Introduction
Bipolar disorder (BD), also known as bipolar affective disorder, ranks among the top ten causes of disability globally. Characterized by recurrent episodes of mania or hypomania that alternate with periods of depression, bipolar disorder is frequently misdiagnosed, especially at its onset. Effective management strategies include pharmacotherapy and psychosocial interventions; however, patients often experience mood relapses and incomplete responses, particularly during depressive phases. Long-term care necessitates continuous assessment and adjustments to treatment plans. Furthermore, managing co-occurring psychiatric and chronic medical conditions is often a crucial aspect of patient care. This article aims to provide a comprehensive review of bipolar affective disorder, covering its etiology, classification, evaluation, management, and prognosis, while emphasizing the vital role of an interprofessional team in optimizing patient outcomes.
Etiology of Bipolar Disorder
The exact cause of bipolar disorder remains elusive, but current understanding points to a complex interplay of genetic predisposition, epigenetic modifications, neurochemical imbalances, and environmental influences. The heritability of bipolar disorder is well-documented. Research has identified numerous genetic loci that may elevate the risk of developing BD; the first genetic link was identified in 1987 with “DNA markers” on chromosome 11’s short arm. Since then, over 30 genes have been associated with an increased susceptibility to this condition.
While establishing direct causation between life events and BD development is challenging, adverse childhood experiences, particularly emotional abuse or neglect, have been consistently linked to an increased risk of developing bipolar disorder later in life. Other stressful life events associated with the onset of BD include childbirth, divorce, unemployment, disability, and early parental loss. In adulthood, a significant majority, exceeding 60% of individuals with BD, report experiencing at least one “stressful life event” in the six months preceding a manic or depressive episode.
Neurochemically, bipolar disorder is believed to involve dysregulation in neurotransmitter systems, especially those involving monoamines like dopamine and serotonin, and intracellular signaling pathways that regulate mood stability. However, it’s important to note that no single, specific dysfunction within these neurotransmitter systems has been definitively identified as the sole cause.
Recent neuroimaging studies, as summarized by the ENIGMA Bipolar Disorder Working Group, indicate “a diffuse pattern of brain alterations including smaller subcortical volumes, lower cortical thickness and altered white matter integrity in groups of individuals with bipolar disorder compared to healthy controls.” These studies also reveal evidence of altered functional connectivity within the brain networks of individuals with bipolar disorder.
Epidemiology of Bipolar Disorder
The World Mental Health Survey Initiative has highlighted the consistent global prevalence, severity, impact, and comorbidity patterns of bipolar spectrum disorders (BD-I, BD-II, and subthreshold BD). The combined lifetime prevalence of bipolar spectrum disorder is estimated at 2.4%. Specifically, lifetime prevalence rates are 0.6% for BD-I, 0.4% for BD-II, and 1.4% for subthreshold BD.
The onset of bipolar disorder typically shows two age peaks: between 15 and 24 years and between 45 and 54 years. Notably, over 70% of individuals with bipolar disorder exhibit clinical symptoms before the age of 25. Bipolar disorder affects individuals across genders, ethnicities, and geographic locations (urban vs. rural) with relatively equal distribution.
Cyclothymic disorder, a milder form of bipolar disorder, has a lifetime prevalence of approximately 0.4-1%, with a balanced male-to-female ratio of 1:1.
Pathophysiology of Bipolar Disorder
Similar to its etiology, the pathophysiology of bipolar disorder is not fully understood. It is thought to arise from complex interactions between genetic, neurochemical, and environmental factors. Recent neurobiological research has extensively explored the “genetic components, signaling pathways, biochemical changes, and neuroimaging findings” associated with BD.
Evidence strongly supports a significant genetic component and the influence of epigenetics in bipolar disorder. Studies on human subjects have demonstrated alterations in neurotrophic factors such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in individuals with BD. These findings suggest that disrupted neurotrophic signaling contributes to reduced neuroplasticity in bipolar disorder. Other proposed mechanisms include mitochondrial dysfunction, oxidative stress, immune-inflammatory imbalances, and disruptions in the hypothalamic-pituitary-adrenal axis. Furthermore, neuroimaging studies have provided “evidence of change in regional activity, functional connectivity, neuronal activity, and bioenergetics associated with BD.” Anatomic studies have also revealed dendritic spine loss in the dorsolateral prefrontal cortex in post-mortem brain tissue of individuals diagnosed with BD.
As previously mentioned, imbalances in monoaminergic neurotransmitter systems, particularly dopamine and serotonin, and disruptions in intracellular signaling pathways that regulate mood are thought to be involved in the pathophysiology of BD. However, a singular, unifying dysfunction in these neurotransmitter systems has yet to be identified.
