Bipolar Disorder

Abstract

The hallmark of bipolar disorder is hypomania or mania, and the predominant phase of illness is depression. Affecting approximately 40 million individuals worldwide, bipolar disorder is associated with a substantial psychosocial, medical, and financial burden and increased mortality from suicide and other causes. Diagnosis can be challenging due to symptom overlap with attention-deficit hyperactivity disorder, major depressive disorder, psychotic spectrum disorders, and personality disorders, which often leads to a delay in diagnosis. Recent advancements in understanding disease risk and pathophysiology have identified multigene risk and possible infectious and mitochondrial causes. Treatment approaches include pharmacotherapy, psychotherapy, and lifestyle modifications, which should always be patient-centred and aligned with individual goals and priorities. Future directions for bipolar disorder care include increasing the availability of psychosocial interventions aimed at self-management, addressing treatment-resistant bipolar depression, deepening the understanding of pathophysiology, and exploring novel interventions, such as ketamine, esketamine, other rapid-acting antidepressants, and various neuromodulation approaches.

INTRODUCTION

Bipolar disorder (BD) is a chronic illness marked by episodes of hypomania or mania, depression, mixed states, and functionally impairing subsyndromal symptoms.^1,2 Bipolar disorder often co-occurs with multiple psychiatric and somatic comorbidities, making it a challenging condition to manage. The disorder has substantial heritability, early age of onset, and high comorbidity rates with anxiety and substance use disorders (SUDs) that lead to substantial psychosocial impairment and a negative impact on overall quality of life.³

Bipolar disorder is one of the costliest mental health conditions,⁴ and its economic burden is substantial.^5–8 In the USA, the economic burden of bipolar disorder exceeds US$195 billion annually, with 25% of this cost attributed to medical expenses.⁶ In the UK, the annual burden was estimated to be £6·4 billion for 2018–19.⁷ Individuals with BD, and particularly those with moderate-to-severe depression, require more health-care services, have more frequent hospitalisations, and incur higher direct health-care costs compared with the general population.⁸

Search strategy and selection criteria:

We searched PubMed for relevant articles, studies, and meta-analyses in English between Jan 1, 2017, and July 22, 2024, using the term “bipolar disorder” along with “depression”, “mania”, “mixed features”, “rapid cycling”, “guidelines”, “management”, and “clinical treatment” (appendix p 2). We prioritised articles using meta-analytic methodologies.¹ We also reviewed guidelines from leading psychiatric associations and studies on epidemiology, treatment outcomes, and patient-reported experiences. The inclusion of people with lived experience is recognised as important, and one of the seminar authors has lived experience of BD.

EPIDEMIOLOGY

According to the WHO World Mental Health Survey Initiative, the 12-month prevalence for bipolar spectrum disorder was 1·5%, with bipolar I disorder (BD-I) at 0·4%, bipolar II disorder (BD-II) at 0·3%, and subthreshold bipolar disorder (ie, meeting at least one hypomania or mania symptom but not meeting full hypomania or mania criteria) at 0·8%.⁹ The prevalence rates are similar in males and females,¹⁰ may vary among countries.² Individuals aged 10–19 years have the highest incidence of new cases of BD,² and individuals aged 20–44 years contribute the most bipolar disorder-related disability-adjusted life-years (DALYs).¹¹ The overall age-standardised rate of DALYs was lowest in east Asia and highest in tropical Latin America.

The age of onset for bipolar disorder differs across various regions, with an increasing incidence of childhood-onset bipolar disorder in the USA compared with Europe, possibly due to increased familial loading and higher stress.¹² In low-income and middle-income countries, inadequate health-care access, economic constraints, and high medication costs restrict bipolar disorder treatment. Socioeconomic factors such as poverty, low education, and poor care continuity hinder adherence, increasing discontinuation rates and worsening outcomes.¹³ Furthermore, individuals with bipolar disorder have a reduced life expectancy, with a weighted average of 12·9 years of potential life lost.¹⁴ A comparison of geographical regions shows the lowest life expectancy among people with bipolar disorder in Africa (54·1 years), followed by North America (65·6 years), Europe (67·3 years), and Asia (68·0 years).

Natural causes, such as general somatic illnesses, are common contributors to reduced life expectancy in individuals with BD.¹⁵ BD is highly comorbid with anxiety and SUDs,³ and there is a significant increase in the burden of cardiovascular diseases, stroke, and metabolic syndrome.¹⁰ In addition, BD is an independent risk factor for major adverse cardiac events, even after accounting for cardiovascular disease.¹⁶

Unnatural causes (ie, suicide and accidents) are another major contributor to mortality for people with BD. The risk of suicide among people with BD is more than 20–30 times higher than that of the general population.¹⁷ Suicide rates in BD range between 5–20%,^10,17 with similar rates for both BD-I and BD-II.¹⁸ In a 2023 systematic review in south Asian individuals with psychosis or BD, the pooled prevalence rate of suicide attempts was 22% (95% CI 17–27) and the pooled prevalence rate of suicidal ideation was 38% (95% CI 27–51).¹⁹ Prominent risk factors for suicide among those with BD include being male, White, single, divorced, childless, younger than 35 years or older than 75 years, or unemployed, and having suicidal ideation, a history of suicide attempts, a depressive or mixed mood state, a rapid-cycling pattern, an early age of illness onset, a family history of attempting or dying by suicide, and depressive-predominant polarity.^17,20,21 Women are more likely to attempt suicide overall, whereas men have a higher risk of dying by suicide. Furthermore, individuals with BD have an increased risk of accidents, road injuries, and accidental poisoning.²²

DIAGNOSIS

BD is categorized into two primary subtypes in both the International Classification of Diseases, 11th revision (ICD-11) and the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, Text Revision (DSM-5-TR): BD-I and BD-II. A single manic episode is sufficient for a diagnosis of BD-I, whereas BD-II requires at least one major depressive episode and one hypomanic episode. A hypo/manic episode is marked by a distinct period of elevated, expansive, or irritable mood with increased activity or energy. It requires at least 3 symptoms (or 4 with irritability) Table-1. A manic episode must last at-least 7 days unless it leads to hospitalization, whereas a hypomanic episode must last at-least 4 days. There is no upper limit on duration for either mania or hypomania. Diagnosing hypomania can be particularly challenging when relying solely on patient history, making it essential for clinicians to exercise caution in assessing BD-II, as the diagnosis is often uncertain, and corroborative history can be helpful in confirming the diagnosis.

Table 1.

