Disorder

Posted: April 01, 2010

Kiki Chang and Tara Peris: Helping Families Cope with Childhood Mental Illness

Key figures.

research on bipolar disorder

Bipolar disorder affects approximately 5.7 million adult Americans or about 2.8% of the U.S. population age 18 and older every year.*

* Source: National Institute of Mental Health

research on bipolar disorder

* Source: World Health Organization (WHO)

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Meet a Researcher

Fritz A. Henn, M.D., Ph.D.

Fritz A. Henn, M.D., Ph.D.

Professor, Cold Spring Harbor Laboratory

Professor of Psychiatry

2014 Colvin Prize for Outstanding Achievement in Mood Disorders Research

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Huda Akil, Ph.D.

Huda Akil, Ph.D.

Gardner Quarton Distinguished University Professor of Neuroscience and Psychiatry

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In your work with the Pritzker Neuropsychiatric Research Consortium, have you uncovered any new genes that you think might be related to mental illnesses besides major depression?

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Bipolar disorder articles from across Nature Portfolio

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

Latest Research and Reviews

research on bipolar disorder

Processing speed mediates the relationship between DDR1 and psychosocial functioning in euthymic patients with bipolar disorder presenting psychotic symptoms

  • Selena Aranda
  • Esther Jiménez
  • Elisabet Vilella

research on bipolar disorder

Key subphenotypes of bipolar disorder are differentially associated with polygenic liabilities for bipolar disorder, schizophrenia, and major depressive disorder

  • Lina Jonsson
  • Mikael Landén

Pharmacogenomic overlap between antidepressant treatment response in major depression & antidepressant associated treatment emergent mania in bipolar disorder

  • Nicolas A. Nuñez
  • Brandon J. Coombes
  • Mark A. Frye

research on bipolar disorder

Bipolar patients display stoichiometric imbalance of gene expression in post-mortem brain samples

  • Asbjørn Holmgren
  • Ibrahim Akkouh
  • Timothy Hughes

research on bipolar disorder

Oxidation of DNA and RNA in young patients with newly diagnosed bipolar disorder and relatives

  • Klara Coello
  • Ilari Jaakko Olavi Mäkinen
  • Lars Vedel Kessing

research on bipolar disorder

White and gray matter alterations in bipolar I and bipolar II disorder subtypes compared with healthy controls – exploring associations with disease course and polygenic risk

  • Katharina Thiel
  • Hannah Lemke
  • Udo Dannlowski

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research on bipolar disorder

Managing maintenance therapy for bipolar 1 depression

A trial comparing long-term versus short-term antidepressant maintenance therapy fails to show a significant benefit of continued treatment.

  • Karen O’Leary

research on bipolar disorder

Repetitive transcranial magnetic stimulation for bipolar depression: a systematic review and pairwise and network meta-analysis

  • Toshikazu Ikuta
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The conundrum of antidepressant use in bipolar disorder

  • Giselli Scaini
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A shared pathway connects schizophrenia and bipolar disorder

Human and animal studies reveal a neurobiological pathway that connects polygenic risks and behavioural changes that are shared between schizophrenia and bipolar mood disorder.

  • Jake Rogers

research on bipolar disorder

Genetic evidence for the “dopamine hypothesis of bipolar disorder”

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Novel gene loci associated with bipolar disorder

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research on bipolar disorder

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

Bipolar disorder, formerly called manic depression, is a mental health condition that causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression).

When you become depressed, you may feel sad or hopeless and lose interest or pleasure in most activities. When your mood shifts to mania or hypomania (less extreme than mania), you may feel euphoric, full of energy or unusually irritable. These mood swings can affect sleep, energy, activity, judgment, behavior and the ability to think clearly.

Episodes of mood swings may occur rarely or multiple times a year. While most people will experience some emotional symptoms between episodes, some may not experience any.

Although bipolar disorder is a lifelong condition, you can manage your mood swings and other symptoms by following a treatment plan. In most cases, bipolar disorder is treated with medications and psychological counseling (psychotherapy).

Bipolar disorder care at Mayo Clinic

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There are several types of bipolar and related disorders. They may include mania or hypomania and depression. Symptoms can cause unpredictable changes in mood and behavior, resulting in significant distress and difficulty in life.

  • Bipolar I disorder. You've had at least one manic episode that may be preceded or followed by hypomanic or major depressive episodes. In some cases, mania may trigger a break from reality (psychosis).
  • Bipolar II disorder. You've had at least one major depressive episode and at least one hypomanic episode, but you've never had a manic episode.
  • Cyclothymic disorder. You've had at least two years — or one year in children and teenagers — of many periods of hypomania symptoms and periods of depressive symptoms (though less severe than major depression).
  • Other types. These include, for example, bipolar and related disorders induced by certain drugs or alcohol or due to a medical condition, such as Cushing's disease, multiple sclerosis or stroke.

Bipolar II disorder is not a milder form of bipolar I disorder, but a separate diagnosis. While the manic episodes of bipolar I disorder can be severe and dangerous, individuals with bipolar II disorder can be depressed for longer periods, which can cause significant impairment.

Although bipolar disorder can occur at any age, typically it's diagnosed in the teenage years or early 20s. Symptoms can vary from person to person, and symptoms may vary over time.

Mania and hypomania

Mania and hypomania are two distinct types of episodes, but they have the same symptoms. Mania is more severe than hypomania and causes more noticeable problems at work, school and social activities, as well as relationship difficulties. Mania may also trigger a break from reality (psychosis) and require hospitalization.

