Bipolar Disorder

Bipolar disorder is a highly recurrent psychiatric illness characterized by periods of manic/hypomanic features (distractibility, impulsivity, increased activity, decreased sleep, talkativeness, grandiosity, flight of ideas) with or without depressive symptoms. The etiology is unknown but is believed to be a complex interplay of different factors: genetic, neurobiologic, and environmental. Diagnosis is clinical, with the help of screening tools to determine mood and depression symptoms. Underlying substance use or medical conditions need to be ruled out with laboratory and imaging tests if indicated. Treatment of bipolar disorder varies based on the presenting features but usually involves pharmacotherapy with lithium, valproic acid, and/or antipsychotic medications. Other methods include psychotherapy and somatic therapies. Acute severe mania is a medical emergency and generally requires hospitalization. Maintenance therapy is typically necessary to reduce symptoms, prevent new mood episodes, decrease risk of suicide, and improve overall psychosocial functioning.

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Overview

Definition

Bipolar disorder is a psychiatric illness that is characterized by fluctuating periods of elevated mood (mania/hypomania) and periods of low mood (depression).

  • Mania: marked by severe symptoms, longer duration (≥ 1 week), and possible need for hospitalization
  • Hypomania: less severe symptoms than with mania, duration (< 1 week) without need for hospitalization  
  • Depressive episode: low mood, with lethargy, hopelessness, and changes in appetite and sleep

Bipolar disorders are associated with impairments in social, occupational, and cognitive functioning.

Epidemiology

  • Lifetime prevalence: 1%–3% in adults
  • Bipolar disorder I (≥ 1 episode of mania) affects both sexes with similar frequency.
  • Bipolar II (≥ 1 episode of hypomania and depression) is slightly more frequent among women. 
  • The disease manifests clinically in early adulthood at a mean age of 21 years.
  • About 10%–15% of adolescents diagnosed with major depression develop bipolar disorder I.

Pathophysiology

The precise etiology of bipolar disorder is unknown, but a complex interaction of different factors is believed to be involved in the pathogenesis.

  • Genetic predisposition:
    • ≥ ⅔ of cases have a family history of the disorder.
    • Individuals with a 1st-degree relative with bipolar disorder: 5%–10% risk of developing the disease
    • Those with monozygotic co-twin affected by bipolar disorder: 40%–70% risk
  • Biochemical and biologic influence:
    • Disruption of developmental processes affecting the brain networks controlling emotional behavior (prefrontal cortex and limbic structures)
    • A decrease in the amount of certain neurotransmitters (e.g., ↓ available norepinephrine in depression) might contribute.
    • Abnormalities in the hypothalamic–pituitary–adrenal–thyroid axis are noted to be common.
    • Studies show elevation of peripheral inflammatory cytokine levels as compared with healthy individuals.
  • Environmental:
    • Environmental factors can exacerbate the genetic and biologic defects in these individuals.
    • Factors include:
      • Abuse during childhood
      • Exposure to long-term stress
      • Sleep deprivation
      • Substance use
      • Advanced paternal age  (↑ mutations in spermatogenesis) 
  • Pharmacologic factors: Antidepressant use may precipitate bipolar and manic episodes in high-risk individuals.

Clinical Presentation

Clinical features

Bipolar disorder can present with:

  • Mania
  • Hypomania
  • Depression
  • Mixed features (meet criteria for both depressive and manic episodes simultaneously)

Major depression (55%) is usually the most common 1st lifetime episode, followed by mania (22%).

  • Given the likelihood of presenting with depressive episodes 1st, it is important to inquire about prior episodes of mania.
  • Additionally, criteria for at ≥ 1 manic (for bipolar I) or one hypomanic (for bipolar II) episode must be met.

Mania

Mania is a period of elevated, expansive, or irritable mood for ≥ 1 week, with symptoms for most of nearly every day.

  • Symptoms:
    • Distractibility
    • Impulsivity
      • Involvement in high-risk behavior or activities without thinking
      • Examples: buying sprees, multiple sexual encounters
    • Increased goal-directed activity or psychomotor agitation (plans many activities but unable to complete any tasks)
    • Decreased sleep (does not feel tired even after just a few hours of sleep)
    • Talkativeness
    • Grandiosity or increased self-esteem
    • Flight of ideas
  • Cause significant decline in function:
    •  A manic episode is a medical emergency, given the risk to self and others.
    • Example: cannot perform assigned job, financial loss, violence/assault on others
  • May have psychotic features (delusions, hallucinations, disorganized thinking and behavior)
  • Symptoms are not due to substance use or underlying medical conditions.

