Bipolar Disorders

How to Cite This Chapter: Cunningham JEA, MacLeod CE, Frey BN. Bipolar Disorders. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed May 30, 2024.
Last Updated: April 5, 2021
Last Reviewed: August 13, 2021
Chapter Information

Definition and epidemiologyTop

Bipolar and related disorders are severe affective disorders that are associated with recurrent episodes of clinically significant elevated mood (ie, mania and hypomania), depression, and periods of clinical remission. There are 2 types of bipolar disorders (BDs): bipolar I disorder (BD-I) and bipolar II disorder (BD-II). As defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), a diagnosis of BD-I requires the presence of ≥1 manic episode, whereas BD-II is defined by the presence of ≥1 hypomanic episode and ≥1 major depressive episode in the absence of a history of manic episodes. Both are contingent on the absence of another psychiatric disorder better explaining the symptoms, such as schizoaffective disorder. Cyclothymic disorder is defined by the presence of both hypomanic and depressive periods for ≥2 years, without meeting the full criteria for manic, hypomanic, or major depressive episodes. Cyclothymic disorder and other-specified and unspecified bipolar and related disorders will not be the focus of this chapter. Along with schizophrenia, BD is the psychiatric condition with the highest risk of death by suicide. The Global Burden of Disease Study 2015 ranked BD as one of the leading causes of disability worldwide in terms of years lived with disability.

BDs represent an estimated lifetime and 12-month prevalence of 2.4% and 1.5%, respectively, across multiple countries. Canadian studies approximate lifetime rates of 0.87% for BD-I and 0.57% for BD-II. BD-I affects men and women equally, while women are predominantly affected by BD-II. Usually the first presentation is with a depressive episode, with a manic or hypomanic episode occurring later. Rates of change in diagnosis from major depressive disorder to a BD is 1.25% per year, although higher rates have also been reported. Unfortunately, the majority of individuals with BDs are not accurately diagnosed until ~6 to 10 years after their first presentation to a health-care professional.

Risk factorsTop

Risk Factors for Developing BD

Genetic factors pose a considerable risk for developing BD. Heritability is estimated at 58% to 85%. Genome-wide association studies have identified ≥30 significant loci encoding different aspects of neuronal functioning, regulation of endocannabinoid signaling, and insulin secretion. However, genetic variants of risk may account for only 25% of heritability, and complex gene-environment interactions, including epigenetics, may be involved.

A number of environmental risk factors have been proposed, including childhood maltreatment, seropositivity to Toxoplasma gondii, and traumatic brain injury.

Long-term BD has been associated with progressive brain changes, such as alterations in gray and white matter, compared with healthy individuals. Current hypotheses propose that neuroinflammation, oxidative stress, mitochondrial dysfunction, and aberrations in the hypothalamic-pituitary-adrenal axis may constitute some of the underlying neurobiologic changes.

Risk Factors for Worse Prognosis

Compared with the general population, persons with BD have twice the mortality rate, including elevated rates of suicide and mortality from cardiovascular diseases. Poor prognostic factors include comorbid medical and psychiatric conditions (eg, metabolic syndrome, diabetes, irritable bowel syndrome, anxiety, personality disorders, and substance use disorders). BD has a natural history characterized by a progressive reduction in the duration of clinical remission, especially if there is poor treatment adherence.

Risk Factors for Suicidal Behavior

As a major cause of death for patients with BD, suicide risk identification and prevention are of great concern. An estimated 25% to 50% of patients with BD attempt suicide at least once over their lifetime, while 8% to 19% complete the attempt. Suicide rates may be 20-fold greater than in the general population, especially in patients not receiving treatment. Patients with predominantly depressive polarity are more at risk of attempting suicide, as are those with a history of past suicidal behavior, first-degree family history of suicide, comorbid personality and substance use disorders, and hopelessness as well as those of female sex and young age of onset. Death by suicide is, however, more strongly associated with male sex, older age, presence of current substance use disorder, and first-degree family history of suicide.

Clinical Features and DiagnosisTop

Manic Episode

A manic episode is defined by the DSM-5 as a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased goal-directed activity or energy lasting ≥1 week for most of the day, nearly every day (or any duration if hospitalization is necessary). Symptoms must include ≥3 (or 4, if mood is only irritable) of the following:

1) Inflated self-esteem or grandiosity.

