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Diagnosis and management of bipolar disorders

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

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

Introduction

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

Sources and selection criteria

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

Modern definitions of bipolar disorder

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

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

Epidemiology

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

Causes of bipolar disorder

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

Insights from genetics

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

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

Insights from neuroimaging

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

Environmental risk factors

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

Comorbidity

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

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

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

Precursors and prodromes: who develops bipolar disorder?

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

Screening for bipolar disorder

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

Racial/ethnic disparities

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

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

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

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

FDA approved medications for bipolar disorder

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

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Acute treatment of mania

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

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

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

Pharmacological approaches to bipolar depression

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

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

Antidepressants

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

Pharmacological approaches to prevention of recurrent episodes

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

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

Psychotherapeutic approaches

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

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

Neurostimulation approaches

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

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

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

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

Treatment resistance in bipolar disorder

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

Treatment considerations to reduce suicide in bipolar disorder

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

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

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

Treatment consideration in BD-II and bipolar spectrum conditions

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

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

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

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

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

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

Emerging treatments

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

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

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

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

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

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

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

Questions for future research

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

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

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

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

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

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

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

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

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

Provenance and peer review: Commissioned; externally peer reviewed.

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Bipolar disorders

Affiliations.

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

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

Copyright © 2020 Elsevier Ltd. All rights reserved.

Publication types

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

• Open access
• Published: 06 November 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

Study on research needs

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

Study on care needs

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

Participants and data collection

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

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

Data analysis

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

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

Ethical considerations

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

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

Characteristics of the participants

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Generic care needs

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

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

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

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

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

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

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

Strengths, limitations and future research

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

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

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

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 ).

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

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

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Bipolar Disorder

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

What is bipolar disorder?

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

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

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

What are the symptoms of bipolar disorder?

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

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

Types of Bipolar Disorder

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

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

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

What causes bipolar disorder?

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

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

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

Brain Structure and Function

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

How is bipolar disorder diagnosed?

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

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

Conditions That Can Co-Occur With Bipolar Disorder

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

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

How is bipolar disorder treated?

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

Medications

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

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

Psychotherapy

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

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

Other Treatments

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

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

Complementary Health Approaches

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

Coping With Bipolar Disorder

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

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

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

Are there clinical trials studying bipolar disorder?

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

Finding Help

Behavioral health treatment services locator.

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

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

Talking to a Health Care Provider About Your Mental Health

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

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

For More Information

MedlinePlus   (National Library of Medicine) ( en español  )

ClinicalTrials.gov  ( en español  )

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

BRIEF RESEARCH REPORT article

Comparison of early risk factors between healthy siblings and subjects with schizophrenia and bipolar disorder.

• 1 Postgraduate Program in Health Psychology of the Dom Bosco Catholic University of Campo Grande - MS, Campo Grande, MS, Brazil
• 2 Medical School of the Federal University of Maranhão, São Luis, MA, Brazil
• 3 Departments of Psychiatry, Neuroscience and Genetics, Icahn School of Medicine at Mt. Sinai Medical Center, New York, NY, United States
• 4 Department of Psychiatry, Weill-Cornell Medical College, New York, NY, United States
• 5 Laboratory of Panic and Respiration, Institute of Psychiatry of the Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

Introduction: The following work aims to compare the types and magnitude of risk events in patients with Schizophrenia and Bipolar Disorder and each of those groups with of a group of healthy siblings, exploring differences and similarities of the two psychotic disorders.

Methods: Retrospective interviews were conducted with 20 families to investigate maternal and obstetric health, social support and the presence of early trauma for the affected family members and healthy siblings. Mothers were interviewed with the Prenatal Psychosocial Profile and each family participant was assessed with the Early Trauma Inventory, Screening Questionnaire of the Genomic Psychiatry Cohort and the Diagnostic Interview for Psychosis and Affective Disorders.