Hypomania

Hypomania is a period of elevated, expansive, or irritable mood for > 4 consecutive days but < 1 week.

  • Symptoms similar to those for manic episode but less severe:
    • Distractibility
    • Impulsivity
    • Increased goal-directed activity or psychomotor agitation
    • Decreased sleep
    • Talkativeness
    • Grandiosity or increased self-esteem
    • Flight of ideas
  • No significant decline in function, no need for hospitalization
  • Change in mood is observable by others.
  • No psychotic features
  • Symptoms are not due to substance use or medical conditions.

Major depressive disorder (MDD)

  • Period of depressed mood or loss of pleasure for ≥ 2 weeks
  • Symptoms:
    • Depressed mood, all day, every day
    • Anhedonia (reduced pleasure from previously enjoyable habits)
    • Appetite/weight changes (increase or decrease)
    • Sleep disturbance (increase or decrease)
    • Psychomotor agitation or retardation (individual is anxious and moves a lot, or barely moves)
    • Loss of energy
    • Feeling worthless or excessively guilty
    • Trouble concentrating
    • Suicidal ideation and/or attempts
  • Causes significant decline in function 
  • Symptoms are not due to substance use or medical conditions.

Mnemonic

  • DIG FAST is the mnemonic used to memorize manic episode symptoms:
    • Distractibility
    • Impulsivity
    • Grandiosity
    • Flight of ideas
    • Activity increase
    • Sleep decrease
    • Talkativeness 
  • SIGECAPS is the mnemonic used to memorize depression symptoms:
    • Sleep
    • Interest decreased
    • Guilt or worthlessness
    • Energy decreased
    • Concentration difficulties
    • Appetite disturbance
    • Psychomotor agitation/retardation
    • Suicidal thoughts

Diagnosis

Diagnostic approach

  • Screening (self-questionnaires and clinician-rated questionnaires) to classify depressive and manic mood symptoms, which includes:
    • Mood Disorder Questionnaire for manic episodes
    • Patient Health Questionnaire (PHQ-9) for depressive episodes
  • Assessment of suicide risk 
  • Laboratory evaluation (used to rule out other causes): 
    • Thyroid function
    • Urine drug screen 
    • Vitamin B12, vitamin D, folic acid levels 
  • Imaging: CT and MRI of brain to rule out organic causes
  • Must rule out these other causes of manic episodes:
    • Medical causes of mania:
      • Neurologic disorders (temporal lobe seizures, multiple sclerosis, viral encephalitis, and cerebral tumors)
      • Metabolic (hypothyroidism, Cushing syndrome)
      • Neoplasms
      • HIV infection
      • Systemic disorders (vitamin B12 deficiency, carcinoid syndrome, uremia)
    • Medication/substance-induced mania:
      • Corticosteroids
      • Sympathomimetics
      • Bronchodilators
      • Levodopa
      • Antidepressants
      • Dopamine agonists
      • Cocaine
      • Phencyclidine
      • Alcohol

Types of bipolar disorders

Bipolar disorder can be classified into several subtypes, depending on the severity and the associated features in the symptoms and history:

  • Bipolar I:
    • 1 manic episode in a lifetime is enough to make the diagnosis. 
    • Depressive episodes may present but are not required for diagnosis.
  • Bipolar II:
    • ≥ 1 hypomanic episode
    • ≥ 1 MDD episode
    • No history of manic episodes
  • Cyclothymic disorder:
    • Numerous periods of hypomania and depression within a distinct time frame, but symptoms do not meet the full criteria of hypomania and depression
    • Symptoms recur in ≥ 2 consecutive years, present ≥ ½ the time, and are not absent for > 2 consecutive months.
    • Cause distress or impaired function
  • Substance/medication-induced bipolar disorder: Mood episode(s) occur soon after use or intake of substance/medication.
  • Bipolar disorder due to another medical condition
  • Other specified bipolar disorder: does not meet full criteria (e.g., short duration of symptoms)