Bipolar and related disorder diagnoses based on DSM-5-TR and ICD-11

Criterion	DSM-5-TR	ICD-11
Disorder Category	Bipolar and Related Disorders	Bipolar or related disorders 6A60–6A6Z
Types	Bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance-induced or medication-induced bipolar and related disorder, bipolar and related disorder due to another medical condition, other specified bipolar and related disorder, and unspecified bipolar and related disorder	Bipolar type I disorder (6A60), bipolar type II disorder (6A61), cyclothymic disorder (6A62), other specified bipolar or related disorders (6A6Y), and bipolar or related disorders, unspecified (6A6Z)
Hypo/Mania symptoms	Flight of ideas, pressured speech, talkativeness, grandiosity, distractibility, reduced need for sleep, impulsivity, increase in goal-directed activities or agitation, and excessive involvement in activities with high potential for painful consequences
Psychotic Features	Present only in mania, not hypomania	Present only in mania, not hypomania
Bipolar I Disorder	At least one manic episode, with or without depression	At least one manic episode, with or without depression
Bipolar II Disorder	At least one hypomanic and one depressive episode	At least one hypomanic and one depressive episode
Cyclothymic disorder	Persistent mood instability with hypomanic and depressive symptoms for at least 2 years, without ever fully meeting criteria for a hypomanic or a major depressive episode; symptoms are present ≥50% of the time without remitting for ≥2 months	Fluctuating hypomanic and depressive symptoms for at least 2 years, never fully meeting criteria for hypomanic or major depressive episodes; symptoms are present ≥50% of the time, without remitting for ≥2 months at a time
Mixed Features/episode	Mixed features as a specifier require at least three symptoms from the opposite pole; when mania or hypomania predominates, depressive symptoms include dysphoria, anhedonia, psychomotor changes, fatigue, inappropriate guilt or worthlessness, and suicidal ideation; when depressive symptoms predominate, manic or hypomanic symptoms include elevated mood, grandiosity, racing thoughts, increased talkativeness, increased energy, decreased need for sleep, and excessive involvement in high-risk activities	A mixed episode is defined as prominent manic and depressive symptoms occurring most days for ≥2 weeks, either simultaneously or alternating rapidly; when hypomanic or manic symptoms predominate, depressive symptoms include dysphoric mood, worthlessness, hopelessness, and suicidal ideation; when depressive symptoms predominate, manic symptoms include irritability, racing thoughts, increased talkativeness, and increased activity
Rapid Cycling	≥4 mood episodes in 12 months	≥4 mood episodes in 12 months
Other specified bipolar and related disorder	Used when bipolar symptoms predominate but do not meet full criteria for bipolar disorder I, bipolar disorder II, or cyclothymia; a clinician specifies why a presentation does not meet criteria for any specific bipolar disorder; examples include short-duration hypomanic episodes (2–3 days) and major depressive episodes, hypomanic episodes with insufficient symptoms and major depressive episodes, a hypomanic episode without a previous major depressive episode, short-duration cyclothymia (less than 24 months), and a manic episode superimposed on schizophrenia or other psychotic disorders.	Presentation includes manic or hypomanic symptoms (with or without depression) but does not meet full criteria for bipolar I disorder, bipolar II disorder, or cyclothymia
Unspecified bipolar and related disorder	This category applies when symptoms do not fully meet criteria for bipolar and related disorders, often due to insufficient information, such as in emergency settings	Bipolar or related disorder, unspecified

The dominance of mania over depressive episodes during the patient’s illness history is associated with several factors; such as younger age, male sex, BD-I, psychotic features, earlier onset, and manic onset of the disorder in mania-predominant polarity. In contrast, depressive-predominant polarity is associated with depressive onset, a higher number of mood episodes, a history of suicide attempts, and being in a relationship.²³ Unipolar mania (UPM) accounts for 5% of BD cases, predominantly type I, and is more prevalent in men.²⁴ Patients with UPM receive earlier clinical interventions, exhibit more psychotic features, and experience higher morbidity and frequent clinic visits. They show fewer depressive symptoms, frequently use mood stabilizers, and rarely use antidepressants.

Cyclothymic disorder involves frequent hypomanic or depressive symptoms that fall short of full hypomanic/depressive episodes, lasting most of the time for at least two years, without remission lasting more than two months. About 35–53% of patients with cyclothymic disorder may develop full manic/hypomanic and depressive episodes, progressing to BD-I in 7–11% of cases or BD-II in 28–42%.²⁵

Additionally, mixed states, during which both hypo/manic and depressive symptoms co-occur—referred to as “mixed episodes” in ICD-11 and “with mixed features” as a specifier in DSM-5-TR—should be identified due to their impact on treatment selection and potential safety risks. Anxiety, agitation, and irritability are three symptoms commonly observed during mixed states that significantly contribute to misdiagnosis and increase the risk of suicide.²⁶ This has important clinical implications; it is recommended to avoid prescribing antidepressants during mixed episodes/features.

Rapid cycling, as a specifier in DSM-5-TR, is characterized by at least four mood episodes of mania, hypomania, or depression within a 12-month period, which can involve episodes of the same or opposite polarity. Rapid cycling is associated with female sex, childhood maltreatment, mixed features, metabolic disturbances, antidepressant exposure, and hypothyroidism.²⁷

Patients with BD are often misdiagnosed with unipolar depression, necessitating a reevaluation of their diagnosis and attention to their history. The delay between diagnosing unipolar depression and BD can be up to 10 years, with nearly a quarter of patients with MDD transitioning to BD, mostly within the first 5 years.²⁸ The misunderstanding and delayed diagnosis of BD are partially due to its association with ‘classic’ mania. Those who have less classic features, predominantly depressive symptoms, or mixed presentations may be overlooked. Furthermore, the median duration of untreated BD is 6 years and is linked to female sex, earlier onset, and non-BD-I diagnosis.²⁹ This delay leads in incorrect treatment, causing treatment resistance and poor outcomes. Predictors of bipolar depression include a family history of BD, early onset of depression, and psychotic symptoms (appendix p 4).²⁸

Over half of individuals with BD-I experience psychotic symptoms, necessitating careful evaluation for other psychotic disorders like schizophrenia.³⁰ Many individuals with BD, particularly BD II and BD-spectrum, risk misdiagnosis as their symptoms may be overlooked or misattributed to personality features.³¹ It is also crucial to rule out BD secondary to general medical conditions,³² especially in atypical or late-onset cases (Figure 1). It is important to rule out substance-induced mania or depression, especially in populations with high SUD rates.³ Steroids and other medications can trigger bipolar-like symptoms, so recognizing these potential causes is crucial for accurate diagnosis.