Results: Obstetric and gestational history, pregnancy weight changes and early trauma were associated with offspring’s mental illness, including statistically significant findings for complications of pregnancy, pregnancy weight changes, general trauma, physical punishment and emotional abuse.

Conclusion: These findings highlight the different risk factor exposures that occur within a family, which may increase the risk for severe mental illness.

Introduction

Schizophrenia is a severe psychiatric disorder that presents with psychotic symptoms in late adolescence or young adulthood. Affecting approximately 1% of the worldwide population, its symptoms include cognitive, behavioural and emotional deficits, that substantially impact functioning ( 1 ). Bipolar disorder can also present with psychosis, but is marked by extreme mood swings that range from extremely elevated and expansive mania to periods of intense sadness, agitation and even suicide attempts ( 2 ).

Both schizophrenia and bipolar disorder have complex genetic influences whose underpinnings include genetic, environmental and psychosocial factors ( 1 , 3 ). Both conditions have developmental components, and the risk-related exposures include events and exposures in the pre and perinatal period, and early childhood trauma ( 4 ). Exposures can alter the expression of genes through epigenetic mechanisms, producing lasting changes in physiology and brain function, which can interact with genetic vulnerability to increase the risk for mental disorder ( 5 ).

Our initial hypothesis was that adverse events could trigger such disorders and thus that affected offspring would have more exposures than their healthy siblings and that Schizophrenia and Bipolar Disorder share similar types of risk events but may differ in term of magnitude and also show qualitative differences. The current study was a case-control investigation on exposures to risk events, including maternal health in pregnancy, obstetric complications, psychological and social health, and early trauma (general trauma, physical abuse, emotional abuse and sexual abuse) simultaneously comparing offspring with Schizophrenia and Bipolar Disorder to their own healthy siblings.

A case-control study was conducted in a sample of 20 families (N = 20 mothers; N = 20 offspring with schizophrenia (N = 12) or bipolar I disorder (N = 08) and N = 20 healthy control offspring). Recruitment was done by convenience with patients awaiting outpatient medical consultation at two Psychosocial Care Centres (PCC) for mental health in Campo Grande, Mato Grosso do Sul State – Brazil. Interviews lasted an average of 40 minutes and were carried out at both PCCs, as well as at the individual’s home when appropriate.

Inclusion criteria for offspring included subjects from both sexes (male/female), older than 18 years old, with a diagnosis of schizophrenia or bipolar disorder I according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Health – 5 ( 2 ), who were in outpatient treatment at a PCC in Brazil. All subjects signed an Informed Consent Form (ICF). The study was approved by the local Ethics Committee (n° 2.797.686) according to the protocol of Helsinki, and all patients provided informed consent after receiving complete explanation of the study protocol.

The affected offspring in each family (20 cases) were interviewed with the Screening Questionnaire for the Genomic Psychiatry Cohort (Portuguese Version) to identify symptoms of schizophrenia, mania, depression, substance use and health history. We also used the Diagnostic Interview for Psychosis and Affective Disorders (Di-PAD) ( 6 ), which uses diagnostic criteria for schizophrenia and bipolar disorder and sociodemographic data and questions to identify the presence of depression, psychotic symptoms and mania. And the Early Trauma Inventory Self Report–Short Form (ETISR-SF) ( 7 ), a 27 item scale assessing the occurrence of early trauma (general trauma, physical abuse, emotional abuse and sexual abuse) after 18 years-old. The Screening Questionnaire for the Genomic Psychiatric (Portuguese Version) and the Early Trauma Inventory were also administered to the healthy siblings. Comparison was made between siblings, therefore, individuals with schizophrenia were compared with their own siblings, and individuals with bipolar disorder were also compared with their own siblings.