In the diagnosis of bipolar disorder, mood specifiers can be used, such as:

  • Rapid cycling:
    • Experience ≥ 4 mood episodes during a 12-month period
    • Episodes take place in any order.
  • Psychotic features
  • Mixed features
  • Catatonia
  • Anxious distress
  • Melancholic features
  • Peripartum onset
  • Atypical features

Management

Principles of therapy

  • Treatment of bipolar disorder begins with assessment of the individual’s ability to function and their need for hospitalization. 
  • Treatment options for bipolar I and II are the same.
  • Treatment is lifelong; options involve pharmacotherapy, behavioral therapy, and electroconvulsive therapy.
  • Medication classes (antimanic drugs (drugs that reduce manic/hypomanic symptoms)):
    • Lithium:
      • Mood stabilizer with narrow therapeutic index (monitoring needed)
      • About 80% of those with mania respond to lithium.
      • May be used as adjunct to treatment of major depression
    • 2nd-generation antipsychotics (SGAs; e.g., quetiapine, aripiprazole)
    • Anticonvulsants:
      • Valproic acid: wider therapeutic index than lithium
      • Carbamazepine: induces hepatic enzymes, which decrease levels of antipsychotics (so generally not combined with SGAs)
      • Lamotrigine: indicated for maintenance treatment 
  • Benzodiazepines:
    • Not used to treat bipolar disorders 
    • Adjunctive therapy in acute manic episodes to treat insomnia, agitation, or anxiety
  • Monotherapy with antidepressants is generally avoided in bipolar disorder because of the risk of causing manic episodes.

Pharmacotherapy

  • Acute severe mania:
    • Characteristics:
      • Suicidal or homicidal ideation or behavior
      • Psychotic features
      • Aggressiveness
      • Impaired judgment (placing self or others in danger)  
    • Treatment:
      • Generally require hospitalization
      • Stop any agents that elevate mood, such as antidepressants or stimulants.
      • Use lithium or valproic acid with antipsychotic.
    • Episode resistant to initial treatment: 
      • Switch medications (if lithium is used, switch to valproic acid, or vice versa)
      • If no response, switch to a different kind of antipsychotic.
    • Treatment-refractory mania:
      • Consider electroconvulsive therapy if, after 4–6 medication combinations, there is still no response.
  • Hypomania or mild to moderate mania:
    • Without suicidal or homicidal behavior, psychotic features, aggressiveness or judgment endangering self or others
    • Treatment: 
      • Monotherapy with antipsychotic or lithium
      • Valproic acid or carbamazepine are alternatives.
    • Resistant to initial treatment: combination therapy after a trial of 3–5 monotherapy options
  • Rapid cycling:
    • 1st-line: antipsychotic (quetiapine)
    • Failed: Consider combination therapy (lithium or valproic acid and an antipsychotic).
  • Maintenance:
    • Continuous treatment is critical to avoid relapse. 
    • Goals:
      • ↓ Symptoms and risk of suicide
      • Prevent recurrence of new mood episodes.
      • Improve psychosocial functioning.
    • Recommendation is to use same regimen as used initially if the response was good
    • Combination therapy for partial response or recurrences

Precautions in pharmacotherapy

  • Renal disease: Avoid lithium (↑ risk of lithium toxicity).
  • Liver disease: Avoid valproate.
  • Obesity: Avoid quetiapine, olanzapine, and risperidone.
  • Sensitivity to extrapyramidal symptoms: Avoid aripiprazole and risperidone.
  • In women of childbearing age: Avoid valproate (associated with neural tube defects) and lithium (associated with Ebstein’s anomaly).

Psychotherapy

  • Adjunct to pharmacotherapy
  • The forms of psychotherapy include:
    • Psychologic counseling/psychoeducation
    • CBT
    • Interpersonal and social rhythm therapy (IPSRT)
    • Family therapy