2) Decreased need for sleep.

3) Increased talkativeness or pressured speech.

4) Flight of ideas.

5) Distractibility.

6) Psychomotor agitation or increase in goal-directed activity.

7) Excessive involvement in activities with a high potential for painful consequences.

To meet criteria, social or occupational functioning must be impaired as a result of these symptoms, there must be a hospital admission, or psychotic features must be present (as many as 75% of patients endorse psychotic symptoms). Manic symptoms must not be attributable to substance use or the effects of any other medication or another medical condition. However, if a manic episode presents while the patient is undergoing antidepressant therapy and the symptoms persist beyond the physiologic treatment effect, this is sufficient evidence for a manic episode.

Hypomanic Episode

While also defined as a distinct period of abnormally and persistently elevated, expansive, or irritable mood and increased goal-directed activity or energy, a hypomanic episode differs from a manic episode in terms of both duration and severity. Three (or 4, if mood is only irritable) of the core symptoms listed above must be present for ≥4 consecutive days, for most of the day, nearly every day. Patients experiencing hypomania show fewer profound signs of impairment when compared with mania; however, there must be an unequivocal change in functioning that is observable by others and it must not be marked enough to cause impairment in functioning or necessitate hospitalization, nor can there be psychotic symptoms. Again, symptoms must not be attributable to a substance; however, hypomanic symptoms emerging during antidepressant use and persisting past the physiologic effect of treatment are sufficient evidence for a hypomanic episode.

Major Depressive Episode

A major depressive episode is defined by ≥5 core symptoms, ≥1 of which must include depressed mood, diminished interest or pleasure in activities, or both, for most of the day, nearly every day for ≥2 weeks. Other core symptoms include:

1) Changes in appetite or significant changes in weight.

2) Insomnia or hypersomnia.

3) Psychomotor agitation or retardation.

4) Fatigue or loss of energy.

5) Feelings of worthlessness or excessive or inappropriate guilt.

6) Difficulty concentrating or indecisiveness.

7) Recurrent thoughts of death or suicidal ideation or intent.

While the DSM-5 criteria for a major depressive episode are the same for both BD and major depressive disorder, depressive episodes in BD may present in unique ways. For example, depressive symptoms may present prior to manic or hypomanic episodes earlier in life, necessitating consideration of BD on the differential diagnosis. Other defining traits are frequent episodes of shorter duration, a relation to substance misuse, a relation to stressful life events, and atypical symptoms such as hypersomnia, emotional lability, and weight instability. Depressive episodes in BD also present with psychosis, psychomotor retardation, and catatonia more frequently than major depressive disorder does.


General Considerations

This treatment section details the recommended treatment strategies for acute manic, hypomanic, and depressive episodes, as well as maintenance therapies. Given the nature of BD as a chronic and relapsing disorder, a multidisciplinary approach to management should be undertaken whenever possible. For all patients psychoeducation should be prioritized and pharmacotherapy should be undertaken. The health-care team (ideally involving a primary care practitioner, psychiatrist, and allied health-care professionals) should work together to provide ongoing monitoring, treatment adjustments, psychosocial support, and community resources. A shared decision-making model with a strong therapeutic alliance leads to improved treatment adherence and outcomes.

Psychosocial Interventions

While pharmacotherapy is necessary for the treatment of individuals with BD, there may also be a role for psychosocial interventions, particularly concurrent with maintenance therapy and during depressive episodes. Psychosocial interventions during maintenance include psychoeducation, cognitive behavioral therapy, peer support, family-focused therapy, and interpersonal and social rhythm therapy and should be considered as adjunctive treatments for individuals with BD.

Pharmacologic Treatment

Pharmacotherapy is the mainstay of successful treatment for BD. Pharmacologic treatments can be categorized into those targeting acute manic and hypomanic episodes, those targeting acute depressive episodes, and maintenance therapies.

1. Acute manic and hypomanic episodes: Treatment of acute manic and hypomanic episodes typically involves the use of mood stabilizers, antipsychotics, or both. While lithium is the mainstream mood stabilizer for acute mania, long-term maintenance second-generation antipsychotics usually work faster than lithium, particularly in more severe disease. The latest Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines present hierarchical rankings of first-line agents for the management of manic episodes (Table 1), both as monotherapies and in combination. If these agents are not effective or tolerated, second-line and third-line options are also available.