Mothers were interviewed with the Prenatal Psychosocial Profile, translated for use in Brazil in 2007 ( 8 ), in reference to her child participants. Each affected subject had one sibling from the same mother and father selected to participate as a control. The Prenatal Psychosocial Profile is a Likert scale with 44 items that elicit the presence of stress (day-to-day stress, financial concerns, transportation, bills to pay, housing problems, family problems, the loss of a loved one, current pregnancy, situations of abuse or violence, alcohol or drug problems), social support (financial and emotional support from their partner and other people) and self-esteem in women during the pregnancy of their healthy and mentally ill offspring.

The comparisons in this study were between cases and controls. Complex analysis such as clustering or pairing was not considered because of the characteristic of a pilot-study with a small sample. Data analysis was conducted using Stata version 12.0. Continuous variables were tested for normality using the Shapiro-Wilk and Kolmorogov-Smirnov tests. Categorical variables were analysed using Chi-square tests, and continuous variables with Student’s t-test. Significance was set at p < 0.05.

Obstetric complications – offspring with schizophrenia and their healthy siblings

There was no significant statistical difference when comparing to their healthy siblings in adverse obstetric events (complications of pregnancy: viral infections during the second trimester of pregnancy, recurrent urinary tract infections with hospital admissions, depressive disorders with ideation and suicide attempt during the second trimester of pregnancy, and inadequate maternal weight gain due to insufficient supply of caloric and protein intake). There was a trend towards significance in the variables investigated ( p = 0.07), but it was not considered a significant difference for individuals with schizophrenia and their healthy siblings, thus suggesting that the number of prenatal consultations did not influence the event investigated.

An analysis ( Table 1 ) was also performed in relation to prenatal consultations ( p value = 1.0), which showed no significant difference when comparing to their healthy siblings, including such items as type of delivery ( p value = 0.6), therefore, caesarean versus vaginal delivery does not predict the presence or absence of a disorder among siblings in the present sample. Regarding term versus preterm gestational age ( p value = 0.3) there was no significant statistical difference in subjects with schizophrenia.

Table 1 Correlation of obstetric data of offspring with Schizophrenia and their healthy siblings.

There was a trend toward statistical significance in the complications of pregnancy variable ( p value = 0.06), which may indicate that in all of the individuals with pregnancy complications, three had Schizophrenia, thus hinting possible significance, since there were no such complications among healthy siblings. The following variables were tested: complications of pregnancy ( p value = 1.0), medication use during pregnancy ( p value = 0.6), prenatal in other pregnancies ( p value = 0.6), planned pregnancy ( p value = 1.0) and abortion attempt ( p value = 1.0). Those variables showed no significant statistical difference for individuals with mental illness and their siblings.

In contrast, there was a trend toward statistical significance in pregnancy weight changes for both individuals with mental illness and their siblings ( p value = 0.06). Pregnancy weight changes were more present during the pregnancies of individuals with schizophrenia. However, blood pressure problems during pregnancy ( p value = 0.3) and complications of previous pregnancies ( p value = 0.3) showed no statistical significance when comparing to their healthy siblings.

Obstetric complications – offspring with bipolar disorder and their healthy siblings

There was no significant statistical difference between mean values of the variables investigated ( p value = 0.3) for individuals with bipolar disorder and their healthy siblings, implying that the number of prenatal consultations had no influence in the occurrence of the event investigated.

No significant correlation was observed between the following variables: prenatal consultation ( p value = 0.6) and type of delivery ( p value = 0.5). Regarding the gestational age at term or premature birth, no significant difference was found in subjects with bipolar disorder when comparing to their healthy siblings.

Nonetheless, a trend towards significance was found for complications of pregnancy ( p value = 0.05). The three individuals with pregnancy complications all had bipolar disorder in adulthood, in contrast with no such complications in healthy siblings. No significant statistical differences were found in the following variables: complications of pregnancy ( p value = 0.1), medication use during pregnancy ( p value = 1.0), prenatal in other pregnancies ( p value = 0.2), planned pregnancy and abortion attempt ( p value = 0.2), blood pressure problems during pregnancy ( p value = 0.31) and complications of previous pregnancy ( p value = 0.1).