History and Physical Examination in Bipolar Disorder Diagnosis
Bipolar disorder diagnosis is primarily clinical. Accurate diagnosis requires a thorough clinical assessment, including a detailed patient interview, ideally complemented by interviews with family members and a review of the longitudinal course of the patient’s condition. Currently, no definitive biomarker or neuroimaging technique can definitively diagnose bipolar disorder.
A significant challenge in bipolar disorder is the diagnostic delay. Most patients with bipolar disorder are not correctly diagnosed until 6 to 10 years after their initial contact with a healthcare provider, despite exhibiting clinical features of the condition. It’s crucial to differentiate between initial misdiagnosis and the evolution from major depressive disorder (MDD), often the initial presentation, to BD. Estimates suggest that 20-30% of patients initially diagnosed with MDD will transition to bipolar disorder within three years. Therefore, clinicians must remain vigilant about this potential transition in patients with MDD who initially screen negative for bipolar disorder. Furthermore, subthreshold hypomanic symptoms can be present in up to 40% of patients diagnosed with MDD.
While not highly sensitive or specific, self-report screening tools for BD can assist clinicians in making a more accurate diagnosis. Two of the most widely studied screening tools are the Mood Disorders Questionnaire (MDQ) and the Hypomania Checklist 32 (HCL-32). The MDQ has a sensitivity of 80% and specificity of 70%, while the HCL-32 has a sensitivity of 82% and specificity of 57%. Positive results on these screening tools should prompt clinicians to conduct a comprehensive clinical assessment for bipolar disorder.
A key diagnostic challenge is differentiating between unipolar and bipolar depression, as the symptomatic presentation of major depressive episodes in both conditions can be very similar. Clinicians must proactively inquire about past manic, hypomanic, and depressive episodes when evaluating patients presenting with depressive symptoms. Inquiry into past hypomanic or manic episodes is especially critical for patients with early onset of their first depressive episode (i.e., before age 25), a high number of lifetime depressive episodes (five or more), and a family history of bipolar disorder. These historical factors significantly increase the likelihood of a bipolar diagnosis rather than unipolar depression.
Other factors that increase the likelihood of a diagnostic shift from MDD to BD include the presence of psychotic features, lack of response to antidepressants, antidepressant-induced manic or hypomanic symptoms, and polymorbidity, defined as the presence of three or more comorbid conditions.
Evaluation: DSM-5 Bipolar Diagnosis Criteria
The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), provides the standard criteria for diagnosing bipolar and related disorders. These criteria are essential for accurate diagnosis and differentiation between various subtypes of bipolar disorder.
General DSM-5 Diagnostic Categories for Bipolar and Related Disorders:
- Bipolar I Disorder (BD-I): Diagnosis requires meeting the criteria for at least one manic episode. Hypomanic or major depressive episodes may precede or follow a manic episode, but are not required for a BD-I diagnosis.
- Bipolar II Disorder (BD-II): Diagnosis requires meeting the criteria for at least one current or past hypomanic episode and at least one major depressive episode. Critically, there must be no history of a full manic episode.
- Cyclothymic Disorder: Characterized by numerous periods with hypomanic symptoms that do not meet full hypomanic episode criteria and depressive symptoms that do not meet full major depressive episode criteria. These mood fluctuations must be present for at least two years (one year in adolescents and children) for at least half of the time, with no more than two consecutive symptom-free months. Criteria for major depressive, manic, or hypomanic episodes must never have been met.
- Specified Bipolar and Related Disorder: This category is used when bipolar-like symptoms cause clinically significant distress or impairment but do not meet the full criteria for BD-I, BD-II, or cyclothymic disorder. Examples include:
- Short-duration hypomanic episodes and major depressive disorder
- Hypomanic episodes with insufficient symptoms and major depressive episode
- Hypomanic episode without a prior major depressive episode
- Short-duration cyclothymia
- Unspecified Bipolar and Related Disorder: Used when symptoms characteristic of bipolar and related disorders cause clinically significant distress or impairment in social, occupational, or other important areas of functioning, but do not meet the full criteria for any of the specified categories.
It is crucial to note that the symptoms and episodes used to diagnose these disorders must not be attributable to the physiological effects of a substance or another medical condition.
Specifiers for Bipolar Disorders:
Both BD-I and BD-II can be further specified to provide a more detailed clinical picture. Specifiers include:
- Rapid Cycling: Defined as at least four distinct mood episodes (manic, hypomanic, or major depressive) within a 12-month period.