Both a manic and a hypomanic episode include three or more of these symptoms:

  • Abnormally upbeat, jumpy or wired
  • Increased activity, energy or agitation
  • Exaggerated sense of well-being and self-confidence (euphoria)
  • Decreased need for sleep
  • Unusual talkativeness
  • Racing thoughts
  • Distractibility
  • Poor decision-making — for example, going on buying sprees, taking sexual risks or making foolish investments

Major depressive episode

A major depressive episode includes symptoms that are severe enough to cause noticeable difficulty in day-to-day activities, such as work, school, social activities or relationships. An episode includes five or more of these symptoms:

  • Depressed mood, such as feeling sad, empty, hopeless or tearful (in children and teens, depressed mood can appear as irritability)
  • Marked loss of interest or feeling no pleasure in all — or almost all — activities
  • Significant weight loss when not dieting, weight gain, or decrease or increase in appetite (in children, failure to gain weight as expected can be a sign of depression)
  • Either insomnia or sleeping too much
  • Either restlessness or slowed behavior
  • Fatigue or loss of energy
  • Feelings of worthlessness or excessive or inappropriate guilt
  • Decreased ability to think or concentrate, or indecisiveness
  • Thinking about, planning or attempting suicide

Other features of bipolar disorder

Signs and symptoms of bipolar I and bipolar II disorders may include other features, such as anxious distress, melancholy, psychosis or others. The timing of symptoms may include diagnostic labels such as mixed or rapid cycling. In addition, bipolar symptoms may occur during pregnancy or change with the seasons.

Symptoms in children and teens

Symptoms of bipolar disorder can be difficult to identify in children and teens. It's often hard to tell whether these are normal ups and downs, the results of stress or trauma, or signs of a mental health problem other than bipolar disorder.

Children and teens may have distinct major depressive or manic or hypomanic episodes, but the pattern can vary from that of adults with bipolar disorder. And moods can rapidly shift during episodes. Some children may have periods without mood symptoms between episodes.

The most prominent signs of bipolar disorder in children and teenagers may include severe mood swings that are different from their usual mood swings.

When to see a doctor

Despite the mood extremes, people with bipolar disorder often don't recognize how much their emotional instability disrupts their lives and the lives of their loved ones and don't get the treatment they need.

And if you're like some people with bipolar disorder, you may enjoy the feelings of euphoria and cycles of being more productive. However, this euphoria is always followed by an emotional crash that can leave you depressed, worn out — and perhaps in financial, legal or relationship trouble.

If you have any symptoms of depression or mania, see your doctor or mental health professional. Bipolar disorder doesn't get better on its own. Getting treatment from a mental health professional with experience in bipolar disorder can help you get your symptoms under control.

When to get emergency help

Suicidal thoughts and behavior are common among people with bipolar disorder. If you have thoughts of hurting yourself, call 911 or your local emergency number immediately, go to an emergency room, or confide in a trusted relative or friend. Or contact a suicide hotline. In the U.S., call or text 988 to reach the 988 Suicide & Crisis Lifeline , available 24 hours a day, seven days a week. Or use the Lifeline Chat . Services are free and confidential.

If you have a loved one who is in danger of suicide or has made a suicide attempt, make sure someone stays with that person. Call 911 or your local emergency number immediately. Or, if you think you can do so safely, take the person to the nearest hospital emergency room.

There is a problem with information submitted for this request. Review/update the information highlighted below and resubmit the form.

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The exact cause of bipolar disorder is unknown, but several factors may be involved, such as:

  • Biological differences. People with bipolar disorder appear to have physical changes in their brains. The significance of these changes is still uncertain but may eventually help pinpoint causes.
  • Genetics. Bipolar disorder is more common in people who have a first-degree relative, such as a sibling or parent, with the condition. Researchers are trying to find genes that may be involved in causing bipolar disorder.

Risk factors

Factors that may increase the risk of developing bipolar disorder or act as a trigger for the first episode include:

  • Having a first-degree relative, such as a parent or sibling, with bipolar disorder
  • Periods of high stress, such as the death of a loved one or other traumatic event
  • Drug or alcohol abuse

Complications

Left untreated, bipolar disorder can result in serious problems that affect every area of your life, such as:

  • Problems related to drug and alcohol use
  • Suicide or suicide attempts
  • Legal or financial problems
  • Damaged relationships
  • Poor work or school performance

Co-occurring conditions

If you have bipolar disorder, you may also have another health condition that needs to be treated along with bipolar disorder. Some conditions can worsen bipolar disorder symptoms or make treatment less successful. Examples include:

  • Anxiety disorders
  • Eating disorders
  • Attention-deficit/hyperactivity disorder (ADHD)
  • Alcohol or drug problems
  • Physical health problems, such as heart disease, thyroid problems, headaches or obesity

More Information

  • Bipolar disorder and alcoholism: Are they related?

There's no sure way to prevent bipolar disorder. However, getting treatment at the earliest sign of a mental health disorder can help prevent bipolar disorder or other mental health conditions from worsening.

If you've been diagnosed with bipolar disorder, some strategies can help prevent minor symptoms from becoming full-blown episodes of mania or depression:

  • Pay attention to warning signs. Addressing symptoms early on can prevent episodes from getting worse. You may have identified a pattern to your bipolar episodes and what triggers them. Call your doctor if you feel you're falling into an episode of depression or mania. Involve family members or friends in watching for warning signs.
  • Avoid drugs and alcohol. Using alcohol or recreational drugs can worsen your symptoms and make them more likely to come back.
  • Take your medications exactly as directed. You may be tempted to stop treatment — but don't. Stopping your medication or reducing your dose on your own may cause withdrawal effects or your symptoms may worsen or return.
  • Reilly-Harrington NA et al. A tool to predict suicidal ideation and behavior in bipolar disorder: The Concise Health Risk Tracking Self-Report. Journal of Affective Disorders. 2016;192:212.
  • Bipolar and related disorders. In: Diagnostic and Statistical Manual of Mental Disorders DSM-5. 5th ed. Arlington, Va.: American Psychiatric Association; 2013. http://www.psychiatryonline.org. Accessed Dec. 2, 2016.
  • Bipolar disorder. National Institute of Mental Health. https://www.nimh.nih.gov/health/topics/bipolar-disorder/index.shtml. Accessed Dec. 2, 2016.
  • Bipolar disorder. National Institute of Mental Health. https://www.nimh.nih.gov/health/publications/bipolar-disorder-tr-15-3679/index.shtml. Accessed Dec. 2, 2016.
  • Bipolar disorder in children and teens. National Institute of Mental Health. https://www.nimh.nih.gov/health/publications/bipolar-disorder-in-children-and-teens-qf-15-6380/index.shtml. Accessed Dec. 2, 2016.
  • Bipolar disorder. National Alliance on Mental Illness. https://www.nami.org/Learn-More/Mental-Health-Conditions/Bipolar-Disorder. Accessed Dec. 2, 2016.
  • AskMayoExpert. Bipolar disorder. Rochester, Minn.: Mayo Foundation for Medical Education and Research; 2016. Accessed Dec. 2, 2016.
  • Suppes T, et al. Bipolar disorder in adults: Clinical features. http://www.uptodate.com/home. Accessed Dec. 2, 2016.
  • Axelson D, et al. Pediatric bipolar disorder: Overview of choosing treatment. http://www.uptodate.com/home. Accessed Dec. 2, 2016.
  • Birmaher B. Pediatric bipolar disorder: Epidemiology, pathogenesis, clinical manifestations, and course. http://www.uptodate.com/home. Accessed Dec. 2, 2016.
  • Picardi A, et al. Psychotherapy of mood disorders. Clinical Practice and Epidemiology in Mental Health. 2014;10:140.
  • Fountoulakis KN, et al. The International College of Neuro-Psychopharmacology (CINP) treatment guidelines for bipolar disorder in adults (CINP-BP-2017), part 2: Review, grading of the evidence and a precise algorithm. International Journal of Neuropsychopharmacology. In press. http://ijnp.oxfordjournals.org/content/early/2016/11/05/ijnp.pyw100.long. Accessed Dec. 6, 2016.
  • Beyer JL, et al. Nutrition and bipolar depression. Psychiatric Clinics of North America. 2016;39:75.
  • Qureshi NA, et al. Mood disorders and complementary and alternative medicine: A literature review. Neuropsychiatric Disease and Treatment. 2013;9:639.
  • Sansone RA, et al. Getting a knack for NAC: N-acetyl-cysteine. Innovations in Clinical Neuroscience. 2011;8:10.
  • Sylvia LG, et al. Nutrient-based therapies for bipolar disorder: A systematic review. Psychotherapy and Psychosomatics. 2013;82:10.
  • Hall-Flavin DK (expert opinion). Mayo Clinic, Rochester, Minn. Dec. 27, 2016.
  • Krieger CA (expert opinion). Mayo Clinic, Rochester, Minn. Jan. 4, 2017.
  • Post RM. Bipolar disorder in adults: Choosing maintenance treatment. http://www.uptodate.com/home. Accessed Jan. 4, 2016.
  • Janicak PG. Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects. http://www.uptodate.com/home. Accessed Jan. 4, 2017.
  • Stovall J. Bipolar disorder in adults: Pharmacotherapy for acute mania and hypomania. http://www.uptodate.com/home. Accessed Jan. 4, 2017.
  • Bipolar disorder in children: Is it possible?
  • Bipolar medications and weight gain
  • Bipolar treatment: I vs. II

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Clinical Trials

Bipolar disorder.

Displaying 18 studies

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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What Is Bipolar Disorder?

  • 1 Contributing Writer, JAMA
  • Review A Review of the Diagnosis, Treatment, and Prognosis of Bipolar Disorder Andrew A. Nierenberg, MD; Bruno Agustini, MD, PhD; Ole Köhler-Forsberg, MD, PhD; Cristina Cusin, MD; Douglas Katz, PhD; Louisa G. Sylvia, PhD; Amy Peters, PhD; Michael Berk, MD, PhD JAMA

Bipolar disorder is characterized by mood swings ranging from depressive lows to manic highs.

Bipolar disorder affects about 8 million people in the US and an estimated 40 million individuals worldwide. Symptoms of bipolar disorder typically start between age 15 to 25 years, often with an initial episode of depression.

What Are the Types of Bipolar Disorder?

Individuals with bipolar I disorder have at least 1 episode of mania, defined as an elevated or irritable mood lasting at least 1 week that may require hospitalization. Symptoms of mania include impulsivity, risk-taking behavior, restlessness, grandiosity, racing thoughts, decreased need for sleep, increased productivity, and impaired judgment.

Individuals with bipolar II disorder have hypomania (a milder form of mania) for at least 4 consecutive days along with a previous episode of depression.

How Is Bipolar Disorder Diagnosed?

Bipolar disorder is diagnosed in individuals who have episodes of depression and mania. Clinicians should ask all patients with depression about symptoms of mania, such as excessive energy, reduced need for sleep, increased sexuality, and elevated or irritable mood. Family members often can provide insight into their relative’s recent patterns of behavior and decision-making. It is important to identify individuals with bipolar disorder because early diagnosis and treatment often results in a better prognosis.

Approximately 70% of people with bipolar disorder also have an anxiety disorder and slightly more than half have a substance use disorder. Personality disorders affect about one-third of individuals with bipolar disorder and approximately 10% to 20% have attention-deficit/hyperactivity disorder.

How Is Bipolar Disorder Treated?

Medication is the mainstay of treatment for bipolar disorder. Most people with bipolar disorder need lifelong treatment to decrease manic or depressive symptoms, reduce relapses, and improve functioning and quality of life. Treatment should be tailored to a patient’s symptoms, presence of other mental health conditions, prior response to treatment, and personal preferences. Treatment for bipolar disorder typically includes 1 or more of the following:

Mood stabilizers such as lithium, valproate, and lamotrigine

Atypical antipsychotic drugs such as quetiapine, aripiprazole, and cariprazine

Psychotherapy to reduce relapses and symptoms, lower hospitalization rates, and improve medication adherence

Inpatient care if a patient’s judgment is severely impaired during a manic episode

Electroconvulsive therapy, which delivers electrical shocks to the brain under anesthesia, for patients with severe bipolar depression who do not improve with conventional treatments

Life Expectancy of Individuals With Bipolar Disorder

Individuals with bipolar disorder have a life expectancy that is 12 to 14 years shorter than the general population, primarily due to an increased risk of suicide and heart disease. Bipolar disorder is associated with metabolic syndrome (high blood pressure, high blood glucose, excess body fat around the waist, and abnormal cholesterol levels), obesity, cigarette smoking, and type 2 diabetes.