Figure 1.

Secondary causes of mania

Distinguishing BD from attention deficit hyperactivity disorder (ADHD) or borderline personality disorder can be particularly challenging, as behavioral features like hyperactivity, impulsivity, emotional instability, and disruptive behaviors overlap (Table 1). The clinical presentation of BD can be further complicated by comorbid conditions, including anxiety disorders, SUDs, ADHD, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), eating disorders, and personality disorders. It is essential to assess whether these behaviors occur exclusively during mood episodes or are persistent features of the patient’s condition. Such comorbidities frequently contribute to treatment resistance in BD, underscoring the need for comprehensive assessment in clinical decision-making.

Importantly, the ICD-11 or DSM-5-TR diagnosis represents only one aspect of a thorough case formulation. Beyond diagnosis, a careful evaluation of the biological, psychological, and social dimensions of the patient’s condition is necessary to fully understand their clinical picture and to develop a multidimensional treatment plan.

PATHOPHYSIOLOGY

BD is characterized by multifactorial pathophysiology, encompassing genetic, inflammatory, mitochondrial processes, and neurostructural alterations. BD is highly heritable (60–80%),³³ with genome-wide association studies (GWAS) revealing a polygenic architecture. The largest GWAS by the Psychiatric Genomics Consortium identified 298 risk loci.³⁴ Post-GWAS analyses suggest enrichment in genes associated with synaptic functions, dopamine and calcium signaling, and GABAergic interneuron development.³⁴ Genetic correlations between BD and conditions such as schizophrenia (rg = 0.54–0.70), major depression (rg = 0.36–0.52), substance use, and self-harm suggest overlapping pathophysiological mechanisms rather than discrete entities as other medical conditions.³⁴ Environmental factors, including childhood adversity,³⁵ cardiometabolic disorders,³⁶ and lifestyle factors,³⁷ interact with genetic risk to shape clinical manifestations.³⁸

Mitochondrial dysfunction is implicated in BD pathophysiology. Magnetic resonance spectroscopy studies reveal abnormal brain energy metabolism, while animal models of mitochondrial DNA mutations replicate depressive and manic states.³⁹ Postmortem studies show reduced electron transport chain activity, particularly complex I subunits, contributing to oxidative stress.^40,41 Regional mitochondrial DNA depletion,⁴² increased mitochondrial DNA copy number-seemingly modulated by lithium,⁴³ and mitochondrial tRNA heteroplasmy⁴⁴ further underscore mitochondrial involvement. Nevertheless, the implication of mitochondrial alterations in BD remains uncertain; for instance, mitochondrial modulators cannot be recommended to date due to the heterogeneity of study designs and the preliminary nature of many findings.⁴⁵

Circadian rhythm dysregulation is another putative etiologic factor. Abnormalities in circadian gene expression have been implicated in animal models of BD with disturbances in circadian periodicity characterizing BD psychopathology at both the cellular and behavioral levels.⁴⁶

Inflammatory mechanisms are also implicated in BD, driven by genetic predisposition, HPA axis dysregulation, and infections. Elevated antibodies to cytomegalovirus^47,48 and herpes simplex virus 2 are reported,⁴⁸ alongside increased leukocytes, neutrophils,⁴⁹ and T-cell dysfunction.⁵⁰ Pro-inflammatory mediators, such as C-reactive protein (CRP), interleukin-6, and tumor necrosis factor-alpha (TNF-a), are elevated during euthymic states, with fluctuations across mood episodes.^40,51 Chronic inflammation may induce microglial activation, excitotoxicity, and oxidative stress, disrupting cognition and mood regulation circuits. High cardiometabolic comorbidities in BD⁵² likely exacerbate these inflammatory changes.⁵³

Structural brain alterations in BD are well-documented. ENIGMA Consortium meta-analyses highlight cortical thinning in frontal, parietal, and temporal areas, worsening with manic episodes.⁵⁴ Lithium treatment, however, is associated with increased cortical thickness and brain volume.^54,55 White matter disruptions, notably reduced fractional anisotropy (FA) in the corpus callosum and cingulum, reflect broader microstructural abnormalities. Interestingly, higher FA is observed in cases with shorter illness duration, later onset, and lithium use.⁵⁶

Functional MRI studies reveal frontolimbic network dysfunction in BD, with the amygdala and hippocampal hyperactivation and frontal hypoactivation during emotion processing and dlPFC hypo-activation during emotion regulation and executive function,^57,58 which scales with behavioral impairment in emotion regulation and global cognition, respectively.⁵⁹ These abnormalities are seen in at-risk individuals and vary by mood state.^60,61 Frontolimbic, cognitive, and neurotransmitter-related networks, particularly elevated dopamine synthesis capacity⁶² and serotonin systems, are consistently implicated.⁶³ Tackling clinical and biological heterogeneity in BD will require advanced machine learning and AI-driven approaches.^64,65

MANAGEMENT

Pharmacotherapy and psychotherapy are the most extensively studied treatment options for BD. Moreover, chronotherapy and lifestyle interventions play a vital role in a comprehensive management plan for long-term recovery. Treatment approaches are individualized to meet each patient’s needs. For women, it is important to plan for pregnancy and postpartum periods, addressing important issues such as medication adjustments, childcare, sleep management, and breastfeeding.

Pharmacotherapy

Pharmacological treatments (Figure 2) are central to managing BD.⁵ The CINP issued treatment guidelines in 2017, while CANMAT and the ISBD published theirs in 2018 and updated them in 2023.⁶⁶ Treatment approaches vary by region due to insurance and government formularies. In North America and Europe, second generation antipsychotics (SGAs) are common, whereas in Asia, mood stabilizers or first-generation antipsychotics are frequently used.^3,67

Figure 2. Pharmacotherapeutic treatments for bipolar disorder.

LAI= Long acting injectable; Li=lithium; SSRI= Selective Serotonin Reuptake Inhibitor; VLP=Valproate

*Used as an adjunct with a mood stabilizer (2^nd line agent).