On the contrary, pregnancy weight changes showed significant statistical difference in subjects with schizophrenia in comparison with their healthy siblings ( p value = 0.05). This variable was more frequently present in the pregnancy of offspring with bipolar disorder 100% ( N = 3 ) ( Table 2 ).

Table 2 Correlation of obstetric data of offspring with bipolar disorder and their healthy siblings.

Early trauma – offspring with schizophrenia and their healthy siblings

Affected offspring with schizophrenia had a higher score of general trauma (4.7 ± 2.1) in comparison with their healthy siblings (3.08 ± 2.02). Compared to their siblings, patients with schizophrenia had higher scores for physical punishment ( p value = 0.006) (4.75 ± 2.1 vs 2.6 ± 1.5), for emotional abuse ( p value = 0.009), (2.6 ± 1.6 vs 0.75 ± 1.2), and for sexual abuse ( p value = 0.006), (3.1 ± 2.1 vs 1 ± 2.2). Lastly, there was no significant statistical difference in reaction to trauma (fear or depersonalisation) ( p value = 0.3) among both groups of subjects when comparing to their healthy siblings ( Figure 1 ).

Figure 1 Correlation of early trauma data (ETISR-SF) between offspring with schizophrenia and their healthy siblings. * p < 0.05.

Early trauma – offspring with bipolar disorder and their healthy siblings

For comparison between early trauma data (ETISR-SF) in subjects with bipolar disorder and their healthy siblings ( Figure 2 ), total scores and subscales were analysed.

No significant statistical difference was found for general trauma ( p value = 0.3), but a significant difference was found for physical punishment ( p value = 0.008), which points to a greater presence of physical punishment in individuals with bipolar disorder (3.75 ± 1.5) compared to their healthy siblings (3.25 ± 2.08). No significant statistical difference was found for emotional abuse ( p value = 1.0), sexual abuse ( p value = 0.3), reaction to trauma ( p value = 0.0009), although subjects with bipolar disorder showed higher scores for reaction to trauma (1.3 ± 0.5) when compared to their healthy siblings (0.3 ± 0.5) ( Figure 2 ).

Figure 2 Correlation of early trauma data (ETISR-SF) between offspring with bipolar disorder and their healthy siblings. * p < 0.05.

The present investigation revealed that complications in pregnancy and childbirth are similar in rates in the offspring with schizophrenia and bipolar disorder, and more frequent in the pregnancies of these individuals than in those of their unaffected siblings.

The significance found in the variables complication of pregnancy and pregnancy weight changes are in line with previous study ( 9 ), which reported pregnancy and obstetric complications, maternal weight change (malnutrition or overweight) and maternal diseases in pregnancy are associated with schizophrenia onset, as well as nutritional and multivitamin deficiencies (iron, vitamin D, folic acid, iodine). Obstetric occurrences, are also important risk factors, either due to physiological impairment or foetal neurodevelopment, which ultimately compromise the individual’s mental health in early life ( 4 , 10 ).

General trauma was also more prevalent in the mentally ill group, with a significant statistical difference ( p value = 0.02). In trauma for physical punishment ( p value = 0.0004) and emotional abuse ( p value = 0.003) the score was also higher in mentally ill individuals. Our findings are in accordance with researches pointing out that traumatic events in childhood may favour mental disorders such as schizophrenia and bipolar disorder because of genetic interaction with environmental exposure ( 11 ). However, those with later illness also could have greater early behavioral problems, leading to negative parental conflicts.

In the group of offspring with mental illness, there were more reports of events of general and emotional trauma and physical punishment, which may have contributed to the onset of the disorders in this group. Our findings are in agreement with the scientific literature that points to the registry of trauma, abuses, abandonment and neglect in childhood as variables present when diagnosing Bipolar Disorder and schizophrenia ( 11 , 12 ). And these gene-environment interactions (genetic susceptibility), coupled with childhood traumata, in the presence of bipolar disorder, are presented in a much more serious way, with the clinical expression of the disorder for suicidal behaviour ( 12 ).