Interventions to Decrease Risk of Heart Disease in Individuals With Bipolar Disorder

Individuals with bipolar disorder who smoke cigarettes benefit from intensive smoking cessation programs with tailored behavioral counseling and care coordination to reduce the risk of heart disease. Physical activity and dietary modifications are recommended for all individuals with bipolar disorder.

For More Information

American Psychiatric Association

Substance Abuse and Mental Health Services Administration

Published Online: February 16, 2024. doi:10.1001/jama.2023.24844

Conflict of Interest Disclosures: None reported.

Source: Nierenberg AA, Agustini B, Köhler-Forsberg O, et al. Diagnosis and treatment of bipolar disorder: a review. JAMA . 2023;330(14):1370-1380. doi:10.1001/jama.2023.18588

See More About

Voelker R. What Is Bipolar Disorder? JAMA. Published online February 16, 2024. doi:10.1001/jama.2023.24844

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Innovations in the treatment of bipolar disorder Stanford University School of Medicine

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Servings our Nation's Veterans Stanford University School of Medicine in Collaboration with VA Palo Alto Healthcare System

The bipolar and depression research program.

The Bipolar and Depression Research Program is a clinical research program focused on treatment of individuals with bipolar and major depressive disorders directed by Drs. Trisha Suppes and Michael Ostacher . It is located on the campus of the VA Palo Alto Health Care System and affiliated with the VA and the Stanford School of Medicine. All studies are open to the general public as well as veterans and active duty military personnel. Our research focuses on Bipolar Disorder, including Bipolar Disorder that occurs with Generalized Anxiety Disorder or Life Time Panic Disorder, Major Depressive Disorder and Post Traumatic Stress Disorder (PTSD). We have several current studies underway.  A new division of our research efforts is addressing moods disorders using exploratory therapeutics.  Compounds under consideration for depressed individuals:  Psilocybin and Pramipexole.

Learn more about our current studies

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Bipolar Disorder Research Roundup: February 9, 2024

What is new in research on bipolar disorder?

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research on bipolar disorder

In this Research Roundup, we explore new studies on bipolar disorder, its connections to neuroendocrine/glucose metabolism and suicide attempt risk, and more.

Assessing Neuroendocrine/Glucose Metabolism and Clinical Outcomes in Bipolar Disorder This study assessed the impact of hypothalamic-pituitary-adrenal (HPA) axis/hypothalamic-pituitary-thyroid (HPT) axis and glucose metabolism on clinical outcomes in bipolar depression (BD-D) and manic bipolar (BD-M) disorders. It involved 500 patients with BD across 15 hospitals in Western China, tracking symptoms and hormone levels over 12 weeks. Results revealed correlations between hormone levels and symptom severity, suggesting potential biomarkers for treatment response, such as thyroid hormone (T3) for BD-D and insulin resistance for BD-M, indicating avenues for personalized treatment strategies.

The investigators concluded that, “If confirmed in further longitudinal studies, monitoring T3 in BD-D patients and the homeostatic model assessment of insulin resistance for BD-M could be used as potential treatment response biomarkers.”

Zhang X, Zhou Y, Chen Y, et al. The association between neuroendocrine/glucose metabolism and clinical outcomes and disease course in different clinical states of bipolar disorders .  Front Psychiatry . 2024;15:1275177.

Efficacy of Aripiprazole Once Monthly for Bipolar Disorder This 1-year retrospective analysis assessed the effectiveness and safety of aripiprazole once monthly (AOM) in patients with bipolar disorder (BD). Findings showed a significant reduction in mood episodes, particularly manic and depressive episodes, along with decreased use of psychiatric medications and pills post-AOM treatment.

Although limitations such as a small sample size and potential selection bias were noted, the results suggest that AOM could be a clinically beneficial treatment option for patients with BD, potentially mitigating issues related to polypharmacy.

Woo YS, Jeong JH, Kang H, et al. Preventive effect of aripiprazole once-monthly on relapse into mood episodes in bipolar disorder: a multicenter, one-year, retrospective, mirror image study .  J Affect Disord . Published online January 30, 2024.

Investigating Potential Biomarkers for Suicide Attempts in Bipolar Disorder This study investigated DNA methylation patterns as potential biomarkers for suicide attempts in individuals with bipolar disorder (BD). Epigenome-wide association studies (EWAS) identified immune-related genes with differential methylation between individuals with BD who had and did not have a history of suicide attempt. Integrating methylation data with clinical interviews showed promising accuracy in predicting suicide attempt risk.

The investigators concluded that, “Our results provide novel insight to the role of immune system functioning in suicide attempt and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for suicide attempt in adults with BD.”

Mirza S, Lima CNC, Del Favero-Campbell A, et al. Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder .  Transl Psychiatry . 2024;14(1):70.

Note: This Research Roundup was prepared with the assistance of ChatGPT.

Let us hear from you!  Want to share your insights with colleagues on the latest research on bipolar disorder and other psychiatric disorders, treatments, and issues? Write to us at [email protected] .

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Adults: Bipolar Disorder

A family study, what impacts mood, sleep, and energy.

Enrolling locally from the Washington, D.C. metro region

This research study is enrolling people to help us understand how physical activity, daily rhythms, and light affect mental health. 

Depression & Transcranial Electric Stimulation Therapy (TEST)

Enrolling nationally from around the country

Researchers are testing a new type of non-invasive brain stimulation treatment to see if it is safe and potentially helpful to treat depression symptoms.

Investigating the Genetics of Bipolar Disorder in those affected and their family members

Researchers are looking for genes that may affect a person's chances of developing bipolar disorder. You can participate in this research study if you are over 18, have a bipolar diagnosis, or have a family member with bipolar disorder.

NIMH Family Study of Health and Behavior

The major goal of this study is to examine how mood disorders, anxiety disorders and migraine run in families. We study both genetic and environmental factors that may contribute to these conditions.

Suicide and the Brain

National Institute of Mental Health (NIMH) researchers seek adults 18 to 70, who have a history of attempted suicide but are not currently suicidal, for a study of suicide and brain function. Participation includes up to seven days as an inpatient at the NIH Clinical Center in Bethesda, Maryland. Procedures include blood tests, medical evaluations, brain imaging, sleep studies and psychiatric interviews. Participants do not need to stop their current medications. Compensation and transportation are provided. Pregnant women and individuals with serious medical conditions are not eligible.