For acute mania, first-line monotherapy options include lithium, quetiapine, divalproex (DVPX), asenapine, aripiprazole, paliperidone, risperidone, and cariprazine.⁶⁶ First-line combination therapies involve lithium or DVPX paired with quetiapine, aripiprazole, risperidone, or asenapine. Combination therapy using antipsychotics with lithium or DVPX is frequently more effective than monotherapy for managing acute mania.⁶⁸ Second-line treatments for acute mania include olanzapine, carbamazepine, ziprasidone, haloperidol, and electroconvulsive therapy (ECT).⁶⁶ Third-line options for acute mania comprise carbamazepine or oxcarbazepine in combination with lithium or DVPX, as well as chlorpromazine, clozapine, tamoxifen, and tamoxifen combined with lithium or DVPX. Recent RCTs demonstrated the efficacy of iloperidone and olanzapine/samidorphan, which offers the advantage of lower weight gain compared to olanzapine, in treating bipolar mania.^69,70

For bipolar depression, olanzapine plus fluoxetine, quetiapine, olanzapine, lurasidone, lumateperone, cariprazine, and lamotrigine have shown significant efficacy in reducing depressive symptoms.⁷¹ Lithium reduces suicidality, prevents mood episode recurrence, and decreases depression-related hospitalization.⁷² Second-line options for bipolar depression include DVPX, adjunctive selective serotonin reuptake inhibitors (SSRIs), adjunctive bupropion, and ECT. Despite the limited efficacy of antidepressants and the risk of mania, antidepressants continue to be prescribed frequently in BD.³ While there is some evidence of the safety and effectiveness of SSRIs and venlafaxine monotherapy for BD-II⁷³, if an antidepressant is pursued for someone with BD-I, it should be prescribed alongside a mood stabilizer or SGA. Treatments with limited supporting data and considered third line in the CANMAT guidelines are adjunctive aripiprazole, armodafinil/modafinil, asenapine, carbamazepine, ketamine, levothyroxine, light therapy, N-acetylcysteine, dopamine agonists such as pramipexole, transcranial magnetic stimulation (TMS), and adjunctive serotonin-norepinephrine reuptake inhibitors or monoamine oxidase inhibitors.⁶⁶

For maintenance relapse prevention, lithium, quetiapine with or without DVPX/lithium, DVPX, lamotrigine, asenapine, and aripiprazole as first-line options.⁶⁶ Olanzapine, risperidone long-acting injectable (LAI), carbamazepine, paliperidone, lurasidone, and ziprasidone with adjunctive lithium/DVPX are considered second-line treatments. There is limited long-term data comparing LAIs to oral SGAs in BD. Comparative effectiveness studies of DVPX, examining serum concentrations, suggest that a valproate serum level between 50–74 micrograms/mL is optimal for reducing or preventing mood episodes during maintenance treatment.⁷⁴

In mixed episodes, treatment options include mood stabilizers and SGAs, while lithium may not be as effective and antidepressants are avoided.^26,66 Treatment options include aripiprazole, asenapine, carbamazepine, cariprazine, DVPX, iloperidone, olanzapine, olanzapine/samidorphan, quetiapine, risperidone (adjunct), lumateperone, and ziprasidone. Lurasidone is considered a second line option for depression with mixed features.²⁶ Antidepressants or stimulants require dose reduction or discontinuation, while mood stabilizers need optimization. ECT is a key option for severe mixed states.

Often, the decision to choose between a mood stabilizer and an SGA depends on the side-effect profile and patient preference. Lithium requires regular monitoring due to thyroid and kidney risks, while SGAs may cause metabolic syndrome, diabetes mellitus, and movement disorders. Valproic acid (VPA)/DVPX is associated with teratogenicity, intellectual disability, and behavioral disorders in offspring of mothers using VPA, as well as risks of sexual dysfunction, infertility in males, and neurodevelopmental issues in offspring of males using VPA. The UK’s Medicines and Healthcare Products Regulatory Agency recommends avoiding initiating VPA in individuals younger than 55, unless the condition is treatment-refractory and documented by two specialists.⁷⁵ A NMA evaluating the metabolic effects of mood stabilizers and SGAs found that risperidone ranked first in increasing fasting serum glucose and serum insulin, while olanzapine ranked first in elevating serum total cholesterol, triglycerides, and low-density lipoprotein.⁷⁶ Lumateperone, olanzapine, and quetiapine were associate with higher odds of sedation. Lumateperone had a lower rate of ≥7% weight gain compared to placebo and other treatments.⁷⁷

PSYCHOSOCIAL INTERVENTIONS:

Psychotherapy is a crucial component of BD treatment. Consensus guidelines^78,79 recommend four evidence-based (defined by meta-analyses or replicated double-blind RCT that includes a placebo or active control comparison with n≥30 in each arm) psychosocial interventions for BD, administered adjunctive to pharmacotherapy: psychoeducation (PE), cognitive behavioral therapy (CBT), family focused therapy (FFT) and interpersonal and social rhythm therapy (IPSRT), Figure 3. PE helps individuals to self-manage, better understand BD and adhere to pharmacotherapy. CBT encourages patients to challenge negative thought patterns and develop more adaptive behaviors. IPSRT addresses disturbances in relationships and circadian rhythms by encouraging individuals to improve interpersonal communication and develop more regular daily routines. FFT, administered conjointly with family members or partners, uses a skills-based approach to help families communicate more effectively and acquire better tools for managing BD.

Figure 3.

Bipolar-Specific Therapeutic Strategies

CBT, IPSRT, and FFT are considered evidence-supported treatments for acute depression; CBT, IPSRT, FFT, and PE are indicated for maintenance treatment.⁷⁹ Effect sizes, as estimated by meta-analysis, are modest ranging from 0.2 (for depression symptom reduction) to 0.7 (for risk of relapse).⁸⁰ Thus, psychotherapy has its largest effects on prevention of new episodes, contributing to approximately 50% reduction in relapse risk.⁸¹ PE, CBT, IPSRT, and FFT are all indicated for use in euthymic patients to prevent future episodes whereas CBT, IPSRT, and FFT (but not PE) can be used for syndromally depressed individuals to hasten recovery from depressive episodes or in euthymic patients to prevent relapse and recurrence. There are no studies showing superiority of one modality over another. Other therapeutic modalities (e.g., short-term psychodynamic therapy, peer support, mindfulness-based cognitive therapy, dialectal behavior therapy, cognitive remediation) have been explored as treatments for BD but lack adequate empirical support to recommend them unequivocally at present.^78,79 Nevertheless, they can be considered emerging treatments that merit further study.

Very few studies have compared specific psychotherapies to each other, so it is impossible to recommend one modality over another. Systematic reviews suggest considerable overlap in treatment approaches across therapies.⁸² A recently published NMA evaluated “active ingredients” (components) of bipolar-specific psychotherapies finding that cognitive restructuring, regulating daily rhythms, and communication training were most potent for reducing depression severity. Delivery of therapy in a family format and encouraging patients to monitor prodromal symptoms were associated with lower recurrence rates.⁸¹ Figure 3 summarizes types of strategies used in each psychotherapy.

