Bipolar I Disorder
- A chronic, treatable mood disorder with a relapsing and remitting course marked by manic episodes, with most patients also experiencing major depressive episodes
- Manic episodes are periods of elevated mood, elevated self attitude (e.g. self esteem or self confidence), and increased vital sense (physical and mental energy).
- Depressive episodes are characterized by the triad of low mood, self-attitude and vital sense.
- Previously known as manic-depressive illness
- Lifetime prevalence is 1%.
- Equally common in men and women
- Women with bipolar I disorder are at very high risk for postpartum mania and psychosis.
- Women are also more likely to have rapid cycling, which is defined as having four or more manic or depressive episodes per year.
- Onset of symptoms is typically in the late teens or early twenties, but earlier or later onset can occur.
- Often a 5- to 10-year lag between onset of symptoms and correct diagnosis
- Patients are often initially diagnosed with major depressive disorder and only receive the diagnosis of bipolar I disorder after a later manic episode.
- Common psychiatric comorbidities include alcohol use disorder and other substance use disorders, generalized anxiety disorder, panic disorder, and personality disorders.
- Increased mortality is primarily due to a higher risk of suicide (25-50% attempt suicide, and 15% die by suicide) but also due to increased risk of cardiovascular disease and accidents.
- Suicide risk is even greater if a patient with bipolar I disorder also has a substance use disorder.
- Bipolar disorder has a strong genetic component; individuals with a first-degree relative with bipolar disorder have a ten-fold risk of developing the disorder compared with the general population.
Course of Illness
- Bipolar I disorder has a relapsing and remitting course that is marked by manic episodes, with most patients also experiencing major depressive episodes.
- A manic episode is required for diagnosis of bipolar disorder; hypomanic and depressive episodes are common, but not required for diagnosis.
- If episode causes marked impairment in social/occupational functioning, requires hospitalization, or has associated psychotic symptoms (e.g., hallucinations or delusions), it is mania as compared to hypomania.
- Manic symptoms should not be caused by medications, substances, or medical conditions; although if manic symptoms arise during treatment for depression (e.g., anti-depressants or ECT), they can be considered evidence of manic episode.
- A manic episode is required for diagnosis of bipolar disorder; hypomanic and depressive episodes are common, but not required for diagnosis.
- Nearly all patients who have one manic episode will have another; the number of manic episodes varies from person to person, but the average number of episodes a patient will have in a lifetime is nine.
- Some patients have rapid cycling - with four or more manic or depressive episodes in a year.
- Depressive episodes often occur immediately before or after a manic episode.
- Some patients have hypomanic symptoms that progress to a manic episode.
- Many patients return to normal mood between episodes, although others have residual mood symptoms between episodes, and 10% remain chronically ill.
- Even when mood symptoms improve, patients often do not return to their previous level of functioning.
- Risk factors for impaired functioning include substance abuse, earlier age at onset of disease, and family history of mood disorder.
- Stress is associated with onset of manic episodes and depressive episodes, though less so with episodes later in the course.
- Sleep deprivation, drug/alcohol use, and antidepressants can also trigger manic episodes.
- These are marked by elevated/irritable mood and increased activity, as well as other symptoms that can include inflated self-esteem, decreased need for sleep, pressured speech, racing thoughts, increased distractibility, and increased, reckless involvement in pleasurable activities like spending sprees, sexual activity, and substance abuse.
- Patients may not have insight regarding their elevated mood, but they may notice that they are having trouble controlling their drinking or drug use, or that they are having relationship problems.
- The hedonistic triad of spending sprees, sexual activity, and substance abuse can have catastrophic financial and personal consequences.
- Patients can have delusions or hallucinations during manic episodes.
- The most common delusions are delusions of grandiosity (often with a religious theme) or paranoid delusions.
- Hallucinations are less common than delusions; when patients do have hallucinations, auditory hallucinations are more common than visual hallucinations.
- Although the beginning of a manic episode can be experienced by the patient as pleasant and is marked by elated mood, a severe manic state can be very unpleasant for the patient and can involve bizarre delusions, frenzied activity, and disorganized cognition.
- Severe mania is dangerous due to agitation and an increased risk of violence toward both self and others.
- Most patients also have major depressive episodes, marked by low mood and anhedonia, decreased self attitude and vital sense.
- Associated changes include variation in sleep patterns, changes in appetite, reduced libido, diurnal variation in symptoms, recurrent thoughts of death, and suicidality.
- Patients with bipolar I disorder are at greatest risk for suicide during depressive episodes and mixed episodes.
- In addition to manic episodes and major depressive episodes, some patients have mixed states that combine the symptoms of a manic episode and a major depressive episode. These episodes are typified by low/irritable mood with increased activity, as well as other symptoms that can include pressured speech, insomnia, grandiosity, thoughts of death or suicide, and other combinations of manic or depressive episodes.
