Bipolar Disorders

Bipolar disorders are a group of chronic mental disorders that include bipolar I disorder and bipolar II disorder.

Bipolar I disorder is defined by the presence of a syndromic manic episode and bipolar II disorder by the presence of a syndromic hypomanic episode and a major depressive episode. Although some people with bipolar I disorder may experience only manic or predominantly manic episodes, most people with bipolar I disorder are affected differently by depressive symptoms and episodes.

A finding widely replicated in studies of people with bipolar disorders is the early age of onset, in which more than 70% of those affected manifest the clinical characteristics of the disease before the age of 25.

Despite the achievements and productivity of many people with bipolar disorders, the majority of individuals involved have substantial illness-related disability, reduced psychosocial functioning, and increased economic costs. Evidence also indicates that a considerable percentage of the cost of bipolar disorders is due to chronic noncommunicable diseases (e.g., cardiovascular disease).

Mortality studies indicate that bipolar disorders, like schizophrenia, are associated with a loss of approximately 10 to 20 years of potential life. The mortality gap between people with bipolar disorders and the general population is enormous and increasing, especially in younger populations (ages 15 to 29). Cardiovascular disease is the most common cause of premature mortality.

People with bipolar disorders are approximately 20 to 30 times more likely to die by suicide compared to the general population. In fact, approximately 30 to 50 percent of adults with bipolar disorders have a lifetime history of suicide attempts, and it is estimated that 15 to 20 percent of affected individuals die by suicide.

Suicide attempts and death by suicide are more likely to occur in people who have depressive or mixed symptoms as part of their bipolar disorder than in those who do not. Available evidence also suggests that bipolar II disorder has a higher suicide rate than bipolar I disorder, underscoring its complexity and severity.

The objective of this report is to provide an overview of the diagnostic, pathogenic, and treatment considerations in bipolar disorders.

The diagnosis of bipolar disorders is made through a comprehensive clinical evaluation and is supplemented, when possible, with information from third parties (e.g., family members). Unfortunately, there is no biomarker that informs the diagnosis, prognosis, or treatment outcome of bipolar disorders.

The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) has amended the previous edition’s revised text diagnostic criteria for mania and hypomania to include a persistent increase in energy or activity along with an elevated, expansive or irritable mood as essential elements. Therefore, diagnosing mania based solely on mood instability is no longer sufficient; instead, the coexistence of mood instability with increased energy or activity is required.

Another important change was the replacement of mixed states (i.e., mania and syndromic depression) with the mixed features specifier. The DSM-5 defined the mixed feature specifier as the presence of symptoms of opposite polarity during a manic or major depressive episode. Although some symptoms of mania and depression overlap (e.g., agitation), these overlapping symptoms are not included in the diagnostic criteria for mixed features.

Clinicians should be aware that people with bipolar disorders who present with depression will often manifest symptoms of anxiety, agitation, anger-irritability, and impaired attention-distraction , all of which are highly suggestive of mixed features.

The differential diagnosis of bipolar disorders includes other mental disorders characterized by impulsivity, affective instability, anxiety, cognitive disorganization, depression and psychosis. For example, although depression is the index and predominant presentation of bipolar disorder, differentiating bipolar disorder from major depressive disorder is the most common clinical challenge for most clinicians .

Characteristics that would suggest a greater likelihood that a patient with depression has bipolar disorder, rather than major depressive disorder, include younger age at illness onset, phenomenology (e.g., hyperphagia, hypersomnia, and psychoses are more common in bipolar disorders than in major depressive disorder), a higher frequency of affective episodes, pattern of comorbidity (e.g., substance use disorders, anxiety disorders, binge eating disorders, and migraines affect disproportionately to people with bipolar disorders) and a family history of psychopathology. An insufficient response to antidepressants, which is known to occur more frequently in adults with bipolar disorders than in those with major depressive disorder, could also inform the diagnosis of bipolar disorders.

Other differential diagnoses to consider in people with possible bipolar disorders are attention deficit hyperactivity disorder (ADHD), borderline personality disorder, substance use disorders, and schizophrenia.

Differentiation of bipolar disorders from ADHD is based on an earlier age of symptom onset in ADHD than in bipolar disorders and the absence of psychosis and affective episodes in people with ADHD.

The distinction between bipolar disorders and borderline personality disorder is based on the core attachment disturbance that is central to the definition of borderline personality disorder but is not a defining characteristic of bipolar disorders. In contrast, syndromic affective episodes and associated alterations in circadian rhythm are more suggestive of bipolar disorder than borderline personality disorder. Furthermore, unlike bipolar disorder, the psychopathology of borderline personality disorder often attenuates with age.