Despite their benefits, many patients are unable to access bipolar-specific psychotherapy. In this situation, the Japanese Society of Mood Disorders guidelines recommend that all patients should receive the psychoeducation focusing on the Minimal Essentials, which are the common factors of bipolar-specific psychotherapies.⁸³ Technology-enabled interventions may help expand the reach of bipolar-specific psychotherapy by facilitating self-management strategies. Early studies have identified several facilitators, such as focused interventions addressing patient needs, simple digital interfaces, and support from humans, while also noting barriers like the complexity of interventions and discomfort with self-reflection, and overcoming these should facilitate further research.⁸⁴ Digital self-management strategies are used by over 40% of individuals with BD.⁸⁵ Commonly used self-management strategies include mood monitoring, psychoeducation about BD, regulating routines (including sleep schedules), developing plans for maintaining wellness and crisis intervention, and maintaining hope.⁸⁶ Despite limited evidence from RCTs, these approaches are widely used and perceived as helpful by many living with BD (see figure 3).

CHRONOTHERAPY AND LIFESTYLE INTERVENTIONS

Chronotherapy plays a crucial role in BD, particularly in managing bipolar depression. Bright light therapy, typically delivering 7,000 to 10,000 lux in the morning, is a promising treatment approach for bipolar depression.⁸⁷ A recent RCT demonstrated the efficacy of adjunctive midday bright light therapy, using a lightbox with 7000 lux intensity between noon and 2:30 p.m. for 45–60 minutes daily, without increasing the risk of treatment-emergent affective switching.⁸⁸ Recent data provide preliminary evidence for the use of light therapy in managing irritability in bipolar depression.⁸⁹ Partial wake therapy combined with light therapy has shown effectiveness in patients with bipolar depression.⁹⁰ However, it poses a risk of affective switching and necessitates careful monitoring to ensure safety. Preliminary evidence suggests that blue-spectrum-light-blocking glasses used in the evening may serve as an adjunctive treatment for acute mania.⁹¹

From a lifestyle intervention standpoint, a recent meta-analysis of two studies found that combined diet and physical activity interventions—consisting of a CBT-based approach focusing on nutrition psychoeducation and improving food choices, promoting moderate-intensity exercise (5 days per week, 30 minutes per day), and enhancing problem-solving skills—as well as sleep interventions (modified CBT for insomnia), led to significant improvements in depressive symptoms.⁹² Regulating sleep-wake cycles, limiting stimulants, and managing disruptions like shift work are crucial for mood stability in BD. Seasonal mood changes are common, with depression in fall/winter and hypomania/mania in spring/summer. Maintaining circadian rhythm and good sleep hygiene supports well-being. Social rhythm therapy, a component of IPSRT focused on helping individuals develop regular daily routines, has evidence of efficacy⁹³ and has been deployed as a self-help intervention.⁹⁴

NEUROMODULATION (ELECTROCONVULSIVE TREATMENT AND TRANSCRANIAL MAGNETIC STIMULATION):

ECT is highly effective for treatment-resistant bipolar depression (TRBD) and severe mixed states, but its use is often limited due to stigma from both patients and clinicians.⁹⁵ It is typically considered after pharmacotherapy fails or in cases of catatonia unresponsive to benzodiazepines. An RCT comparing right unilateral ECT (RUL-ECT) to pharmacological treatment in TRBD (n=73) showed that RUL-ECT was significantly more effective, with a response rate of 73.9% versus 35.0% for pharmacotherapy (p=0.01).⁹⁶ A recent meta-analysis of 12 studies from Asia (n=863) found that ECT combined with medication outperformed medication alone for acute mania after just 3–5 ECT sessions, with a standardized mean difference of −3.5 (95% CI: −4.6, −2.4, p<0.0001).⁹⁷ Large Swedish registry studies have shown response rates of 80.2% for bipolar depression (n=1251) and 84% for mania.^98,99 The ISBD guidelines recommend ECT as a second-line treatment for mania and depression.⁷⁹ In unipolar depression, higher level of treatment resistance was found to be a poor predictor for response, suggesting that ECT should be offered timely and not as a last-resort option.¹⁰⁰

Regarding repetitive TMS, a meta-analysis in mania (n=102) and a systematic review in bipolar depression (24 studies with mean sample size of 22) have concluded that findings were non-significant or in very small samples.^101,102 Although TMS response rates are variable, a meta-analysis of 19 studies (n=181) found no significant difference in the risk of affective switching between active TMS and sham treatment (0.9% vs. 1.3%) in acute bipolar depression.¹⁰³ More adequately powered sham-controlled studies are required to verify its efficacy.

SPECIAL ISSUES

1. SUICIDE

For people with BD, the highest cause-specific elevated risk of premature mortality is seen for death by suicide.¹⁰⁴ Comprehensive suicide prevention is a complex endeavour that requires widespread interventions across society and healthcare ecosystems¹⁰⁵ and therefore may seem daunting at the clinical level, however there are key new approaches that provide greater agency for clinicians and patients. Although established risk factors with the highest impact such as a history of suicide attempts and depressive or mixed mood state exist, it is evident in the literature that suicide prediction is nearly impossible with accuracy based on the current state of knowledge.¹⁰⁶ Many patients with BD who die by suicide were not considered to be at high risk at the time of their last clinical encounter.¹⁰⁷ These findings support the importance of emphasizing suicide prevention efforts for all people with BD, irrespective of perceived risk status.¹⁰⁸

What is considered to be an anti-suicide intervention in BD is also shifting. Historically, much of the emphasis was placed on the role that lithium can play, especially due to putative suicide protective effects independent of mood stabilization.¹⁰⁹ While lithium remains a first-line mood stabilizer and can be foundational for suicide prevention, there are more general approaches that should also be considered¹¹⁰ in addition to the delivery of the usual evidence-based pharmacological and psychotherapeutic approaches. These include structured universal screening for suicidal thoughts and behaviours,¹¹¹ conducting a safety planning intervention,¹¹² delivering caring contacts after acute care interactions,¹¹³ ensuring access to care during high-risk transitions,¹¹⁴ and limiting access to the means of suicide.¹¹⁵ Based on the nature of these interventions, all inter-professional care providers can and should play a role, emphasizing the need to implement systems of care that incorporate anti-suicide interventions for all people with BD across varied care settings.