Finally, results of the data collected revealed that variables related to the gestational age and medical history of mothers were important (complications of pregnancy and pregnancy weight changes), as risk factors associated with the events of early trauma, which were relevant in the group with mental illness. Our findings confirm and are in accordance with scientific literature, that points to schizophrenia and bipolar disorder as a consequence of the association between adverse events and biopsychosocial risk factors during pregnancy and childhood of the investigated individuals.

Some limitations of our study deserve further comment. Firstly, the cross-sectional retrospective nature of our study, thereby precluding any firm conclusion on the cause-effect relation between emotional trauma and clinical features of schizophrenia. In addition, there is a potential recall bias in self-reported data of the affected subjects, once patients are affected by severe mental health suffering in comparison to controls. Secondly, the lack of primary sources of medical information, e.g., obstetric and paediatric records and the potential influence of memory bias on the data collected. Thirdly, our study was conducted with a small sample of patients with schizophrenia (N = 12) and bipolar I disorder (N = 8). Although it is not a homogeneous sample, both share psychosis and risk factors, as observed in our study. However, the size of the sample could not allow a generalization of the comparison between these two disorders. A higher-powered study could provide stronger statistical support for these findings. Despite these constraints, data was consistently confirmed and re-checked to ensure its reliability and all interviews were carried out with standardized and valid instruments for the Brazilian environment, therefore providing consistent findings.

In our study, the use of sibling controls may have contributed to better estimate the importance of early risk factors in the development of schizophrenia and bipolar disorder. However, adding another set of patients not related to siblings for an additional comparison with the groups of this study would have been helped to clarify even more questions about the importance of the researched risk factors. Future researches may contribute with this methodological improvement.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by CEP Universidade Católica Dom Bosco. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

RN: Writing – review & editing, Writing – original draft. CC: Writing – original draft. GA: Writing – review & editing. DM: Writing – review & editing. JK: Writing – review & editing. AN: Writing – review & editing. AV: Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. AV was a Senior Post-doctorate supported by grant 10/2022 from the Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ).

Acknowledgments

Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

1. Ambroz P, Janoutova J, Machaczka O, Kovalova M, Pohlidalova A, Varechova K, et al. Are risk factors in prenatal and perinatal period important for develompent of schizophrenia? Ces Gynekol . (2017) 82:24–7.

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4. Sugranyes G, de la Serna E, Borras R, Sanchez-Gistau V, Pariente JC, Romero S, et al. Clinical, cognitive and neuroimaging evidence of a neurodevelopmental continuum in offspring of probands with schizophrenia and bipolar disorder. Schizophr Bull . (2017) 43:1208–19. doi: 10.1093/schbul/sbx002

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7. Bremner JD, Bolus R, Mayer EA. Psychometric properties of the early trauma inventory-self report. J Nerv Ment Dis . (2007) 195:211–8. doi: 10.1097/01.nmd.0000243824.84651.6c

8. Weissheimer AM, Mamede MV. Prenatal Psychosocial Profile: Translation, cross-cultural adaptation and validation to its use in Brazil. Midwifery . (2015) 31(12):1157–63. doi: 10.1016/j.midw.2015.08.001

9. Pugliese V, Bruni A, Carbone EA, Calabrò G, Cerminara G, Sampogna G, et al. Maternal stress, prenatal diseases and obstetric complications: Risk factors for spectrum disorders, bipolar disorder and major depressive disorder. Psychiatry Res . (2019) 271:23–30. doi: 10.1016/j.psychres.2018.11.023

10. Aldinger F, Schulze TG. Environmental factors, life events, and trauma in the course of bipolar disorder. Psychiatry Clin Neurosci . (2017) 71:6–17. doi: 10.1111/pcn.12433