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Connection Between Bipolar Disorder and Narcissism

They have some overlapping symptoms

  • What Are BP and NPD?
  • The BD-NPD Relationship

Traits of bipolar disorder (BD) can sometimes include signs of narcissism, or a sense of grandiosity and self-importance. It doesn't occur in everyone and can depend on the type and episode of bipolar disorder, and it's not the same thing as narcissistic personality disorder (NPD) .

In most cases, they are not co-occurring conditions, either. Research suggests about 4.5% of people diagnosed with bipolar disorder also have narcissistic personality disorder. The traits are similar, though, despite BD and NPD being two different mental disorders.

This article will explain the similarities and differences between BD and NPD, including their symptoms and underlying causes. It discusses treatment and self-care options for these conditions.

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What Are Bipolar Disorder and Narcissistic Personality Disorder?

Bipolar disorder is a mental health condition with mood changes among its key symptoms, and distinct subtypes and patterns. The mood changes may last weeks or longer. These include:

  • Manic episodes : Extreme energy, elation, or irritability
  • Depressive episodes: Sadness, hopelessness, and lack of interest
  • Mixed episodes: Symptoms of both moods at the same time

Meanwhile, the key NPD symptoms include an inflated sense of importance and extreme preoccupation with the self. People diagnosed with narcissistic personality disorder often demonstrate a sense of entitlement and a lack of empathy toward others.

What Are the Types of Bipolar Disorder?

Bipolar disorder has three main types:

  • Bipolar 1 : “Classic” bipolar, it often involves the characteristic manic episodes alternating with depressed mood.
  • Bipolar 2 : This type involves depressive and hypomanic episodes. Hypomania is a milder version of mania.
  • Cyclothymic disorder : It involves less intense symptoms and more rapid mood swings.

Symptoms of Bipolar Disorder and NPD

Most people with BD or NPD don’t have the other disorder, but they do have their similarities. In particular, the manic phase of bipolar disorder can make a person feel that they’re especially powerful, important, or talented.

That’s a key trait of narcissism, although not everyone with BD has this symptom. Other symptoms that BD and NPD have in common include:

  • Setting high, often unachievable goals
  • Impulsivity and risky behavior (excessive spending, drinking, drugs, sex, etc.)
  • Relationship problems
  • Appearing to be insensitive or dismissing the needs of others

The nature of BD can help you distinguish between garden-variety narcissism and the pathological symptoms of NPD. 

  • In NPD, narcissistic personality traits are always present (although the person may try to mask them)
  • In BD, narcissistic traits only tend to surface during manic episodes.

It also helps to look at other symptoms. That may help you rule out one of these disorders.

Elation or feeling “high”

Irritability 

Inflated belief in importance, talent

Short temper

Racing thoughts

Talking fast

Needing less sleep

Risky behavior and poor judgment

Rage, shame, or humiliation in response to criticism

Taking advantage of other people

Excessive feelings of importance

Exaggerating talents and achievements

Preoccupation with fantasies of power, and intelligence

Unreasonable expectations of special treatment

Constant need for attention, admiration

Lack of empathy

Obsessive self-interest

In NPD, what appears as arrogance is an attempt to hide deep-seated fears and insecurities. This can lead to depression and other traits that may be similar to depressive symptoms of bipolar disorder.

Suicidal thoughts and behaviors are common in both disorders.

If you or someone you know are having suicidal thoughts, dial  988  to contact the  988 Suicide & Crisis Lifeline  and connect with a trained counselor. If you or a loved one are in immediate danger, call 911 .

For more mental health resources, see our  National Helpline Database .

Relationship Between Bipolar Disorder and Narcissism

Bipolar disorder and narcissistic personality disorder are not the same, but people with BD sometimes exhibit traits of narcissism.

Research continues into the causes of these symptoms, but there's some evidence that brain changes and neurotransmitters (chemical messengers) are at work in similar ways. Studies have demonstrated that stress and trauma play a role in both bipolar disorder and narcissism, along with other conditions that have similarities. So does genetics.

People experiencing a manic state in BD often demonstrate grandiosity and an inflated sense of self, but their narcissistic behavior isn't the same thing as NPD. Studies find this may be more common in males diagnosed with BD rather than females.

Diagnosing Bipolar Disorder and NPD

BD and NPD have similar diagnostic processes. It may begin with your healthcare provider, who will give you a physical exam and look at your medical and family histories.

Depending on your symptoms, your healthcare provider may order blood work or other tests to rule out other conditions.

You will then undergo a mental health evaluation. Your primary care provider may perform this themselves or refer you to a mental health specialist.

How BD and NPD Are Treated

Some of the treatments for bipolar disorder and narcissistic personality disorder are the same. These include psychotherapy and medication.  

There are no specific medications to treat NPD, but medications may be used to treat symptoms of the anxiety and depression that commonly accompany the disorder. Treatment involves:

  • Psychotherapy : Includes traditional talk therapy, psychodynamic psychotherapy, and cognitive behavioral therapy (CBT)
  • Medication : Includes mood stabilizers, antipsychotics, and antidepressants

What is CBT?

Cognitive behavioral therapy is a type of psychotherapy that focuses on changing behavior or mood problems by addressing negative thought patterns.

Bipolar Disorder Treatments

Additional treatments for bipolar include:

  • Electroconvulsive therapy (ECT) : Controlled electric currents pass through the brain which causes a brief seizure that can change brain chemistry and the function of neurons (brain cells)
  • Transcranial magnetic stimulation (TMS) : Magnetic fields stimulate neurons linked to depression.
  • Other types of psychotherapy : Interpersonal and social rhythm therapy, dialectical behavior therapy (a type of CBT), and family-focused therapy
  • Self-management : Regular exercise, meditation, education about BD, and learning to recognize and manage episode triggers

ECT and TMS are primarily used when psychotherapy and medications don’t provide enough relief.

