Bipolar Disorder

Etiology

Currently, the etiology of BD is unknown but appears to be due to an interaction of genetic, epigenetic, neurochemical, and environmental factors. Heritability is well established.[3][4][5] Numerous genetic loci have been implicated as increasing the risk of BD; the first was noted in 1987 with "DNA markers" on the short arm of chromosome 11. Since then, an association has been made between at least 30 genes and an increased risk of the condition.[6]

Although it is difficult to establish causation between life events and the development of BD, childhood maltreatment, particularly emotional abuse or neglect, has been linked to the later development of the condition. Other stressful life events associated with developing BD include childbirth, divorce, unemployment, disability, and early parental loss.[7] In adulthood, more than 60% of patients with BD report at least one "stressful life event" before a manic or depressive episode in the preceding 6 months.[6]

The etiology of BD is thought to involve imbalances in systems associated with monoaminergic neurotransmitters, particularly dopamine and serotonin, and intracellular signaling systems that regulate mood. However, no singular dysfunction of these neurotransmitter systems has been identified.[8]

In a recent neuroimaging review article, the ENIGMA Bipolar Disorder Working Group stated, "Overall, these studies point to 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."[9] Neuroimaging studies have also shown evidence of changes in functional connectivity.[10][11]

Epidemiology

In the World Mental Health Survey Initiative, the use of mental health services for the bipolar spectrum (BD-I, BD-II, and subthreshold BD) concluded, “Despite cross-site variation in the prevalence rates of bipolar spectrum disorder, the severity, impact, and patterns of comorbidity were remarkably similar internationally.” The aggregate lifetime prevalence of BD-I was 0.6%, BD-II 0.4%, subthreshold BD 1.4%, and bipolar spectrum 2.4%.[2]

There are two peaks in the age of onset: 15-24 years and 45-54 years, with more than 70% of individuals manifesting clinical characteristics of the condition before 25 years of age.[12][13] Bipolar disorder shows a relatively equal distribution across sex, ethnicity, and urban compared to rural areas.[7][14]

Cyclothymia is associated with a lifetime prevalence of approximately 0.4-1% and a male-to-female ratio of 1:1.[15]

Pathophysiology

As with the etiology, the pathophysiology of BD is unknown and is thought to involve interactions between multiple genetic, neurochemical, and environmental factors. A recent neurobiology review article discusses in detail the “genetic components, signaling pathways, biochemical changes, and neuroimaging findings” in BD.[10]

Evidence supports a strong genetic component and an epigenetic contribution. Human studies have shown changes in brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in patients with BD, indicating neurotrophic signaling is a molecular mechanism associated with decreased neuroplasticity. Other proposed mechanisms include mitochondrial dysfunction, oxidative stress, immune-inflammatory imbalance, and compromised hypothalamic-pituitary-adrenal axis. Additionally, neuroimaging studies have shown “evidence of change in regional activity, functional connectivity, neuronal activity, and bioenergetics associated with BD,” and anatomic studies have revealed dendritic spine loss in the dorsolateral prefrontal cortex in the post-mortem brain tissue of patients with BD.[10][16]

As mentioned, imbalances in systems associated with monoaminergic neurotransmitters, particularly dopamine and serotonin, and intracellular signaling systems that regulate mood are thought to be involved. However, no singular dysfunction of these neurotransmitter systems has been identified.[8]

History and Physical

Because bipolar disorder is a clinical diagnosis, making the correct diagnosis requires a comprehensive clinical assessment, including the directed patient interview, preferably supplemented by interviews of their relatives and the longitudinal course of their condition. Currently, there is no biomarker or neuroimaging study to aid in making the diagnosis.

Most patients with bipolar disorder are not correctly diagnosed until approximately 6 to 10 years after first contact with a healthcare provider, despite the presence of clinical characteristics of the condition.[17] Notably, misdiagnosing BD after first contact differs from not recognizing the transition from major depressive disorder (MDD), the most common index presentation, to BD. Estimates of patients transitioning to BD within three years of an MDD diagnosis range from 20-30%; therefore, clinicians must maintain an awareness of the potential for this transition when caring for patients with MDD who initially screened negative for BD.[18] Also, subthreshold hypomanic symptoms can occur in as many as 40% of patients with MDD.[19]

Although not highly sensitive and specific, self-report screening tools for BD may aid clinicians in making an accurate diagnosis. The most studied screening tools are the Mood Disorders Questionnaire (sensitivity 80%, specificity 70%) and the Hypomania Checklist 32 (sensitivity 82%, specificity 57%).[20] Positive results should motivate the clinician to conduct a thorough clinical assessment for bipolar disorder.