2. FEMALE POPULATIONS

Female individuals with bipolar disorder have an increased likelihood of having depressive episodes and developing thyroid disorders compared with male individuals with bipolar disorder, and can be affected by interactions between psychotropic drugs and oral contraceptives, which necessitates careful monitoring. In female individuals with bipolar disorder, some phases of life, such as menarche, peripartum, postpartum, perimenopause, and postmenopause, carry a higher risk of mood instability. Data from 2024 indicate that perimenopause is a high-risk period for the first episode of mania, with rates of first-onset mania returning to premenopause rates during the postmenopause phase.¹¹⁶ Understanding of the role of hormone replacement therapy in bipolar disorder is still evolving. Interest in understanding bipolar disorder during the menopausal transition is growing, but despite clear evidence of clinical worsening during this life stage, effective symptom management remains poorly understood.¹¹⁷

Additionally, the postpartum period is another high-risk phase. In female individuals with bipolar disorder, the risk of postpartum relapse (hypomania or mania, depression, or mixed states) is 39% (95% CI 29–49).¹¹⁸ Relapse rates are more than double in studies without medication use, with 58·1% relapse in those without medication compared with 25·9% in those with medication use (p = 0·04).¹¹⁸ Female individuals with bipolar disorder are often advised to continue taking mood stabilisers during pregnancy and postpartum, except for valproic acid due to it leading to a high risk of birth defect.¹¹⁹ Lithium is usually recommended despite a slight increase in fetal cardiac abnormality risk during the first trimester.¹¹⁹ Clinicians should monitor mood during pregnancy and the peripartum period, involve a perinatal psychiatrist, educate their patients about relapse risks, and discuss breastfeeding and sleep management. Shared decision making is essential during peripartum and postpartum care.

3. COGNITION

Cognitive dysfunction affects 50–70% of patients with BD, impacting their psychosocial functioning and quality of life, making it an important treatment target independent of affective symptomology.^120,121 Cognitive functioning is heterogeneous in BD, with substantial evidence pointing to a subgroup of patients with normal or even supernormal cognition, a subgroup with mild to moderate impairments, and another subgroup with more significant deficits.^122,123 In addition to deficits across traditional cognitive measures, abnormal performance on tasks of emotional and social cognition is impaired in many people with BD, especially on tasks of facial emotion recognition and implicit emotion regulation.¹²⁴ Impaired reward processing and affective decision-making (non-emotional cognition) are more closely associated with affective episodes, while trait-related impairments include facial expression recognition and implicit emotion regulation (emotional cognition).¹²⁴

Factors contributing to cognitive impairment in BD include sleep problems¹²⁵, comorbid SUD¹²⁶, cardiovascular burden, sedative use, high dose antipsychotics, anticholinergic medication burden, and frequent episodic recurrence. At a brain circuitry level, cognitive impairment in BD is accompanied by hypoactivity in the fronto-parietal cognitive control network coupled with hyperactivity in the default mode network.⁵⁷ Inflammation may play a key role in cognitive impairment in BD. The neuroprogression model suggests that recurrence of episodes, especially acute mania, affects brain structure and function.¹²⁷ Studies show elevations in inflammation markers like CRP and TNF-a¹²⁸ and decreases in neurotrophic factors like BDNF during severe episodes. Early in the illness, these biomarkers normalize during remission, but later stage disease shows chronic inflammation even during euthymia. This suggests inflammation correlates with cognitive changes in BD, making it a promising target for prevention and intervention efforts.¹²⁹

To mitigate cognitive impairment, optimize physical health, treat somatic comorbidities, avoid high doses of antipsychotics, minimize sedatives, reduce anticholinergic burden, address comorbid SUD, and focus on sleep management and physical activities. Although cognitive remediation strategies have proven effective in treating cognition in BD, their impact on improving psychosocial functioning is uncertain.¹³⁰ However, recent data suggest that cognitive reserve may protect against cognitive decline if targeted early in the illness.¹³¹

4. AGING

Older Age Bipolar Disorder (OABD) refers to individuals aged 50 and above and who have been diagnosed with BD. Despite the increasing prevalence of OABD, research in this area remains limited, hindering the development of evidence-based guidelines tailored to the specific needs of this population.¹³² OABD is characterized by cognitive deficits¹³³, an increased risk of dementia,¹³⁴ impaired psychosocial functioning,¹³⁵ frequent physical comorbidities,^136,137 and premature mortality.^138,139 Several factors associated with aging further negatively influence outcomes in OABD, including shrinking social networks, loss of support from friends and family, lifestyle choices, reduced mobility, and other age-related challenges.

The Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) project demonstrated that patients with OABD experience more physical morbidities compared to matched controls,^140,141 with women bearing a significantly higher health burden.¹⁴² Additionally, lower functioning in OABD was linked more closely to higher depressive and manic symptoms than to the elevated somatic burden.¹⁴³ These findings highlight the urgent need for integrated care approaches in the management of BD.

Cognitive impairment in OABD is particularly pronounced in the domains of verbal learning and delayed memory¹⁴⁴ and occurs more frequently than in major depressive disorder or in healthy controls.¹⁴⁵ The severity of BD and medication use are key determinants of cognitive dysfunction.¹⁴⁶ Follow-up studies have identified three distinct cognitive trajectories in BD: normal aging (32–38%), selective impairment (28–45%), and a progressive course leading to dementia (18–40%),^147,148 that need conformation in OABD.

For individuals with BD, the presence of somatic and cognitive comorbidities further impedes daily functioning and limits treatment options. It remains unclear whether these comorbidities are intrinsic to BD or are a consequence of lifestyle choices and medication use. Future longitudinal studies comparing patients with BD with healthy peers or patients with BD not on maintenance medication are necessary to provide further insights.

5. SUBSTANCE USE DISORDER

Epidemiological studies report a 60.7% lifetime prevalence of any SUD in BD³ with alcohol use disorder (AUD) most prevalent.¹⁴⁹ A meta-analysis showed that AUD rates are 42%, cannabis use disorder (CUD) at 20%, and other disorders include cocaine (~12.5%), amphetamine (~6%), and opiates (~6%).¹⁵⁰ Higher rates of AUD (70%) and CUD (39%) are reported in those seeking treatment.¹⁵¹ Co-occurring SUD has multiple potential causes, including shared neurobiological factors like impaired cognitive control^152,153 and reward processing.¹⁵⁴ The ‘self-medication hypothesis’ suggests substances might be used to reduce symptoms or enhance mood, but evidence is limited.^155,156

Co-occurring SUD has been linked to a worse symptom trajectory (earlier age of onset, more depressive episodes, decreased recovery time, rapid cycling, greater inter-episodic affective instability, higher rates of suicide attempts) and worse psychosocial functioning.¹⁵⁷ In addition, new research suggests that alcohol use increases risk of future depressive and hypomanic/manic symptoms,¹⁵⁵ highlighting the need for ongoing monitoring of and attention to alcohol use in BD treatment regardless of SUD diagnostic status.