2. Acute depressive episodes: Most of the disease burden over the course of BD is associated with depressive episodes: Individuals with BD spend one-third of their lives suffering from syndromal or subsyndromal depressive symptoms. The presence of syndromal or subsyndromal depression is one of the main predictors of poor psychosocial functioning, low quality of life, and risk of suicide. The CANMAT guidelines recommend the following first-line agents for the management of acute BD-I depression, in rank order: quetiapine, lurasidone with lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to insufficient high quality evidence studies, imprecision, and potential bias. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disorders. 2018 Mar;20(2):97-170. doi: 10.1111/bdi.12609. Epub 2018 Mar 14. PMID: 29536616; PMCID: PMC5947163. Second-line options include divalproex, selective serotonin reuptake inhibitors (SSRIs) or bupropion adjunctive to an antimanic agent, electroconvulsive therapy (ECT), cariprazine, or olanzapine with fluoxetine.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to insufficient high quality evidence studies, imprecision, and potential bias. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disorders. 2018 Mar;20(2):97-170. doi: 10.1111/bdi.12609. Epub 2018 Mar 14. PMID: 29536616; PMCID: PMC5947163.

3. Maintenance therapy: Given the highly recurrent and chronic nature of BD and extensive data showing worsening of clinical outcomes particularly in untreated cases, the long-term use of prophylactic treatment is indicated in virtually all cases of well-established BD. Pharmacologic treatments and psychosocial interventions, including lifestyle modifications, are critical for long-term clinical remission. The CANMAT guidelines recommend a hierarchical list of first-line agents for the maintenance phase of BD treatment (Table 2). If these agents are not effective or tolerated, second-line and third-line options are also available.

Monitoring and Adverse Effect ManagementTop

Prior to beginning pharmacotherapy for BD, a full baseline medical evaluation should be conducted. This should include body mass index assessment and laboratory investigations (Table 3). There should be a discussion with women of childbearing age regarding the potential for lamotrigine and carbamazepine to affect the efficacy of oral contraceptive pills, as well as the possibility of teratogenicity with certain medications such as divalproex, carbamazepine, and lithium.

For patients taking lithium, there should be regular monitoring (every 6-12 months) of thyroid function, renal function, and plasma calcium concentration. Patients taking lithium should have their serum medication levels (trough) assessed on a regular basis. Our pattern of practice is to check it 1 week after each dose change. Then, once the final desired dose is achieved, lithium levels should be checked every 6 to 12 months. The recommended therapeutic level of lithium is typically 0.6 to 1.2 mEq/L in adults and 0.4 to 0.8 mEq/L in individuals aged >60 years. Lithium treatment has been associated with weight gain, as well as with nausea, vomiting, and diarrhea, which may be reduced by gradual dose titration and slow-release preparations. This medication should preferably be taken with food. Lithium has a potential to induce both acute renal toxicity and chronic kidney disease (with chronic use of the medication). Many patients (up to 70%) taking lithium experience polyuria. Nephrogenic diabetes insipidus has been associated with long-term therapy with lithium, which may occur in up to 10% to 20% of patients. Plasma electrolytes, creatinine, and estimated glomerular filtration rate (eGFR) should be measured in patients taking lithium every 6 to 12 months, and our pattern of practice is to consult a nephrologist if the eGFR is rapidly declining, if it falls <45 in 2 consecutive readings, or if there is sufficient clinical concern. In addition, there is an increased risk of QT prolongation or T-wave abnormalities in patients taking lithium, especially in older individuals.

Lithium treatment is also associated with the development of hypothyroidism and hyperparathyroidism, so patients on lithium treatment should undergo routine thyroid and serum calcium screening. Hypothyroidism is not typically an indication for cessation of lithium treatment; in these cases thyroid supplementation is recommended. Up to 10% of patients taking lithium may experience tremor. Lithium is also associated with acne, psoriasis, hair loss, eczema, hidradenitis suppurativa, and mucosal lesions.