- Seasonal Pattern: Episodes show a temporal relationship to specific seasons of the year.
- With Psychotic Features: Presence of delusions or hallucinations during mood episodes. These can be mood-congruent (themes consistent with mood state) or mood-incongruent. Psychotic features are, by definition, absent in hypomanic episodes.
- With Catatonia: Presence of catatonic symptoms during mood episodes.
- With Anxious Distress: Presence of significant anxiety symptoms alongside mood episodes.
- With Melancholic Features: Presence of severe anhedonia or lack of reactivity to pleasurable stimuli during depressive episodes.
- With Peripartum Onset: Onset of mood episodes during pregnancy or in the postpartum period.
- With Mixed Features: This specifier acknowledges the presence of symptoms from the opposite mood pole during a manic, hypomanic, or depressive episode.
- Manic or Hypomanic Episode with Mixed Features: Meets full criteria for mania or hypomania and includes at least three depressive symptoms (depressed mood, anhedonia, psychomotor retardation, fatigue, excessive guilt, or suicidal ideation).
- Major Depressive Episode with Mixed Features: Meets full criteria for a major depressive episode and includes at least three manic/hypomanic symptoms (elevated mood, grandiosity, increased talkativeness, racing thoughts, increased goal-directed activity, risky behavior, decreased need for sleep). Mixed features must be present for “most days” of the episode.
DSM-5 Diagnostic Criteria for Bipolar I Disorder: Manic Episode
A manic episode is the cornerstone of a Bipolar I Disorder diagnosis. It is defined as a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least one week and present most of the day, nearly every day (or any duration if hospitalization is necessary).
During this period, three or more of the following symptoms (or four if the mood is only irritable) must be present to a significant degree and represent a noticeable change from usual behavior:
- Inflated self-esteem or grandiosity
- Decreased need for sleep (e.g., feels rested after only 3 hours of sleep)
- More talkative than usual or pressure to keep talking
- Flight of ideas or racing thoughts
- Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli)
- Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation (purposeless non-goal-directed activity)
- Excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
The episode must be sufficiently severe to cause marked impairment in social or occupational functioning or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. The episode is not attributable to the physiological effects of a substance (e.g., drug of abuse, medication, other treatment) or another medical condition.
DSM-5 Diagnostic Criteria for Bipolar II Disorder: Hypomanic Episode
A hypomanic episode is essential for the diagnosis of Bipolar II Disorder. It is defined as a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least four consecutive days and present most of the day, nearly every day.
During this period, three or more of the following symptoms (or four if the mood is only irritable) must be present to a significant degree and represent a noticeable change from usual behavior:
- Inflated self-esteem or grandiosity
- Decreased need for sleep (e.g., feels rested after only 3 hours of sleep)
- More talkative than usual or pressure to keep talking
- Flight of ideas or racing thoughts
- Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli)
- Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation (purposeless non-goal-directed activity)
- Excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
The episode is associated with an unequivocal change in functioning that is uncharacteristic of the individual when not symptomatic. The disturbance in mood and change in functioning are observable by others. The episode is not severe enough to cause marked impairment in social or occupational functioning or to necessitate hospitalization. There are no psychotic features. The episode is not attributable to the physiological effects of a substance (e.g., drug of abuse, medication, other treatment) or another medical condition.
DSM-5 Diagnostic Criteria for a Major Depressive Episode
A major depressive episode is required for the diagnosis of Bipolar II Disorder and can occur in Bipolar I Disorder. It is defined by the presence of five or more of the following symptoms during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
- Depressed mood most of the day, nearly every day (as indicated by either subjective report [e.g., feels sad, empty, hopeless] or observation made by others [e.g., appears tearful]). (Note: In children and adolescents, can be irritable mood.)
- Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (anhedonia)
- Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.)
- Insomnia or hypersomnia nearly every day
- Psychomotor agitation or retardation nearly every day (observable by others; not merely subjective feelings of restlessness or being slowed down)
- Fatigue or loss of energy nearly every day
- Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)
- Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others)
- Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The episode is not attributable to the physiological effects of a substance or another medical condition.