Treating co-occurring SUDs are challenging, requiring integrated treatments. Limited RCTs exist, but the CANMAT taskforce published recommendations for managing alcohol, cannabis, and cocaine abuse/dependence in BD.¹⁵⁸ Naltrexone 50 mg daily may reduce alcohol use and cravings.¹⁵⁸ Mood stabilizers like DVPX, carbamazepine, and gabapentin can help with alcohol withdrawal.¹⁵⁸ Adding VPA to lithium has shown to reduce heavy drinking days and delay relapse in BD-I and AUD.¹⁵⁹ Evidence for VPA or lithium in CUD and stimulant use disorder is weak.¹⁵⁸ Integrated Group Therapy, consisting of 12 sessions, addresses dual diagnosis, promoting abstinence, medication adherence, symptom recognition, skill development, and relapse prevention. More RCTs are urgently needed for patients with co-occurring SUD.

EXPERTS BY EXPERIENCE

Clinicians often prioritize eliminating symptoms in BD treatment, whereas PWLE emphasize building a meaningful life despite symptoms.¹⁶⁰ Treatment plans should align with each patient’s self-identified goals. The experience of personal recovery in BD from the perspective of PWLE was summarized in the following framework: Purpose/Meaning, Optimism/Hope, Empowerment, Tensions, Identity, Connectedness.¹⁶¹ “Tensions” refers to the conflicts inherent in living with BD, such as balancing acceptance with ambition, opposing goals surrounding disclosure, and ambivalence about hypomania. A range of self-management strategies, including sleep regulation, mood monitoring, and peer support may enhance an individual’s ability to live well with BD.^162,163 Resources for these strategies are available through organizations such as the Depression and Bipolar Support Alliance, Bipolar UK, and The German Society for Bipolar Disorders; clinicians should encourage use of these and similar resources. Stigma and self-stigma negatively impact PWLE,¹⁶⁴ correlating with poorer functioning,¹⁶⁵ worse depressive symptoms,¹⁶⁶ and diminished quality of life.¹⁶⁷ Development of anti-stigma initiatives and interventions should be a priority. In recent years, research initiatives around the globe have been shifting towards coproduction with PWLE and stakeholders involved at every step, from identifying research questions in priority setting partnerships (such as James Lind Alliance) to selecting patient-reported outcome measures to dissemination of results within the lived experience community. These efforts should be continued and expanded.

CHALLENGES AND FUTURE DEVELOPMENTS:

Limited funding and lack of understanding about pathophysiology have significantly restricted research on treatment options for bipolar depression. Recognizing hypomania/mixed states, improving diagnosis, and reducing treatment delays are key clinical challenges. In addition, individuals with BD often experience high treatment non-adherence and suboptimal care, with major barriers including non-specialist care and lack of continuity. Although ongoing maintenance treatment for individuals with BD is recommended by all current treatment guidelines, some investigators have begun to wonder whether indefinite treatment is needed for all patients. Well-designed longitudinal studies are needed to evaluate this intriguing (if preliminary) concept. To improve treatment outcomes and maintain continuity, a collaborative care approach is essential. Integrating lifestyle interventions and self-management is key.

There is an urgent need for pro-cognitive treatments for the 50–70% of patients with BD who experience persistent cognitive impairment. Advancing cognition-targeted therapies is essential for enhancing daily functioning and improving the quality of life for these individuals. Treatment resistance or refractoriness is commonly observed in BD, with many patients struggling with subsyndromal symptoms that contribute to functional impairment.⁹⁵ Although a universally accepted definition for TRBD is lacking, an international panel of BD experts defined TRBD as the failure to achieve sustained remission after at least two adequate treatment trials, each lasting a minimum of 8 weeks at therapeutic dosages with acceptable adherence. These trials should involve monotherapy with quetiapine, lurasidone, lamotrigine, or the olanzapine/fluoxetine combination, or one of these as monotherapy and another in combination with lamotrigine, DVPX, or lithium.¹⁶⁸

Neuromodulation is a novel therapeutic approach that warrants further investigation, especially for difficult-to-treat depression or TRBD.¹⁶⁹ Most studies have employed repetitive TMS targeting the left dorsolateral prefrontal cortex in bipolar depression.¹⁷⁰ Recent studies have been exploring accelerated TMS combined with neuronavigation, allowing for precise targeting and multiple treatment sessions per day. This innovation reduces the overall treatment duration and is hypothesized to achieve faster response rates. Pilot studies have shown promising results without increasing the rates of treatment-emergent affective switching.^171,172

With advancements in understanding of glutamatergic and GABAergic neurotransmitter systems, there has been growing interest in rapid-acting antidepressants. The N-methyl-D-aspartate receptor (NMDA) antagonists, such as ketamine and esketamine, dextromethorphan/bupropion, have demonstrated promising results. Racemic intravenous ketamine and intranasal esketamine have been used off-label to treat bipolar depression.¹⁷³ Non-randomized studies indicate that single and serial IV ketamine infusions may offer promising short-term benefits, with response rates of 53% and remission rates of 38% during the acute phase.¹⁷³ Treatment-emergent affective switching has been reported in 2.4% of cases, though long-term data on switching rates with ketamine and esketamine in BDs remains limited. RCTs exploring the efficacy of serial ketamine treatments and longitudinal studies assessing long-term outcomes and dose escalation are needed in TRBD.¹⁷⁴

There is renewed interest in psilocybin and other psychedelics for treating depression. A recent open-label trial with a small sample size of 15 participants with BD-II depression reported significant reductions in depressive symptoms after administering 25 mg of psilocybin alongside psychological support.¹⁷⁵ However, concerns regarding psilocybin use in BD highlight the need for cautious optimism and more rigorous investigations.¹⁷⁶

CONCLUSIONS

Bipolar disorder is a chronic illness with a genetic basis that is associated with high rates of comorbid anxiety, SUDs, and cognitive and psychosocial impairment. Cardiovascular comorbidities and overall mortality rates are notably higher than in the general population, highlighting the need for thorough assessment and early intervention to improve long-term outcomes. Suicide rates are elevated among people with BD, but new approaches to suicide prevention in this population emphasise the importance of not only evidence-based treatments, but also safety planning, ensuring access to care during high-risk periods, and means restriction.