A significant diagnostic challenge is distinguishing between unipolar and bipolar depression because episodes of unipolar major depression and bipolar depression have the same general diagnostic criteria. Clinicians must inquire about past manic, hypomanic, and depressive episodes in patients presenting with symptoms of a depressive episode. Inquiry into past hypomanic or manic episodes is particularly important for patients with early onset of their first depressive episode (ie, in patients younger than 25 years), a high number of lifetime depressive episodes (5 or more episodes), and a family history of bipolar disorder. These findings in the patient’s history have been shown to increase the likelihood of a bipolar rather than a unipolar diagnosis.[21] 

Other factors increasing the likelihood of a diagnostic change from MDD to BD include the presence of psychosis, unresponsiveness to antidepressants, the induction of manic or hypomanic symptoms by antidepressant drug treatment, and polymorbidity, defined as 3 or more comorbid conditions.[18][22]

Evaluation

General DSM-5 Diagnostic Criteria for Bipolar and Related Disorders (American Psychiatric Association. Diagnostic and StatisticalManual of Mental Disorders 5th edition (DSM-5). Arlington, VA: American Psychiatric Publishing; 2013)

BD-I: Criteria met for at least one manic episode, which might have been preceded or followed by a hypomanic episode or major depressive episode (hypomanic or major depressive episodes are not required for the diagnosis).

BD-II: Criteria met for at least one current or past hypomanic episode and a major depressive episode; no manic episodes.

Cyclothymic disorder: Hypomanic symptoms that do not meet the criteria for hypomanic episodes and depressive symptoms that do not meet the criteria for major depressive episodes in numerousperiods (at least half the time) for at least 2 years (1 year in those aged ≤18 years); criteria for major depressive, manic, or hypomanic episodes have never been met.

Specified bipolar and related disorders: Bipolar-like phenomena that do not meet the criteria for BD-I, BD-II, or cyclothymic disorder due to insufficient duration or severity, ie, 1) short-duration hypomanic episodes and major depressive disorder, 2) hypomanic episodes with insufficient symptoms and major depressive episode, 3) hypomanic episode without a prior major depressive episode, and 4) short-duration cyclothymia.

Unspecified bipolar and related disorders: Characteristic symptoms of bipolar and related disorders that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning but do not meet the full criteria for any category previously mentioned.

The symptoms and episodes used to diagnose these disorders must not be related to the physiological effects of a substance or general medical condition.

BD-I and BD-II can be further specified as rapid cycling or seasonal patterns and whether the episodes have psychotic features, catatonia, anxious distress, melancholic features, or peripartum onset. Rapid cycling refers to 4 or more distinct mood episodes during a 12-month period. 

Mood-congruent delusions may be present in either a depressive or manic episode, including delusions of guilt or grandiose delusions of power and wealth. Psychotic features, by definition, are absent in hypomanic episodes. 

To better account for "mixed features," the current diagnostic criteria implements specifiers. Manic or hypomanic episodes with mixed features meet the full criteria for mania or hypomania and have at least 3 of the following signs or symptoms: depressed mood, anhedonia, psychomotor retardation, fatigue, excessive guilt, or recurrent thoughts of death. Major depressive episodes with mixed features meet the full criteria for a major depressive episode and have at least 3 of the following signs or symptoms: expansive mood, grandiosity, increased talkativeness, flight of ideas, increased goal-directed activity, indulgence in activities with a high potential for "painful consequences," and decreased need for sleep. The mixed features must be present during "most days."

DSM-5 Diagnostic Criteria for Bipolar I Disorder

For a diagnosis of BD-I, it is necessary to meet the following criteria for a manic episode. The manic episode may have been preceded by and may be followed by hypomanic or major depressive episodes (hypomanic or major depressive episodes are not required for the diagnosis).

A manic episode is defined as a distinct period of persistently elevated or irritable mood with increased activity or energy lasting for at least 7 consecutive days or requiring hospitalization. The presence of 3 or more of the following is required to qualify as a manic episode. If the mood is irritable, at least 4 of the following must be present:

• Inflated self-esteem or grandiosity
• Decreased need for sleep
• A compulsion to keep talking or being more talkative than usual
• Flight of ideas or racing thoughts
• High distractibility
• Increased goal-directed activity (socially, at work or school, or sexually) or psychomotor agitation (non-goal-directed activity)
• Excessive involvement in activities that have a high potential for painful consequences, such as engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments

The episode is not attributable to the physiological effects of a substance or general medical condition.

The symptoms of a manic episode are markedly more severe than those of a hypomanic episode and result in impaired social or occupational functioning or require hospitalization.

DSM-5 Diagnostic Criteria for Bipolar II Disorder

For a diagnosis of BD-II, it is necessary to have met the criteria for at least one current or past hypomanic episode and a major depressive episode without a manic episode (see below for major depressive episode criteria).