Narcissistic Personality Disorder Treatments

NPD is difficult to treat, as it’s common for people with NPD to reject therapy or refuse to admit they have a problem.

A type of therapy called individual psychodynamic psychotherapy is believed to be effective for NPD. However, it’s generally a lengthy and difficult process. 

Can These Conditions Be Prevented?

There’s no known way to prevent bipolar disorder or narcissistic personality disorder. However, because childhood trauma is linked to both, it may help to get therapy for issues as soon as possible.

If you’re concerned about NPD in children , parenting classes or therapy may help you to understand the role of adverse childhood events and other factors that can contribute to narcissistic traits.

Some bipolar mania symptoms mimic narcissistic traits. True NPD alongside BD is rare, although some people diagnosed with bipolar disorder may demonstrate an inflated sense of self and a lack of empathy or concern for others.

Genetics, brain chemistry, and childhood trauma may all contribute to the development of these disorders. They're diagnosed through mental health evaluations and treated with medications and psychotherapy.

If you or someone close to you has BD or NPD, a proper diagnosis and treatment are essential.

Bezerra-Filho S, Galvão-de Almeida A, Studart P, Rocha MV, Lopes FL, Miranda-Scippa Â. Personality disorders in euthymic bipolar patients: a systematic review . Braz J Psychiatry . 2015;37(2):162-167. doi:10.1590/1516-4446-2014-1459

Medline Plus. Bipolar disorder .

American Psychiatric Association. 2013.  Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, DSM-5 .  New Delhi, India: CBS Publishers & Distributors.

American Psychiatric Association. What is bipolar disorder? .

Caligor E, Levy KN, Yeomans FE. Narcissistic personality disorder: diagnostic and clinical challenges . Am J Psychiatry . 2015;172(5):415-422. doi:10.1176/appi.ajp.2014.14060723

Schimmelpfennig J, Topczewski J, Zajkowski W, Jankowiak-Siuda K. The role of the salience network in cognitive and affective deficits . Front Hum Neurosci . 2023 Mar 20;17:1133367. doi:10.3389/fnhum.2023.1133367

National Alliance on Mental Illness. Bipolar disorder .

Irving J, Colling C, Shetty H, Pritchard M, Stewart R, Fusar-Poli P,  et al .  Gender differences in clinical presentation and illicit substance use during first episode psychosis: a natural language processing, electronic case register study .  BMJ Open . 2021 Apr 20;11(4):e042949. doi:10.1136/bmjopen-2020-042949. 

Depression and Bipolar Support Alliance.  Medications for mood disorders .

National Institute of Mental Health.  Bipolar disorder .

National Alliance on Mental Illness. ECT, TMS and other brain stimulation therapies .

Kealy D, Goodman G, Rasmussen B, Weideman R, Ogrodniczuk JS. Therapists' perspectives on optimal treatment for pathological narcissism .  Personal Disord . 2017;8(1):35-45. doi:10.1037/per0000164

By Adrienne Dellwo Adrienne Dellwo is an experienced journalist who was diagnosed with fibromyalgia and has written extensively on the topic.

Psychiatric Polygenic Risk Scores Across Youth With Bipolar Disorder, Youth at High Risk for Bipolar Disorder, and Controls

Affiliations.

  • 1 Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, Canada; University of Toronto, Toronto, Canada.
  • 2 Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, Canada; University of Toronto, Toronto, Canada; Tanenbaum Centre for Pharmacogenetics, Psychiatric Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
  • 3 Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, Canada.
  • 4 University of Toronto, Toronto, Canada; Tanenbaum Centre for Pharmacogenetics, Psychiatric Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
  • 5 University of Toronto, Toronto, Canada; Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
  • 6 Western Psychiatric Hospital, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
  • 7 University of Toronto, Toronto, Canada; Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, Canada. Electronic address: [email protected].
  • PMID: 38340895
  • DOI: 10.1016/j.jaac.2023.12.009

Objective: There is a pronounced gap in knowledge regarding the polygenic underpinnings of youth bipolar disorder (BD). This study aimed to compare polygenic risk score (PRS) in youth with BD, youth at high clinical and/or familial risk for BD (HR), and controls.

Method: Participants include a total of 344 youth of European ancestry, ages 13-20 years old, including 136 youth with BD, 121 HR youth, and 87 controls. PRS for BD, schizophrenia (SCZ), major depressive disorder (MDD), or attention-deficit/hyperactivity disorder (ADHD) were constructed using independent genome-wide summary statistics from adult cohorts. Multinomial logistic regression was used to examine the association between each PRS and diagnostic status (BD vs. HR vs. controls). All genetic analyses controlled for age, sex, and 2 genetic principal components.

Results: BD group showed significantly higher BD-PRS than the control group (OR=1.54, 95% CI=1.13-2.10, p=0.006), with the HR group numerically intermediate. BD-PRS explained 7.9% of phenotypic variance. PRS for SCZ, MDD, and ADHD were not significantly different among groups. Within the BD group, BD-PRS did not significantly differ in relation to BD subtype, age of onset, psychosis, and family history of BD.

Conclusion: BD-PRS derived from adult genome-wide summary statistics is elevated in youth with BD. Absence of significant between-group differences in PRS for other psychiatric disorders supports the specificity of BD-PRS in youth. Present findings add to the biological validation of BD in youth and could have implications for early identification and diagnosis. To enhance clinical utility, future GWAS that focus specifically on early-onset BD are warranted, as are studies integrating additional genetic and environmental factors.

Keywords: bipolar disorder; high risk; polygenic risk score; youth.

Copyright © 2024. Published by Elsevier Inc.

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Man, 27, with severe bipolar disorder shares how a keto diet helped him: ‘It’s all worth it’

In 2016, Matt Baszucki was a freshman in college and taking engineering classes when he began experiencing manic symptoms.

“It was like sleeping less and less, having grandiose thoughts, rapid speech,” Matt Baszucki, 27, told NBC’s Kate Snow in a segment aired Feb. 21. “Going, going, going, spending, talking fast, not sleeping, doing all this wild impulsive behavior.”