Considering Secondary Causes of Bipolar Disorder
In certain clinical scenarios, healthcare professionals should consider the possibility of a secondary cause for bipolar-like symptoms. Factors that should raise suspicion for a secondary cause include:
- First onset of symptoms after age 50
- Abnormal vital signs or neurological examination findings
- Recent change in health status or medication regimen temporally associated with symptom onset
- Unusual or lack of response to standard treatments for bipolar disorder
- Absence of personal or family history of psychiatric disorders
In such cases, initial evaluation to rule out secondary causes may include:
- Urine drug screen
- Complete blood count with blood smear
- Comprehensive metabolic panel
- Thyroid function tests
- Vitamin B12 and folate levels
Treatment and Management of Bipolar Disorder
While numerous clinical practice guidelines exist for the treatment and management of bipolar disorder, a universally accepted ‘meta-consensus’ model is lacking. The absence of standardized language and recommendations across current guidelines may complicate the consistent implementation of evidence-based treatments for BD. The following summarizes key guidelines published by reputable organizations such as the National Institute for Health and Care Excellence (NICE), British Association for Psychopharmacology, International College of Neuro-Psychopharmacology (CINP), Canadian Network for Mood and Anxiety Treatments (CANMAT), International Society for Bipolar Disorders (ISBD), and Indian Psychiatric Society (IPS).
Management of Manic Episodes
Mania is considered a psychiatric emergency, often requiring hospitalization. Initial treatment focuses on stabilizing the acutely agitated patient to de-escalate distress, prevent dangerous behaviors, and facilitate comprehensive assessment. A calm environment with minimal stimulation is ideal. Benzodiazepines can be used as adjunctive therapy alongside mood stabilizers and antipsychotics to reduce agitation and promote sleep.
A review of the patient’s current medications is crucial. For example, if a patient is already on lithium monotherapy, adding a second agent is generally recommended. Antidepressants are typically tapered and discontinued during a manic phase due to the risk of exacerbating mania. First-line monotherapy options include mood stabilizers like lithium or valproate, or antipsychotics such as aripiprazole, asenapine, cariprazine, quetiapine, or risperidone.
If symptoms remain inadequately controlled or mania is severe, combination therapy is indicated. Common combinations include lithium or valproate with an antipsychotic (aripiprazole, asenapine, olanzapine, quetiapine, or risperidone). Electroconvulsive therapy (ECT) may be considered as monotherapy or in combination, particularly for severe or treatment-resistant mania and in pregnant women with severe mania.
It is critical to avoid valproate in women of childbearing potential due to the significant risk of teratogenicity and impaired intellectual development in the fetus.
Management of Hypomanic Episodes
Hypomanic episodes, by definition, are less severe and do not cause marked impairment or psychosis. Therefore, they can often be managed in an outpatient setting. Pharmacotherapy approaches are similar to those for mania, although potentially higher doses may be required for mania.
Management of Acute Bipolar Depression
Suicide and self-harm risk are paramount in managing bipolar depression, as most suicides in BD occur during depressive episodes. Hospitalization may be necessary depending on risk and severity.
For patients not currently on long-term BD medication, first-line monotherapy options include quetiapine, olanzapine, or lurasidone (though lurasidone’s effectiveness in acute bipolar mania is less studied). Combination therapies like olanzapine-fluoxetine, lithium plus lamotrigine, and lurasidone plus lithium or valproate are also considered.
Cognitive behavioral therapy (CBT) can be a valuable adjunct to pharmacotherapy. However, CBT alone is generally insufficient for acute bipolar depression, and pharmacological treatment is typically essential.
ECT is a consideration for refractory bipolar depression or as a first-line treatment when psychotic features or high suicide risk are present.
For patients experiencing a depressive episode while on maintenance medication (breakthrough episode), it’s important to ensure their current regimen provides adequate protection against manic relapse (e.g., mood stabilizer or antipsychotic). Medication adherence, dosage, drug interactions, serum concentrations, and current stressors, substance use, and adherence to psychosocial interventions should be reviewed.
Treatment strategies for BD-II depression are generally similar to those for BD-I depression.
Antidepressants should not be used as monotherapy in most bipolar disorder patients. Evidence supporting their efficacy is limited, and there is a significant risk of switching to mania or mood destabilization during bipolar depression. Antidepressants can be used adjunctively with mood stabilizers (lithium, lamotrigine) and second-generation antipsychotics when necessary.
Maintenance Treatment for Bipolar Disorder
Most individuals with bipolar disorder require long-term maintenance treatment, potentially lifelong, to prevent recurrent episodes and restore pre-illness functioning. Continuous treatment is generally recommended over intermittent approaches. Medications effective during acute phases are often continued initially to prevent early relapse. Mood stabilizers and atypical antipsychotics, alone or in combination, form the cornerstone of maintenance pharmacotherapy.
Lithium monotherapy has substantial evidence supporting its effectiveness against manic, depressive, and mixed relapses. Lithium is also associated with a reduced risk of suicide in BD patients. Regular monitoring, including serum lithium levels, is a standard of care.