Differentiating bipolar disorders from alcohol use disorders and substance use disorders is done by observing the patient during periods of sobriety (whenever possible). Clinicians are encouraged to be alert to the association between psychoactive substance use and the presence of psychopathology. The presence of phenomenology related to bipolar disorders before the onset of alcohol or substance use disorders, or bipolar phenomenology that persists during periods of sobriety, is more likely to suggest an underlying diagnosis of bipolar disorder.

It is often difficult to distinguish bipolar disorders from schizophrenia in the first episode of the illness because both conditions frequently present with prominent psychosis and mood symptoms.

Longitudinally, however, people with schizophrenia exhibit psychosis as a primary clinical presentation in the absence of clinically significant mood symptoms, and are also more likely to show greater psychosocial impairments and less favorable illness trajectories than people with bipolar disorders. In contrast, people with bipolar disorders exhibit affective episodes and symptoms as the predominant presentation of the illness and, in general, do not present the degree of psychosocial impairment that is often observed in people with schizophrenia.

Most people with bipolar disorders do not receive an accurate diagnosis until approximately 6 to 10 years after first contact with a primary care physician, a specialist, or both, despite having the clinical characteristics of the illness.

However, misdiagnosis of bipolar disorders is often found when a patient transitions from major depressive disorder to bipolar disorder. For example, most people with bipolar disorders have depressive episodes as their initial presentation, with hypomania and mania occurring later.

Clinicians should remain vigilant for bipolar disorders in anyone who initially tests negative for bipolar disorders but subsequently develops clinically significant affective symptoms.

High rates of misdiagnosis and the longitudinal transition from major depressive disorder to bipolar disorders drive routine and systematic screening for bipolar disorders in all patients presenting with depressive symptomatology.

Several self-report screening tools for bipolar disorders have been validated and are available free of charge in multiple languages. The most studied screening resources are the Mood Disorders Questionnaire and the Hypomania Checklist. These surveys are intended for use at the point of care and, if positive, invite the need for careful and thorough clinical evaluation.

The lifetime prevalence of psychiatric and medical comorbidities in adults with bipolar disorders is estimated to be approximately 90%. Additionally, approximately 50% of people with bipolar disorders are affected by polymorbidity (i.e., have three or more comorbid conditions).

Comorbidity in bipolar disorders is associated with an earlier age of onset and more complex presentation of bipolar disorders, higher rates of suicidality, and less favorable treatment responses and prognosis than bipolar disorders without comorbidity.

Anxiety disorders are the most common psychiatric comorbidity in people with bipolar disorders; Approximately 70 to 90% of people with bipolar disorders meet criteria for generalized anxiety disorder, social anxiety disorder, or panic disorder.

About 30 to 50 percent of adults with bipolar disorders have a substance use disorder or an alcohol use disorder, and 25 to 45 percent meet criteria for ADHD. Personality disorders (20-40%) and binge eating disorder (10-20%) are also recognized as common in people with bipolar disorders.

The high prevalence of psychiatric comorbidity in bipolar disorders could, in some cases, reflect an overlapping pathogenesis. For example, brain regions implicated in affective instability and cognitive function in bipolar disorders are also implicated in ADHD and anxiety disorders.

In some cases, what appears to be a comorbidity in childhood, manifesting as ADHD, anxiety disorders, or both, could in fact be a phenotypic variant of bipolar disorders rather than a discrete comorbid condition. The higher prevalence of alcohol and drug abuse in people with multiple episodes of bipolar disorder compared with first episode of bipolar disorder suggests a progressive impairment in cognitive control, reward-based decision making, or both.

Further evidence of shared pathogenesis between bipolar disorders and comorbidities is the high prevalence of cardiovascular disorders at index presentation in individuals with bipolar disorders.

Bipolar disorder is a risk factor for cardiovascular disease, reflecting intrinsic and shared causal substrates. The staggering rates of cardiovascular disease and related risk factors (e.g., obesity) and their contribution to premature mortality in people with bipolar disorders are a critical reason to prioritize physical and mental health.

The heritability of bipolar disorders is approximately 60 to 80%. Bipolar I disorder is closely related genetically to schizophrenia and bipolar II disorder to major depressive disorder. Despite its genetic basis, tests to diagnose bipolar disorders are not currently validated or recommended and diagnosis remains a clinical endeavor.

A new technology that could provide insight into the pathogenesis of bipolar disorders and the mechanism of action of treatments is human induced pluripotent stem cells.