Mood stabilisers and SGAs are effective treatments for BD, with lithium remaining the cornerstone therapy despite the increasing use of SGAs. Psychotherapeutic interventions are crucial for improving outcomes, with sleep regulation, mood monitoring, and stigma reduction playing key roles in enhancing the quality of life for individuals with BD. Developing anti-stigma initiatives, fostering meaningful collaboration with individuals with lived experience, and engaging these individuals in every step of the process is essential.

Emerging therapies and therapies with renewed interest, including rapid-acting antidepressants such as ketamine and esketamine, accelerated TMS with neuronavigation, GABAergic modulators, and psilocybin, are promising interventions. These novel treatments bring cautious optimism, as their mechanisms and therapeutic roles are fundamentally different from conventional treatments; however, this difference underscores the importance of large-scale investigations that focus on mechanisms and biomarker development to facilitate advancing treatment options and improving patient outcomes with an evidence-based medicine approach.

An integrated, patient-centred approach to treatment fosters collaboration and empowers individuals with BD to self-manage their symptoms while optimising their physical and mental health. As individuals often prioritise building a meaningful life even in the presence of symptoms, treatment plans should be tailored to align with each individual’s self-identified goals and priorities.

Table 2.

Features of bipolar disorder, borderline personality disorder, and ADHD

Feature	Bipolar Disorder	Borderline Personality Disorder	ADHD
Onset	Episodes of syndromal depression or activated mood, energy, or cognition that represent a clear departure from baseline; first episode usually occurs before age 25 years	Chronic (often long-term) depression and poor self-image, often emerging in the context of abuse, neglect, or insecure attachments	Onset during childhood in most cases, consistent, and not episodic
Activation vs. Lability	Activation affecting mood or affect, cognition, psychomotor function, and energy that lasts for days or weeks	Lability reflecting rapid changes in emotional reactivity, typically lasting from minutes to a few hours	Mood changes are usually situational
Core Symptoms	Euphoria, irritability stemming from euphoria, manic or hypomanic expansiveness, and excess energy	Irritability, rage, or anxiety stemming from interpersonal setbacks, abandonment fears, intolerance of aloneness, self-loathing; elation is rarely present	Inattention, distractibility, difficulty relaxing, hyperactivity, impulsivity, or a combination of these traits; low frustration tolerance; and irritability
Impulsivity	Motivated by manic or hypomanic expansiveness or excess energy; confined to activated mood states	Trait-like, often self-destructive impulsivity (eg, reactive suicidality or self-injury) that is often cue-dependent (eg, interpersonal events, perceived abandonment, etc)	Impulsivity is mostly chronic, especially if untreated; can present as being fidgety, on the go, talking excessively, or difficulty waiting turn
Thoughts Racing	Usually motivated by manic or hypomanic expansiveness and confined to activated mood states	Cued to external stressors, often driven by feelings of anxiety or anger, in absence of grandiosity or enhanced self-esteem	Cued to external stressors, often with coexisting anxiety
Sleep	Sleep deficits and preserved or even enhanced energy and goal-directed activity (sleep-deprived energy enhancement), and confined to episodes (decreased need for sleep; ask about nocturnal and daytime activity)	Chronic or stress-related sleep deficits and nightmares are common with history of trauma; sleep deficits usually lead to worse functioning and emotional dysregulation	Sleep deficits are situational, usually lead to worse functioning, and respond well to pharmacotherapy
Management	Mood stabilisers and psychotherapy are often helpful	Mood stabilisation using mood stabilisers and antidepressants (in some cases) can be helpful, but psychotherapy is typically the first-line treatment	Stimulants, noradrenergic medications, and α2-adrenergic agonists have the most evidence; psychotherapy can be helpful as well

Summary.

Prevalence and Impact:

• Chronic illness with episodes of hypo/mania, depression, and mixed symptoms.

• Affects approximately 40 million individuals worldwide.

• Significant psychosocial, somatic, and financial burden.

• High rates of substance use that worsen clinical course and treatment response.

• Increased mortality from natural and unnatural causes.

• Mixed symptoms are a risk factor for suicidality.

Diagnostic Challenges:

• Symptoms overlap with major depressive disorder, ADHD, psychotic spectrum disorders, and personality disorders.

• 7–10-year delay in the correct diagnosis of bipolar disorder

• Screen for hypo/mania and mixed symptoms for someone presenting with depression

• Key risk factors: early onset (<25 years), multiple episodes, family history of bipolar disorder, worsening with antidepressants, psychosis, psychomotor impairment, mood lability or hypo/manic symptoms

• Late-onset cases should be assessed for secondary causes

• High comorbidity rates with anxiety and substance use disorders

Pathophysiology:

• Highly heritable illness (60–80%)

• Genome-wide association studies reveal a polygenic architecture

• Mitochondrial dysfunction and circadian rhythm dysregulation are common

• Elevated pro-inflammatory mediators and structural brain alterations are seen

Treatment Approaches:

• Self-management and psychoeducation accessible through national/international bipolar support groups

• Mood stabilizers (e.g., lithium, lamotrigine, carbamazepine, and valproate) and second-generation antipsychotics are the key pharmacotherapeutic agents

• Lithium is the ideal mood stabilizer, reducing mania, depression and an excellent maintenance agent

• Avoid monoaminergic antidepressants in mixed episodes or rapid cycling

• Psychotherapy: Cognitive Behavioral Therapy, Family Focused Therapy, Interpersonal and Social Rhythm Therapy, psychoeducation

• Chronotherapy and lifestyle interventions—sleep hygiene, exercise, and social rhythm modification as self-help interventions

• Emerging treatments: Transcranial magnetic stimulation, Ketamine, esketamine, psilocybin

Special Considerations:

• Bipolar disorder carries a high risk of suicide, with rates more than 20 times higher than the general population

• Older adults with bipolar disorder face unique challenges, including cognitive impairment, depressive symptoms, and medication non-adherence

• Importance of patient-centered treatment plans tailored to individual goals and priorities

Future Directions:

• Increasing availability of psychosocial interventions aimed at self-management

• Addressing treatment-resistant bipolar depression

• Exploring novel interventions and deepening understanding of pathophysiology

• Accelerating discovery and translation to patient care