Somatic therapies

  • Electroconvulsive therapy (ECT):
    • Procedure done under general anesthesia during which brief seizures are intentionally induced via small electric currents 
    • Releases neurotransmitters (dopamine, serotonin, and norepinephrine) and hormones (prolactin, thyroid-stimulating hormone, and endorphins)
    • Usually indicated in cases of failure of multiple drug therapies or for bipolar cases with psychotic features or catatonia
    • Typical course usually has 6–12 sessions.
    • Side effects include the complications from the general anesthesia as well as short-term memory problems. 
  • Transcranial magnetic stimulation (TMS):
    • Current passed through a metal coil (applied against the scalp) generates a magnetic field.
    • Short pulses of magnetic energy stimulate a specific region of the brain.
    • Unlike ECT, does not require anesthesia 
    • Efficacy noted in bipolar major depression and bipolar disorder with mixed features
    • Rate of TMS causing manic switch in bipolar major depression appears low.
    • Side effects include scalp pain/discomfort and possible generalized tonic-clonic seizure

Differential Diagnosis

  • Major depressive disorder (MDD): marked by depressed mood, sleep disturbance, anhedonia, feelings of guilt or worthlessness, loss of energy, low concentration, weight or appetite changes, psychomotor retardation or agitation and suicidal ideation. These symptoms last for ≥ 2 weeks. Individuals with bipolar disorder are often likely to present with depressive symptoms, but careful history taking reveals past incidents of mania or hypomania. Individuals with bipolar disorder are more likely to have poor response to antidepressant monotherapy, greater risk of hospitalizations/suicide attempts, family history of bipolar disorder, and higher rates of comorbid substance use disorders, anxiety disorders, and personality disorders. 
  • Personality disorders: cluster of mental diseases that involve semipermanent patterns of thoughts and behavior that can be harmful and obstinate. Individuals with personality disorders have difficulty handling everyday stresses and issues and their behavior can lead to serious issues with relationships and work. Prognosis of bipolar disorder is often complicated because of comorbid personality disorders. 
  • Cyclothymia: milder form of bipolar II disorder. Cyclothymia is marked by chronic episodes of hypomania and mild depression for a period of at ≥ 2 years. Neither the hypomanic episodes nor the depressive episodes are severe enough to meet criteria for bipolar disorder or major depression. Mood stabilizers are 1st-line therapy for pharmacologic treatment. Lifelong psychosocial therapy is also recommended because of the long-term nature of this disorder.

References

  1. Demuri-Maletic, B. (2021). Bipolar disorders and their clinical management, part II: ciagnosis, differential diagnosis, and treatment. Retrieved March 13, 2021. doi:10.2310/PSYCH.1640
  2. Le, T., Bhushan, V. (2019) First aid step 1, 29th ed. McGraw-Hill Education.
  3. Loosen P.T., Shelton R.C. (2019). Mood disorders. Chapter 17 of Ebert M.H., Leckman J.F., Petrakis I.L. (Eds.), Current Diagnosis & Treatment: Psychiatry, 3rd ed. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2509&sectionid=200804247
  4. Maletic, V. (2021). Bipolar disorders and their clinical management, part I: epidemiology, etiology, genetics, and neurobiology. Retrieved March 13, 2021. doi:10.2310/PSYCH.1640
  5. Rowland, T. A., Marwaha, S. (2018). Epidemiology and risk factors for bipolar disorder. Therapeutic advances in psychopharmacology 8(9):251–269. https://doi.org/10.1177/2045125318769235
  6. Rush, A. (2020). Unipolar major depression in adults: Choosing initial treatment. UpToDate. Retrieved March 10, 2021, from https://www.uptodate.com/contents/unipolar-major-depression-in-adults-choosing-initial-treatment
  7. Sadock, B. J., Sadock, V. A., Ruiz, P. (2014). Mood disorders. Chapter 8 of Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 11th ed. Philadelphia: Lippincott Williams and Wilkins, pp. 347–386.
  8. Stovall, J. (2021) Bipolar disorder in adults: epidemiology and pathogenesis. UpToDate. Retrieved July 19, 2021 from https://www.uptodate.com/contents/bipolar-disorder-in-adults-epidemiology-and-pathogenesis
  9. Stovall, J, (2020). Bipolar mania and hypomania in adults: choosing pharmacotherapy. UpToDate. Retrieved March 13, 2021, from https://www.uptodate.com/contents/bipolar-mania-and-hypomania-in-adults-choosing-pharmacotherapy
  10. Suppes, T. (2020). Bipolar disorder in adults: clinical features. UpToDate. Retrieved March 13, 2021, from https://www.uptodate.com/contents/bipolar-disorder-in-adults-clinical-features

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