Pluripotent stem cells are derived from somatic cells that are easily accessible (e.g., oral mucosa). Preliminary evidence obtained through the use of this technology suggests that mitochondrial dysfunction could be relevant to the pathogenesis of bipolar disorders. These observations are consistent with the results of studies using magnetic resonance spectroscopy, which have also implicated alterations in mitochondrial function.

Despite the promise of this new research, it is still in the study phase and the role these methods have in developing disease models and new therapies is unknown.

Replicated evidence suggests that inflammatory alteration could contribute to the pathogenesis of bipolar disorders. The infectious activation of the inflammatory system in bipolar disorders is intuited by the high seropositivity for infectious agents in the uterus (for example, Toxoplasma gondii, cytomegalovirus and herpes simplex virus).

Despite accumulating evidence implicating inflammatory systems in the pathogenesis of bipolar disorders, the precise role of these systems is not yet fully understood. Similarly, several lines of research suggest that alterations in central insulin signaling and function could also be part of the pathogenesis of bipolar disorders in some cases.

The neurobiological progression hypothesis is the notion that people with bipolar disorders may exhibit progressive neurobiological changes depending on the duration of the illness and the number of previous episodes. However, the generalizability of these data is limited by the fact that many patients included in these studies have a history of multiple hospitalizations, and therefore the findings may not apply to adults with bipolar disorders but no history of hospitalization. .

The therapeutic objectives in bipolar disorders are: prevention and treatment of hypomania, mania and depression syndromes; the decrease in interepisodic depressive symptoms; normalization of circadian alterations; the improvement and preservation of cognitive function; the treatment and prevention of psychiatric and medical comorbidity; progress in patient-reported outcomes (e.g., quality of life) and reduction in suicidality.

The relapse rate for people recovering from their first episode of mania is approximately 40 to 60% within 1 to 2 years. In general, recovery rates are higher for people with fewer episodes and shorter durations of illness, underscoring the need for timely diagnosis and initiation of effective treatment.

Integrating specialized services into the continuum of care has been shown to improve health outcomes in people with bipolar disorders. In particular, increased physical health surveillance should be prioritized in adults with bipolar disorders considering high rates of chronic medical disorders, habitual inactivity, poor food choices, smoking, weight gain, and concerns about medication tolerability.

The basic principles in the management of bipolar disorders are to incorporate measurement-based care, prioritize treatments that have the most compelling evidence base, consider short- and long-term safety and tolerability, integrate treatment decisions informed by guidelines, prioritize mental and physical well-being, and involve patients and stakeholders in the decision-making process.

The primary therapy modalities in bipolar disorders are pharmacotherapeutic, psychosocial, neurostimulatory (e.g., electroconvulsive therapy), and lifestyle modification. Pharmacological treatments are the foundation of any treatment plan and have been studied to a greater extent than other modalities, especially for the management of acute mania.

Pharmacological treatments are the standard of care for adults experiencing an acute manic episode. Acute mania is a medical emergency that requires urgent treatment to reduce the risk of harm to the patient and others. Antimanic efficacy has been established for multiple agents, but particularly for the antipsychotics, lithium, divalproex, and carbamazepine.

Antipsychotic agents are associated with considerable tolerability problems that are particularly relevant during long-term exposure. These include weight gain, metabolic disturbances, elevated prolactin, sedation, somnolence, akathisia, heart rate-corrected QT interval prolongation, and tardive dyskinesia.

Lithium is a well - established antimanic agent that is also capable of attenuating depressive symptoms. Lithium is considered the gold standard agent for stabilizing mood. Predictors of a good response to treatment include well-defined episodes of mania and depression separated by periods of complete remission, absence of rapid cycling, mixed mood and psychotic symptoms, family history of bipolar disorders, short illness duration before administration. of lithium, advanced age at onset and low body mass index. The anti-suicide effects of lithium are another advantage.

Adverse effects include tremor, polyuria, cognitive impairment, and weight gain. Safety concerns regarding lithium include narrow therapeutic index, overdose, hypothyroidism, drug interactions, long-term renal toxicity, and teratogenicity.

Although divalproex is effective in mania, its effectiveness in depression and long-term prevention of recurrence have not been well established. Additionally, it has many tolerability and safety concerns, including menstrual irregularities in women of reproductive age, an association with polycystic ovary syndrome, hepatotoxicity, pancreatitis, and teratogenicity.

Like divalproex, carbamazepine is effective in acute mania but there is insufficient evidence to demonstrate long-term prophylactic effects. Additional limitations are drug interactions due to the ability of carbamazepine to induce its own elimination and that of other medications (i.e., cytochrome P450 substrates) and concerns about tolerability and safety (e.g., cognitive impairment, skin rash , tremors, teratogenicity, Stevens-Johnson syndrome)

Effective treatments are cariprazine, lurasidone, quetiapine, and the olanzapine-fluoxetine combination.