A hypomanic episode is defined as a distinct period of persistently elevated or irritable mood with increased activity or energy lasting for at least 4 consecutive days. The presence of 3 or more of the following is required to qualify as a hypomanic episode. If the mood is irritable, at least 4 of the following must be present:

• Inflated self-esteem or grandiosity
• Decreased need for sleep
• A compulsion to keep talking or being more talkative than usual
• Flight of ideas or racing thoughts
• High distractibility
• Increased goal-directed activity (socially, at work or school, or sexually) or psychomotor agitation (non-goal-directed activity)
• Excessive involvement in activities that have a high potential for painful consequences, such as engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments

The episode is an unequivocal change in functioning, uncharacteristic of the person and observable by others. Also, the episode is not severe enough to cause marked impairment, is not due to the physiological effects of a substance or general medical condition, and there is no psychosis (if present, this is mania by definition).

DSM-5 Diagnostic Criteria for a Major Depressive Episode

The presence of 5 or more of the following symptoms daily or nearly every day for a consecutive 2-week period that is a change from baseline or previous functioning:

• Subjective report of depressed mood most of the day (or depressed mood observed by others)
• Anhedonia most of the day
• Significant weight loss when not dieting or weight gain or decrease or increase in appetite
• Insomnia or hypersomnia
• Psychomotor agitation or retardation
• Fatigue or loss of energy
• Feelings of worthlessness or excessive or inappropriate guilt
• Decreased concentration or indecisiveness
• Recurrent thoughts of death, recurrent suicidal ideation without a specific plan

To meet the criteria, at least one of the symptoms must be depressed mood or anhedonia, the symptoms must not be attributable to a substance or general medical condition, and it causes functional impairment (eg, social or occupational).

Possible Secondary Cause of Bipolar Disorder

The following characteristics may heighten the clinical suspicion for a possible secondary cause in patients with signs and symptoms associated with bipolar disorder: older than 50 at the first onset of symptoms, abnormal vital signs or neurological examination, a recent change in health status or medications temporally associated with symptom onset, unusual response or unresponsiveness to appropriate treatments, and no personal or family history of a psychiatric disorder.

Recommended initial evaluation for a possible secondary cause includes a urine drug screen, complete blood count with blood smear, comprehensive metabolic panel, thyroid function tests, and vitamin B and folate levels.

Treatment / Management

Although numerous clinical practice guidelines exist for the treatment and management of bipolar disorder, there is not enough consistency to generate a ‘meta-consensus’ model.[23] Authors of a recent systematic review concluded, “The absence of a uniform language and recommendations in current guidelines may be an additional complicating factor in the implementation of evidence-based treatments in BD.”[24] The following is an abbreviated synthesis of guidelines published by 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).[25][26][27][28][29](A1)

Manic Episode

Mania is considered a medical emergency and often requires psychiatric hospitalization. Initial treatment is aimed at stabilization of the potentially or acutely agitated patient to help de-escalate distress, mitigate potentially dangerous behavior, and facilitate the patient assessment and evaluation. When possible, a calming environment with minimal stimuli should be provided. Adjunctive benzodiazepines may be used concomitantly with mood stabilizers and antipsychotic drugs to reduce agitation and promote sleep.

The patient’s current medications must be considered. For example, a second drug is recommended if the patient presents while the condition is already managed with lithium monotherapy. Also, antidepressants are usually tapered and discontinued in a manic phase. First-line monotherapy includes a mood stabilizer, such as lithium or valproate, or an antipsychotic, such as aripiprazole, asenapine, cariprazine, quetiapine, or risperidone.

Add another medication if symptoms are inadequately controlled, or the mania is very severe. Combination treatments include lithium or valproate with either aripiprazole, asenapine, olanzapine, quetiapine, or risperidone. Electroconvulsive therapy (ECT) may be considered as monotherapy or as part of combination therapy in patients whose mania is particularly severe or treatment-resistant and in women with severe mania who are pregnant. 

Valproate should not be used for women of childbearing potential due to the unacceptable risk to the fetus of teratogenesis and impaired intellectual development.

Hypomanic Episodes

By definition, hypomanic episodes are not severe enough to cause marked impairment, and there is no psychosis; therefore, these episodes can be managed in an ambulatory setting. Pharmacotherapy is similar to that for mania, but higher doses may be required for the latter.

Acute Bipolar Depression

Suicidal and self-harm risk has priority in managing patients with bipolar disorder who present with an acute depressive episode because most suicide deaths in patients with BD occur during this phase. Patients may or may not require hospitalization.

For patients not already taking long-term medication for BD, first-line monotherapy includes quetiapine, olanzapine, or lurasidone (has not been studied in acute bipolar mania). Combination treatment with olanzapine-fluoxetine, lithium plus lamotrigine, and lurasidone plus lithium or valproate may also be considered.

Consider cognitive behavioral therapy (CBT) as an add-on to pharmacotherapy. However, never consider CBT as monotherapy because there is minimal evidence to support psychological treatments without pharmacotherapy in treating acute bipolar depression.