11. Okkels N, Trabjerg B, Arendt M, Pedersen CB. Traumatic stress disorders and risk of subsequent schizophrenia spectrum disorder or bipolar disorder: A nationwide cohort study. Schizophr Bull . (2017) 43:180–6. doi: 10.1093/schbul/sbw082

12. Rowland TA, Marwaha S. Epidemiology and risk factors for bipolar disorder. Ther Adv Psychopharmacol . (2018) 8:251–69. doi: 10.1177/2045125318769235

Keywords: gestational risk factors, early trauma, obstetric history, schizophrenia, bipolar disorder

Citation: Nunes RG, Carrilho CG, Alves GS, Malaspina D, Kahn JP, Nardi AE and Veras AB (2024) Comparison of early risk factors between healthy siblings and subjects with schizophrenia and bipolar disorder. Front. Psychiatry 15:1374216. doi: 10.3389/fpsyt.2024.1374216

Received: 21 January 2024; Accepted: 15 April 2024; Published: 30 April 2024.

Reviewed by:

Copyright © 2024 Nunes, Carrilho, Alves, Malaspina, Kahn, Nardi and Veras. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: André Barciela Veras, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Omega-6 fatty acids could cut risk of bipolar disorder

30 April 2024

Using Mendelian randomization, a powerful causal inference method, researchers tested 913 metabolites across 14,296 Europeans, finding 33 (mostly lipids ) were associated with risk of bipolar disorder.

Bipolar disorder is a debilitating mood disorder characterised by recurring episodes of mania and depression. Although its cause is still unclear, previous studies have shown that bipolar disease is highly heritable. If a parent has bipolar, a child has a one in 10 chance of also developing the condition.

Globally one in every eight people live with mental conditions, with about 40 million experiencing bipolar disorder. Nearly 3% of Australians (568,000 over the age of 16) live with bipolar disorder .

Chief investigator Dr David Stacey says that the new evidence paves the way for novel potential lifestyle or dietary interventions.

“There’s growing evidence to suggest that metabolites play a key role in bipolar and other psychiatric disorders,” Dr Stacey says.

“This is extremely encouraging, because if we can find factors that connect certain health conditions, we can identify ways to negate these through potential lifestyle or dietary interventions.

“In this study, we found that a genetic propensity for higher levels of lipids containing arachidonic acid*, led to a lower risk of bipolar disorder. And conversely, that lower levels of arachidonic acid had a higher risk for bipolar disorder.

“Arachidonic acid can be sourced directly from meat and seafood products or synthesised from dietary linoleic acid (such as nuts, seeds, and oils). But it is also present in human milk, so is considered essential for infant brain development.

“In fact, in many countries, arachidonic acid is added to infant formula to ensure a child gets the best start to life. So, there is certainly potential to boost this through supplements for people at greater risk of bipolar disorder.

“The challenge is, however, that while we know that arachidonic acid is involved in early brain development, it’s unclear whether supplementation for bipolar disorder should occur perinatally, during early life, or even whether it would benefit those already diagnosed.”

Professor Elina Hyppönen , who co-authored the study, says preclinical studies and randomised controlled trials are required to determine the preventative or therapeutic value of arachidonic acid supplements to combat bipolar disorder.

“We need further studies to rigorously assess the potential for arachidonic acid supplementation in bipolar disorder prevention and treatment, particularly in people who carry genetic risks,” Prof Hyppönen says.

“While our findings support potential avenues for precision health interventions for early life nutrition for babies’ brain development, we need to know more about the connection with bipolar disorder.

“If we can establish how, why and when people respond to arachidonic acid supplementation, then we will be one step closer to helping people who are struggling with this serious and lifelong mental health condition.”