Baszucki family

Soon after, doctors diagnosed Baszucki with bipolar disorder, and he was hospitalized. Over the next eight years, he took 29 different medications, visited 40 doctors and was eventually told his condition was treatment-resistant.

He and his family didn’t want to accept this, and they began looking for experts who help people with treatment-resistant forms of mental illness. They found Dr. Christopher Palmer at Harvard Medical School, who had an unusual suggestion to mange Matt Baszucki’s bipolar disorder: eating a ketogenic diet . After three years on the diet, Baszucki feels better.

“It was so shocking. I almost couldn’t believe it,” mom Jan Baszucki, president of the Baszucki group, which invests in research relating to metabolism, mental health and more, told Snow. “I kept saying to my husband, could this really be keto?”

Life with bipolar disorder

While Matt Baszucki experienced stress and anxiety around school, he didn’t really show any signs of bipolar disorder until he was a student at the University of California, Berkeley. His parents noticed their son seemed different after a weekend home. Then he dropped a class. Then they didn’t hear from him for a few days.

“His behavior was completely different from anything we’d ever encountered. It was hard to know. Well maybe … he’s 19, he’s changing. He’s growing,” Jan Baszucki said. “I Googled his symptoms, and it said, ‘Oh manic episode.’”  

By March 2016, Matt Baszucki was in a psychiatric ward in the hospital, where he stayed for two weeks. Doctors diagnosed him with bipolar disorder and prescribed him medication. But he didn’t take it.

“I refused the meds,” he said. “That was a trend that would plague me for the next couple of years.”

His unwillingness to reliably take medications contributed to worsening symptoms, and at one point, he was hospitalized again and was forced to take medication.

Baszucki family

“I was so manic. I was so psychotic,” Matt Baszucki said. “I couldn’t even form a coherent understanding of what was going on with me.”

Jan Baszucki and her husband, David Baszucki, CEO and founder of Roblox, knew their son was struggling. For two years, they watched as he went in and out of hospitals and refused to take medication. After those two years, though, Matt Baszucki began to understand how ill he was.

“He didn’t get well,” Jan Baszucki said. “He got a little more stable.”

The next several years remained challenging as Matt Baszucki tried various medications, most of which didn’t work. Eventually, doctors determined he had treatment resistant bipolar disorder.

“You can’t even imagine what it’s like to be told your child has a treatment resistant form of one of the most serious mental illnesses and that this is going to be a lifelong battle,” Jan Baszucki said. “We thought he was going to be impaired for the rest of his life.”

Frustrated, Jan Baszucki began looking for experts in treatment-resistant mental illness.

“(We got) advice that we should work on acceptance ... that this was going to be his life and that ... our job as parents is to work on acceptance,” she said. “I was like, ‘No, we’re not going to accept this.’”

Someone the family knew introduced them to Palmer at Harvard at first because they were investing in mental health research. Around the same time, Matt Baszucki was making lifestyle changes, such as tracking his sleep and not drinking alcohol. Palmer suggested that Matt Baszucki try a ketogenic diet with exercise and medication.

“I was like, if this is a diet that is specifically designed or can be applied to this illness to stabilize my mood, then I’m ready,” he recalled. “I was taking all the medications as prescribed. I was doing therapy, basically everything that you can imagine in a 21st century mental health program designed by the establishment. I was doing it well. And I was still sick.”

Bipolar disorder and keto

Bipolar disorder is a mental illness characterized by changing moods, energy and concentration, according to the National Institute of Mental Health . People with bipolar disorder often fluctuate between manic periods, where they feel intensely energetic, and depression. Treatment usually includes medications and talk therapy. The exact cause isn't known.

Palmer works in Massachusetts at McLean Hospital, a psychiatric facility, and Harvard Medical School, specifically with patients who have treatment-resistant mental illness.

“I see the patients that other psychiatrists don’t want to treat because they’re too difficult,” he told Kate Snow.

Matt Baszucki fit that description.

“(The) medications weren’t working, his illness was severe and ... unlikely to get better,” Palmer said.

Palmer's approach is different, and he thinks of mental illness unconventionally.

“My understanding is that ... metabolism affects the way the brain works,” he explained. “The science is ridiculously complex. I don’t mean to say that it’s an easy problem to understand.”

While people might think of keto as simply a low-carb diet , it has been used historically to treat people with epilepsy.

“People (on keto) are eating very low carbohydrates, usually less than 20 grams a day," Palmer explained. "They’re eating a moderate amount of protein, and that gets determined by either a dietitian, nutritionist or the clinical treatment team, and they eat a lot of fat.”

Prescribing diet to treat mental illness isn’t usually part of the standard of care, and Palmer acknowledged that there are detractors to his approach.

“When I talk about using the ketogenic diet as a treatment for a serious, crippling mental disorder, people think that I’m a snake oil salesman,” he said.

Baszucki family

Still, he believes there is a role for keto in helping people with mental illness.

“The ketogenic diet is an evidence-based treatment for weight loss, Type 2 diabetes and epilepsy. And there are clinicians and dietitians who know how to use this in a safe and effective way,” he said.

“The ketogenic diet can actually change neurotransmitters in the brain,” Palmer continued. “It can reduce brain inflammation, it can change gene expression, it actually changes the gut microbiome in beneficial ways that affect the brain. Everybody’s heard of the gut-brain connection, and those mechanisms are increasingly understood.”

Critics of the keto diet point to a lack of research and risks, such as nutrient deficiencies, heart disease and low blood pressure. Palmer stressed that he only uses this intervention for people who haven't responded to medication and that he would not recommend it to everyone.

Palmer added there are risks to a keto diet specifically. For example, many people who try it experience something called “keto flu,” where people feel sick when at first.

“I have seen their conditions get worse during this period of time,” Palmer said. “This adaptation period can, in fact, be dangerous, and that is one of the reasons I strongly recommend that people work with mental health clinicians if they’re going to try this.”

When Matt Baszucki switched to a keto diet in January 2021, his symptoms worsened at first. But if he made it through March — the time of year in the past when his symptoms were worst and he was often hospitalized — the family would know it made a difference.