Cariprazine is a dopamine and serotonin receptor partial agonist and antagonist (previously described as a second-generation antipsychotic) that has also demonstrated efficacy in the treatment of acute bipolar depression as monotherapy . It has a minimal chance of causing weight gain and does not negatively affect metabolic variables but is not yet widely available.

Lurasidone has not been studied in acute bipolar mania. It has a negligible chance of causing weight gain and is not known to negatively affect metabolic homeostasis.

Quetiapine is effective in both bipolar I and bipolar II depression and has been shown to help prevent the recurrence of mania and depression.

There is ongoing controversy regarding the safe and appropriate use of antidepressants in bipolar disorders. These drugs are associated with treatment-emergent mania, mood destabilization, induction of dysphoria, and suicidality in people with bipolar disorders.

The International Society of Bipolar Disorders consensus statement recommends the use of antidepressants as adjuvant agents in people who have stable episodic bipolar depression and who do not present with rapid cycling, mixed features, a history of prior antidepressant-induced destabilization, or combinations of these presentations.

Some agents that are approved in some parts of the world as maintenance treatments for bipolar disorders have demonstrated the ability to delay the onset and reduce the recurrence of mania but not depression (e.g., risperidone and aripiprazole). Other agents (e.g., lamotrigine) have shown efficacy in maintaining antidepression, with less efficacy in preventing mania.

The enormous gap in the evidence base for maintenance treatments is largely a consequence of the complexity, costs, and ethical concerns in maintaining adults with bipolar disorders on placebo treatment for several years.

Lithium is an important first-line treatment for bipolar disorders and has demonstrated superiority over divalproex in preventing the recurrence of manic and depressive episodes.

There is evidence of efficacy as maintenance treatments in bipolar disorders for quetiapine and the long-acting injectable agents, risperidone and aripiprazole. Quetiapine has shown antidepressant efficacy but not risperidone or aripiprazole.

A separate line of evidence indicates that, like lithium, some long-acting injectable agents are capable of preventing rehospitalization in patients with bipolar disorders.

Promotion of patient self-management, primary prevention of psychiatric and medical comorbidity, compliance improvement strategies, and psychosocial treatment interventions are crucial elements of care.

Symptomatic and euthymic individuals, and unaffected first-degree relatives of people with bipolar disorders, show deficits in multiple domains of cognitive function (e.g., working memory). Some studies report on a subpopulation of people with bipolar disorders who may have progressive cognitive decline depending on the frequency of episodes.

Despite the importance of cognition, especially with respect to patient-reported outcomes (e.g., quality of life and psychosocial function), no treatment with robust scientific evidence has been well established.

Pragmatic and research strategies for the prevention and treatment of cognitive deficits in people with bipolar disorders include: treating symptoms until complete remission, preventing recurrence of episodes, discontinuing decognitive medications and substances (e.g., benzodiazepines), monitoring psychiatric and medical comorbidities, normalize sleep behavior and recommend physical activity.

New treatments for bipolar disorders target disparate effector systems, including molecular targets involved in neuroplasticity, neurotrophism, apoptosis, inflammation, oxidative stress, mitochondrial function, and metabolic pathways. Examples of such novel treatments are coenzyme Q10, N-acetylcysteine, statins, non-steroidal anti-inflammatory agents, omega-3 fatty acids, incretin-based therapies, insulin, nitrous oxide, ketamine, prebiotics, probiotics and antibiotics.

The main unmet needs in bipolar disorders are accurate and timely diagnosis and prompt implementation of effective therapies. Most people do not receive integrated care based on best practices. Closing this gap provides the greatest opportunity to reduce morbidity and mortality in patients with this pathology.

Despite the requirement for hypomania or mania in the diagnosis of bipolar disorders, the last decade of research has convincingly suggested that long-lasting deficits in general cognition, cognitive emotional processing, reward-based decision making, and chronobiology are the main mediators of health outcomes.

The availability of rapid onset treatments and mitigating suicidality are crucial for clinical decisions. The next decade will see testing of new agents for bipolar disorders targeting glutamate, GABAergic systems, immunoinflammatory systems, metabolic pathways, mitochondrial function, orexin systems, and intracellular neurotrophic and neuroplasticity cascades.

The use of technology awaits empirical evidence on its effects on health outcomes and cost in bipolar disorders, but holds promise for assessment and monitoring of phenomenology and for facilitating self-management.