The new study - A Metabolome-Wide Mendelian Randomization Study Identifies Dysregulated Arachidonic Acid Synthesis as a Potential Causal Risk Factor for Bipolar Disorder – by Dr David Stacey, Assoc Prof Beben Benyamin , Assoc Prof S. Hong Lee , and Prof Elina Hyppönen, is published in Biological Psychiatry.  

Notes to editors:

*Arachidonic acid is a polyunsaturated omega-6 fatty acid

………………………………………………………………………………………………………………………

Media contact: Annabel Mansfield M: +61 479 182 489 E: [email protected]

Researchers : Dr David Stacey E : [email protected]

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April 23, 2024

Research in Context: Treating depression

Finding better approaches.

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

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

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

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

Finding the right treatments

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

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

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

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

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

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

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

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

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

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

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

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

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

New tricks for old drugs

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

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

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

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

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

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

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

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

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

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

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

Better, safer drugs

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

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

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

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

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

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

—by Brian Doctrow, Ph.D.

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

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Personality Disorders

How concept creep is stigmatizing narcissistic personality disorder, how did a severe personality disorder become a go-to insult.

Posted April 29, 2024 | Reviewed by Devon Frye

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Narcissistic personality disorder (NPD) is a Cluster B -Axis II personality disorder comprised of a pervasive pattern of grandiosity in fantasy or behavior, a constant need for admiration, and a lack of empathy. Other personality disorders in this cluster include antisocial personality disorder (ASPD), borderline personality disorder (BPD), and histrionic personality disorder (HPD).

I argue that there may not be another disorder, personality or otherwise, more stigmatized by the general public today. Concept creep—a process in which a word or concept, usually a harm-related one, gradually broadens in meaning until it starts to encapsulate situations well beyond its original scope—has resulted in many unlicensed armchair clinicians diagnosing their family members, coworkers, or ex-romantic partners (often male ones) with NPD. However, unlike many other mental health disorders, there’s rarely much empathy or compassion for such a diagnosis—only judgment and stigma .

Research suggests that only 0.5 to 5 percent of the American population has NPD, making it reasonably unlikely that everyone knows someone with NPD. However, research also suggests that up to 75 percent of people who have NPD are male, so there is some credibility to the general public’s assumption that NPD is more prevalent in men.

Over the past few years, as the term has gained popularity and " therapy -speak" has crept further into the zeitgeist, NPD has become a go-to diagnosis for many who are dissatisfied with the behaviors of their friends, family, and ex-romantic partners. This trend suggests that many of these people view NPD as a malicious choice rather than a personality disorder that nobody chooses to have. This further alienates the few who are diagnosed with NPD into self-censorship and may lead those who want support to instead go it alone.

Instead of denigrating and insulting people with NPD, we can do better by creating a supportive and welcoming environment, just as we would for people with depression , anxiety , or autism . Few would openly humiliate someone with any of these mental health diagnoses; why should NPD be any different? As a society, we can do better than to use a severe personality disorder as a go-to insult to denigrate someone whose behaviors we are dissatisfied with.

False diagnoses through concept creep aside, what’s more concerning is the negativity toward people who are assumed to be suffering from NPD. Let’s not forget that they are suffering from a Cluster B - Axis II personality disorder, a condition with significant genetic foundations that no one chooses to have. Since when do we mock suffering?

It is no one’s place to prescribe behaviors to society, but it is essential to acknowledge cognitive dissonance when it presents itself. We cannot claim to be empathetic and compassionate one moment only to denigrate and insult someone who may have NPD the next.

People suffering from NPD can indeed cause interpersonal harm, but they are also suffering themselves. Their grandiosity typically hides deep self-loathing and an inability to relate to others; many struggle with substance abuse . In short, they can do without the added judgment and stigma placed upon them by the general public.

Destigmatizing narcissistic personality disorder starts with having empathy and compassion for those who are diagnosed with it and those who may have it. We can all do better in this endeavor.

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Dr. Nafees Alam is a professor specializing in nonprofit program evaluation and macro practice, where he has over seven years of experience.

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