- Patients are at increased risk of suicide during mixed episodes given the dangerous combination of low mood and increased energy/restlessness.
Tests and Procedures
- Bipolar I disorder is a clinical syndromal diagnosis based on history and mental status exam, without a diagnostic laboratory test.
- Tests to assess etiologic factors include CBC, BMP, LFTs, TSH, B12, folate, vitamin D, RPR, blood alcohol level, urinalysis, and urine toxicology.
- Obtaining a detailed history is paramount in diagnosis.
- Many patients with bipolar I disorder will present with a depressive episode; it is important to ask about past manic/hypomanic symptoms (mood swings, episodes of increased energy and decreased need for sleep).
- It is also important to ask patients’ family members or friends about past manic/hypomanic symptoms, since patients often lack insight regarding manic/hypomanic symptoms or may not remember them clearly (especially if the patient is currently depressed).
- Patients in a manic or mixed state will often be agitated and unable to give a coherent history; additional information should be obtained from family members or friends.
- It is important to ask about suicidal ideation and substance abuse.
- Eliciting a family history of bipolar disorder is also helpful given the strong genetic basis of bipolar disorder.
- Screening questionnaires, e.g., the Mood Disorder Questionnaire (MDQ), can be filled out by the patient; it is helpful to have a family member fill one out as well, since patients often do not self-report manic symptoms.
- Major depressive disorder
- Bipolar II disorder
- Cyclothymic disorder
- Schizoaffective disorder
- Attention-deficit/hyperactivity disorder (ADHD)
- Personality disorder
- Substance use or withdrawal
- Medication use or withdrawal
- Medications that have been reported to cause mania include corticosteroids, stimulants, levodopa, isoniazid, levetiracetam, decongestants, immunosuppressants, certain chemotherapeutic agents, cimetidine, captopril, cyclobenzaprine, cyproheptadine, disulfiram, felbamate, L-glutamine, L-tryptophan, metrizamide, metoclopramide, procainamide, procarbazine, propafenone, sympathomimetics, thyroxine, tolmetin, triazolam, yohimbine, and zidovudine.
- Medication withdrawal: clonidine, diltiazem, atenolol, isocarboxazid, propanolol
- Mania due to general medical conditions
- Cushing disease; multiple sclerosis; thalamic stroke; traumatic brain injury;Huntington disease; Creutzfeld-Jakob disease; complex partial aeizures; systemic lupus erythematosus; CNS neoplasm; paraneoplastic syndrome; endocrine disorders, especially thyrotoxicosis, Wilson’s disease
- Infections (Lyme disease, HIV, neurosyphilis, influenza, Q fever, post-St. Louis type A encephalitis, cryptococcal meningitis)
- The foundations of treatment include medications and psychotherapy.
- Treatment of bipolar I disorder occurs in three stages: (1) acute treatment of a manic or depressive episode, (2) the improvement phase, and (3) the maintenance phase.
- Treatment of an acute manic or depressive episode focuses on diagnosis, safety, initiation of pharmacological treatment, support, and education.
- Safety assessment is critical.
- Patients are at high risk of suicide, particularly during depressive or mixed states.
- Patients may need psychiatric hospitalization, possibly on an involuntary basis, to ensure safety if the patient is suicidal, homicidal, severely agitated, or not adequately eating/drinking.
- If the patient does not require hospitalization, clinicians should consider limiting access to vehicles, credit cards, etc., given the propensity for reckless behavior in manic or mixed states.
- The mainstay of pharmacological treatment is mood stabilizers.
- A patient may also need antipsychotic medication for severe agitation (typically more quick-acting than "mood stabilizers").
- Behavioral interventions: ensure that the patient is in a calm environment without excessive stimulation.
- Antidepressants are not first-line treatment for depressive episodes in bipolar disorder given their association with switching into hypomanic/manic/mixed episodes as well as increased cycling (in which mood episodes occur more frequently).
- ECT can be used in patients whose symptoms worsen in spite of medication, and ECT is also an option for patients who are not well-suited to medication (e.g., women in the first trimester of pregnancy, elderly patients, or patients with a high risk of suicide).
- The focus of psychotherapy in the acute phase of treatment is support and education.
- It can take 4 weeks or more for a severely manic patient to achieve remission and be ready for outpatient care, which requires both medication adherence and attending regular clinic visits.
- The acute phase usually lasts 6-12 weeks.
Improvement Phase of Treatment
- During this phase of treatment, which lasts 6 months on average, the patient’s mood symptoms have improved, but the patient is still vulnerable to mood instability.
- Treatment during the improvement phase consists of frequent assessments, medication adjustments based on response and side effects, and psychotherapy.
- Psychotherapy during the improvement phase focuses on identifying and addressing stressors that can trigger mood symptoms and dealing with damage to relationships, work, or finances that occurred during a mood episode.