“His family had said, ‘We won’t know if this diet’s working until we get through March Madness. If we can get through March Madness without a hospitalization, then we will know this is a real thing,’” Palmer explained. “Sure enough, he got through March without a hospitalization, without an episode.”

Matt Baszucki continued taking his medications while changing his diet. About six months after starting keto, Palmer noticed Matt Baszucki needed fewer pharmaceuticals to manage his symptoms.   

“Matt has progressively reduced his medications,” Palmer said.

‘It was all worth it’

Come March 2021, Matt Baszucki kept looking for the telltale signs of mania. Yet, he had none.

“I had no symptoms. Zero,” he said. “It was night and day when I started the diet that year. Blatantly obvious.”

His parents also felt surprised.

“It was shocking to us,” Jan Baszucki said.

When he first started the diet, Matt Baszucki struggled when going out with friends and watching them enjoy things like pizza and beer. But the positive effects on his mental health keep him motivated.

“I was like, ‘Oh my God, I’m healthy. I’m getting my brain back,'” he said. “It was all worth it.”

Matt Baszucki didn't experience any mental health symptoms until he was in college. Then he struggled for years with what doctors said was treatment resistant bipolar disorder.

After three years on the keto diet, he works as a project manager at Roblox and life feels “very normal.”

“(I) work full time, exercise, hang out with my friends, get good sleep,” Baszucki said. “My brain has been healing. … Having a normal life is unbelievable.”

Palmer said it’s “absolutely not” as simple as the keto diet fixes bipolar disorder or any other mental illness. “But I think the powerful news today is that dietary interventions can, in fact, be a powerful treatment.”

He emphasized the importance working with a mental health clinician if you’re struggling. And if your condition is serious, then ask if dietary changes might benefit you.

Sunny Choo contributed reporting.

Meghan Holohan is a digital health reporter for TODAY.com and covers patient-centered stories, women’s health, disability and rare diseases.

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

Eva f. maassen.

1 Athena Institute, Faculty of Earth and Life Sciences, VU University Amsterdam, Boelelaan 1085, 1081HV Amsterdam, Netherlands

2 Altrecht Institute for Mental Health Care, Nieuwe Houtenseweg 12, 3524 SH Utrecht, Netherlands

Barbara J. Regeer

Eline j. regeer, joske f. g. bunders, ralph w. kupka.

3 Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Psychiatry, De Boelelaan 1117, Amsterdam, Netherlands

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

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

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

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

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

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

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

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

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

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

Study on research needs

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

Study on care needs

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

Participants and data collection

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

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

Data analysis

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

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

Ethical considerations

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

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

Characteristics of the participants

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

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

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

An external file that holds a picture, illustration, etc.
Object name is 40345_2018_131_Fig1_HTML.jpg

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

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

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

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

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

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

An external file that holds a picture, illustration, etc.
Object name is 40345_2018_131_Fig2_HTML.jpg

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

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

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

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

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

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

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

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

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

An external file that holds a picture, illustration, etc.
Object name is 40345_2018_131_Fig3_HTML.jpg

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

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

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

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

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

Generic care needs

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

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

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

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

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

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

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

Strengths, limitations and future research

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

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

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

Authors’ contributions

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

Competing interests

The authors declare that they have no competing interests.

The authors received no financial support for the research.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

1 Care farm: farms that combine agriculture and services for people with disabilities (Iancu 2013 ). These farms are used as interventions in mental care throughout Europe and the USA to facilitate recovery (Iancu et al. 2014 ).

2 A government agency involved in the implementation of employee insurance and providing labor market and data services.

Contributor Information

Eva F. Maassen, Phone: +31 (0)6 13861504, Email: [email protected] .

Barbara J. Regeer, Email: [email protected] .

Eline J. Regeer, Email: [email protected] .

Joske F. G. Bunders, Email: [email protected] .

Ralph W. Kupka, Email: [email protected] .

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  21. Bipolar Disorder Research Roundup: February 9, 2024

    Front Psychiatry. 2024;15:1275177. Efficacy of Aripiprazole Once Monthly for Bipolar Disorder. This 1-year retrospective analysis assessed the effectiveness and safety of aripiprazole once monthly (AOM) in patients with bipolar disorder (BD). Findings showed a significant reduction in mood episodes, particularly manic and depressive episodes ...

  22. McLean Hospital Launches Clinical Trial of Ketogenic Therapy for

    The $2 million gift to McLean Hospital is the first grant in Baszucki Group's new research program: ReThink Bipolar: Researching Therapeutic Integration of Nutritional Ketosis in Bipolar Disorder. The grant provides support to pioneering McLean scientists with a track record of studying neurometabolism in psychiatric illness. The clinical ...

  23. Adults: Bipolar Disorder

    Enrolling nationally from around the country. National Institute of Mental Health (NIMH) researchers seek adults 18 to 70, who have a history of attempted suicide but are not currently suicidal, for a study of suicide and brain function. Participation includes up to seven days as an inpatient at the NIH Clinical Center in Bethesda, Maryland.

  24. Bipolar Disorder and Narcissism: What's the Relationship?

    Bipolar disorder and narcissistic personality disorder are not the same, but people with BD sometimes exhibit traits of narcissism. Research continues into the causes of these symptoms, but there's some evidence that brain changes and neurotransmitters (chemical messengers) are at work in similar ways.

  25. Psychiatric Polygenic Risk Scores Across Youth With Bipolar Disorder

    3 Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, Canada. 4 University of Toronto, Toronto, Canada; Tanenbaum Centre for Pharmacogenetics, Psychiatric Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.

  26. 'It was all worth it': Man with severe bipolar disorder shares how a

    Bipolar disorder is a mental illness characterized by changing moods, energy and concentration, according to the National Institute of Mental Health. People with bipolar disorder often fluctuate ...

  27. The challenges of living with bipolar disorder: a qualitative study of

    Background. Bipolar disorder (BD) is a major mood disorder characterized by recurrent episodes of depression and (hypo)mania (Goodwin and Jamison 2007).According to the Diagnostic and Statistical Manual 5 (DSM-5), the two main subtypes are BD-I (manic episodes, often combined with depression) and BD-II (hypomanic episodes, combined with depression) (APA 2014).