For patients taking divalproex, a menstrual history, complete blood count, and liver function tests should be taken at 3- to 6-month intervals for 1 year and yearly thereafter. These patients should have their serum medication levels (trough) assessed on a regular basis. Divalproex has also been associated with weight gain, as well as with nausea, vomiting, and diarrhea, which may be reduced with gradual dose titration, slow-release preparations, and by instructing the patient to take the medication with food. Divalproex may lead to sedation and subsequently contribute to medication nonadherence. Up to 10% of patients taking divalproex may experience tremor. Divalproex is also very occasionally associated with the onset of hyperammonemic encephalopathy; in patients with new-onset neurologic symptoms, this should be considered on the differential diagnosis, and if hyperammonemia is present, divalproex should be immediately discontinued, as this condition can be fatal.

Patients taking lamotrigine or carbamazepine should be educated regarding the risks of skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrosis. If these develop, the patients require urgent medical evaluation and possible medication discontinuation and may require other therapeutics to control the rash and treat BD. Additionally, patients at higher genetic risk of having the human leukocyte antigen (HLA)-B*1502 allele (those of Asian ancestry) should be genotyped prior to treatment with carbamazepine due to higher risk of these adverse events. A gradual titration of lamotrigine following a starting daily dose of 25 mg may decrease the risk of serious skin rash in patients taking the drug. Patients taking carbamazepine should have serum sodium levels measured annually due to risk of hyponatremia. Also, they must have their serum carbamazepine level (trough) assessed on a regular basis.

Antipsychotic medications are associated with a variety of possible adverse effects. These may include metabolic changes, extrapyramidal symptoms, and cardiac effects. In brief, the following should be serially followed in patients taking these medications: weight, waist circumference, blood pressure, glucose screening, and screening for extrapyramidal symptoms (following dose changes or new medications). More on monitoring and adverse effect management for antipsychotic medications: see Adverse Effects of Psychotropic Medications; see Schizophrenia Spectrum and Other Psychotic Disorders.


Table 16.6-1. Hierarchical ranking of first-line treatments for the management of manic episodes, with suggested starting doses



First-line monotherapies


300-600 mg/d; final dosage depends on serum medication levels, clinical response, and age (see text)


100 mg/d and increasing daily by 100 mg to a total of 600-800 mg/d


250-500 mg/d (target 1000-1500 mg/d)


5 mg bid (target 5-10 mg bid)


15 mg/d (target 15-30 mg/d)


3 mg/d (target 6-12 mg/d)


2-3 mg/d (target 2-4 mg/d)


Day 1: 1.5 mg/d; day 2+: 3 mg/d

First-line combination therapies

Quetiapine + lithium/divalproex

 See above

Aripiprazole + lithium/divalproex

 See above

Risperidone + lithium/divalproex

 See above

Asenapine + lithium/divalproex

 See above

Table 16.6-2. Hierarchical ranking of first-line maintenance treatments in bipolar disorder, with suggested starting doses




Typically 600-1200 mg/d depending on serum medication levels


Typically 300-600 mg/d


Typically 1000-1500 mg/d


100-300 mg/d


5 mg bid


5-30 mg/d

Quetiapine + lithium/divalproex

See above

Aripiprazole + lithium/divalproex

See above

Aripiprazole OM

400 mg every 3-4 weeks

OM, once monthly.

Table 16.6-3. Baseline and follow-up laboratory investigations in patients with bipolar disorders treated with pharmacotherapy

Baseline tests

– CBC with platelets

– Fasting glucose

– Fasting lipid profile (total cholesterol, VLDL, LDL, HDL, triglycerides)

– Electrolytes and calcium

– Liver enzymes

– Serum bilirubin

– Prothrombin time and partial thromboplastin time

– Urinalysis and urine toxicology (for substance use)

– Serum creatinine, 24-h creatinine clearance (if history of renal disease), and eGFR


– ECG if age >40 years or if indicated

– Prolactin

– Pregnancy test (if relevant)

Follow-up testsa

– Lithium level: 1 week after each dose change, then every 6-12 months during maintenance

– TSH: 4-6 weeks after lithium initiation, then every 6-12 months

– CBC, electrolytes, eGFR/creatinine, calcium: 4-6 weeks after lithium initiation, then every 6-12 months

a Laboratory tests may be conducted more frequently depending on clinical concern (for example, DI or symptoms suggestive of hypothyroidism).

CBC, complete blood count; DI, diabetes insipidus; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TSH, thyroid-stimulating hormone; VLDL, very low–density lipoprotein.

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