Beyond pharmacotherapy, essential components of maintenance treatment include medication adherence, primary prevention and management of psychiatric and medical comorbidities, and psychotherapy when appropriate. Ongoing monitoring for suicidality is crucial throughout the maintenance phase.
Differential Diagnosis of Bipolar Disorder
The differential diagnosis of bipolar disorder is broad, encompassing other conditions characterized by overlapping symptoms like depression, impulsivity, mood lability, anxiety, cognitive dysfunction, and psychosis. Common differential diagnoses include:
- Major Depressive Disorder (MDD)
- Schizophrenia and Schizoaffective Disorder
- Anxiety Disorders (Generalized Anxiety Disorder, Panic Disorder, Social Anxiety Disorder)
- Substance Use Disorders
- Borderline Personality Disorder
- In pediatric populations: Attention-Deficit/Hyperactivity Disorder (ADHD) and Oppositional Defiant Disorder (ODD)
Prognosis of Bipolar Disorder
Bipolar disorder is a significant cause of disability worldwide. Meta-analyses indicate that individuals with BD have a reduced life expectancy compared to the general population, with approximately 13 years of potential life lost. This lifespan reduction is greater than in many other common mental health disorders, including anxiety and depressive disorders. Life expectancy is notably lower in men with BD compared to women. Overall mortality in BD is double that of the general population. Natural deaths, particularly from circulatory and respiratory illnesses, are significantly elevated. Unnatural deaths are approximately seven times more frequent, with a dramatically increased suicide risk (approximately 14 times higher) and increased risk of other violent deaths.
Complications of Bipolar Disorder
Individuals with bipolar disorder face a substantially increased risk of premature death due to suicide and medical comorbidities, particularly cardiovascular, respiratory, and endocrine disorders. Over half of BD patients are overweight or obese, often independent of weight-promoting psychotropic medications. About one-third meet criteria for metabolic syndrome, increasing the risk of heart disease and stroke. Attempted suicides are more common in patients with comorbid metabolic syndrome. Comorbid overweight and obesity are associated with a more severe course of BD, more frequent mood episodes, poorer treatment response, and heightened suicide risk. Migraine is also frequently comorbid with bipolar disorder.
Psychiatric comorbidity is highly prevalent, affecting 50-70% of BD patients. Anxiety disorders (generalized anxiety disorder, social anxiety disorder, panic disorder) occur in 70-90%, and substance use disorders in 30-50%. Psychiatric comorbidities are associated with a more severe BD course, more frequent mood episodes, and reduced quality of life. Personality disorders, especially borderline personality disorder, are comorbid in up to half of BD patients, and binge eating disorder in 10-20%, contributing to more frequent mood episodes, higher suicidality, and increased substance use disorders.
Deterrence and Patient Education
Psychoeducation, delivered individually or in groups, is recommended for patients and their families. It should include strategies for detecting and managing prodromal symptoms of depression and mania, enhancing medication adherence, and promoting healthy lifestyle choices. Patients are encouraged to limit stimulants like caffeine, minimize alcohol, exercise regularly, and practice good sleep hygiene. Clinicians should foster a strong therapeutic alliance, demonstrate empathy, involve patients in treatment decisions, and consistently monitor symptoms. These approaches have been shown to reduce suicidal ideation, improve treatment outcomes, and enhance patient satisfaction. Case management or care coordination can connect patients to community resources like support groups, mental health centers, and substance use treatment programs.
Enhancing Healthcare Team Outcomes
The optimal goal of bipolar disorder treatment is full functional recovery, returning to pre-illness baseline functioning. This is best achieved through integrated psychiatric and medical healthcare using an interprofessional team approach to manage both BD and comorbid conditions. Interprofessional teams may include case managers, primary care physicians, psychiatrists, psychiatric nurse practitioners, psychiatric physician assistants, psychiatric nurse specialists, social workers, psychologists, and pharmacists.
A consistent, long-term alliance between the patient, family, and healthcare team is crucial for effective pharmacotherapy management, psychoeducation, ongoing monitoring, and psychosocial support. Patients with co-occurring substance use disorders benefit from addiction specialist involvement. Pharmacists play a vital role in medication reconciliation to prevent drug-drug interactions. Collaborative care models, emphasizing patient psychoeducation, evidence-based guidelines, shared decision-making, and supportive technology, have proven effective in improving outcomes for BD patients.
An interprofessional approach is fundamental in bipolar disorder treatment. A holistic and integrated team approach maximizes positive outcomes and minimizes adverse events.
Review Questions
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References
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Disclosure: Ankit Jain declares no relevant financial relationships with ineligible companies.
Disclosure: Paroma Mitra declares no relevant financial relationships with ineligible companies.