Also, consider adding ECT for refractory bipolar depression or as a first-line treatment in the presence of psychotic features and a high risk of suicide.

For patients presenting with a depressive episode while taking long-term medication (breakthrough episode), make sure their current treatments are likely to protect them from a manic relapse (eg, mood stabilizer or antipsychotic). When applicable, check the medication dose, patient adherence, drug-drug interactions, and serum concentrations. Also, inquire about current stressors, alcohol or substance use, and psychosocial intervention adherence.

Generally, treatment options for BD-II depression are similar to those for BD-I depression.

Antidepressant medications should not be used as monotherapy in most patients with bipolar disorder, as available evidence does not support their efficacy, and there is a risk of a switch to mania or mood instability during an episode of bipolar depression. Antidepressants can be administered adjunctively to mood stabilizers (eg, lithium and lamotrigine) and second-generation antipsychotics.

Maintenance Treatment

Most patients with bipolar disorder will require maintenance treatment for many years, possibly lifelong, to prevent recurrent episodes and restore their pre-illness functioning. The current recommendation is for continuous rather than intermittent treatment, with treatments that were effective during the acute phase often continued initially to prevent early relapse. Mood stabilizers and atypical antipsychotics alone or in combination are the mainstays of maintenance pharmacotherapy.

There is substantial evidence showing lithium monotherapy’s effectiveness against manic, depressive, and mixed relapse. Additionally, lithium is associated with a decreased risk of suicide in patients with BD. Monitoring during treatment, including serum lithium concentrations, is a standard of care.

In addition to the individualized pharmacotherapy plan, essential components of maintenance treatment include medication adherence, primary prevention and treatment for psychiatric and medical comorbidities, and psychotherapy when appropriate. Suicidality surveillance is critical throughout the maintenance phase.

Differential Diagnosis

The differential diagnosis of bipolar disorder includes other conditions characterized by depression, impulsivity, mood lability, anxiety, cognitive dysfunction, and psychosis. The most common differential diagnoses are MDD, schizophrenia, anxiety disorders, substance use disorders, borderline personality disorder, and in the pediatric age group, attention-deficit/hyperactivity disorder and oppositional defiant disorder.[18][30]

Prognosis

Bipolar disorder is one of the top 10 leading causes of disability worldwide.[31] A recent meta-analysis showed that patients with BD “experienced reduced life expectancy relative to the general population, with approximately 13 years of potential life lost.” Additionally, patients with bipolar disorder showed a greater reduction in lifespan relative to the general population than patients with common mental health disorders, including anxiety and depressive disorders, and life expectancy was significantly lower in men with BD than in women with BD.[32] A different meta-analysis showed that all-cause mortality in patients with BD is double that expected in the general population. Natural deaths occurred over 1.5 times greater in BD, comprised of an “almost double risk of deaths from circulatory illnesses (heart attacks, strokes, etc) and 3 times the risk of deaths from respiratory illness (COPD, asthma, etc).” Unnatural deaths occurred approximately 7 times more often than in the general population, with an increased suicide risk of approximately 14 times and an increased risk of other violent deaths of almost 4 times. Deaths by all causes studied were similarly increased in men and women.[33] A more recent systematic review of the association between completed suicide and bipolar disorder showed an approximately 20- to 30-fold greater suicide rate in bipolar disorder than in the general population.[34]

Complications

Individuals with bipolar disorder show a markedly increased risk of premature death due to the increased risk of suicide and medical comorbidities, including cardiovascular, respiratory, and endocrine causes.[35] More than half of patients are overweight or obese, which appears to be independent of treatment with weight-promoting psychotropic medications.[36] One-third of patients with bipolar disorder also meet the criteria for metabolic syndrome, which increases the risks of heart disease and stroke.[37] Additionally, attempted suicides are more common among patients with concurrent metabolic syndrome.[37] Comorbid overweight and obesity are associated with a more severe course, an increased lifetime number of depressive and manic episodes, poorer response to pharmacotherapy, and heightened suicide risk.[22][38] Migraine is also associated with bipolar disorder.[39]

Psychiatric comorbidity is present in 50 to 70% of patients with BD. Of those diagnosed with the condition, 70% to 90% meet the criteria for generalized anxiety disorder, social anxiety disorder, or panic disorder, and 30 to 50% for alcohol and other substance use disorders.[40][41][42] Psychiatric comorbidities in patients with bipolar disorder are associated with a more severe course, more frequent depressive and manic episodes, and reduced quality of life.[22] Up to half of patients with BD have a comorbid personality disorder, particularly borderline personality disorder, and 10 to 20% have a binge eating disorder, leading to more frequent mood episodes and higher rates of suicidality and alcohol and substance use disorders.[43][44]