- If the patient does not relapse during the improvement phase of treatment, he/she is said to have recovered from the episode and enters the maintenance phase of treatment.
- The goal of maintenance treatment is to prevent future manic or depressive episodes.
- Because of the relapsing and remitting nature of bipolar I disorder, maintenance treatment is indicated after the first manic episode.
- The focus of maintenance treatment is long-term medication management, psychotherapy, and lifestyle changes.
- The mainstay of pharmacological treatment is mood stabilizers; many patients may benefit from being on more than one medication.
- Psychotherapy focuses on medication adherence, education, lifestyle changes, and addressing potentially devastating consequences of the illness.
- It is important to monitor for symptoms of mania, hypomania, or depression.
- It is very important to have good continuity of care, so that the patient’s physician(s) will be familiar with his/her illness and particular constellation of symptoms and/or prodromal symptoms.
- In monitoring for mania or depression, it can be helpful for the patient to keep a journal or mood chart.
- It is also important to ask family members about their observations.
- It is important to treat substance misuse, comorbid anxiety, breakthrough symptoms, and side effects of medications.
- Patients and their family members may also benefit from attending support groups.
- Treatment of women with bipolar I disorder during their childbearing years requires balancing the risk of relapse vs. the risk to the fetus.
- Given that all mood stabilizers are potentially teratogenic, many patients discontinue them during pregnancy, but patients with severe illness may need to continue treatment during pregnancy.
Acute Treatment of a Manic Episode
- The mainstay of pharmacological treatment of manic episodes is mood stabilizers, with antipsychotics or benzodiazepines as needed for agitation.
- Mood stabilization
- Lithium and divalproex are first-line mood stabilizers; other options include carbamazepine, oxcarbazepine, and atypical antipsychotics (e.g., aripiprazole, olanzapine, risperidone, quetiapine, and ziprasidone).
- The above medications can be used as monotherapy for patients with less severe illness.
- A second mood stabilizer and/or atypical antipsychotic can be added if monotherapy is not sufficient.
- Some patients may do well on lithium or divalproex plus an atypical antipsychotic; others may need triple therapy consisting of lithium, divalproex, and an atypical antipsychotic.
- Atypical antipsychotic are also recommended for patients who present with psychotic features (e.g., delusions, hallucinations).
- Medication choice is based on mood symptoms, medication side effects, and past responses to medication, but some degree of trial and error is expected.
- While it is not possible to predict whether a patient will benefit from and/or tolerate a specific medication, ongoing multicenter prospective studies may help understand the genetics and pharmacogenomics of bipolar disorder.
- One needs to carefully monitor mood symptoms and medication side effects, and titrate doses appropriately.
- For lithium, divalproex, and carbamazepine, blood levels are also important in guiding therapy.
- ECT is an option if a patient is not improving on medication or if he/she is not well-suited to medication (e.g., a patient in the first trimester of pregnancy trying to avoid teratogenic effects, a patient with a high risk of suicide, or an elderly patient).
- Severe agitation can be treated with atypical antipsychotics administered parenterally or intramuscularly while waiting for mood stabilizers to take effect.
- Benzodiazepines are not as effective for acute manic agitation.
Acute Treatment of a Bipolar Depressive Episode
- First-line treatments for bipolar depressive episodes include lithium or lamotrigine monotherapy.
- For more severe cases, can add second mood stabilizer (e.g., lamotrigine combined with lithium or divalproex).
- Atypical antipsychotics can be added for patients with psychotic features (e.g., delusions, hallucinations).
- Antidepressant monotherapy is contraindicated in bipolar depressive episodes since antidepressants can cause rapid cycling or switches into mania/hypomania.
- Antidepressants (e.g., an SSRI or bupropion) can be used as adjuncts if the patient is not improving on a combination of two mood stabilizers or a mood stabilizer plus an atypical antipsychotic.
- Must monitor for increased cycling or switch into mania/hypomania/mixed state.
- Consider ECT if there is a high risk of suicide or the patient is not well-suited to medication (i.e., the patient is pregnant, elderly, or previously experienced rapid cycling or a switch into mania/hypomania/mixed state on antidepressants).
- Continue medications from acute episode.
- Assess mood symptoms and side effects frequently to guide dosage.
- Many patients do well on lithium or divalproex as monotherapy maintenance treatment and can taper off adjunctive medications that were added during treatment of the acute episode; others will need combination maintenance treatment.
- The decision to taper adjunctive medications used during an acute episode is based on the individual patient’s response to medication and weighing side effects of continuing adjunctive medications vs. risk of relapse.
- First-line options for maintenance treatment are lithium, divalproex, and lamotrigine; carbamazepine and atypical antipsychotics are also options.
- Lithium or lamotrigine for prevention of depressive episodes
- Divalproex and carbamazepine for rapid cycling
- Antidepressant should generally be tapered and discontinued after a depressive episode.
- Maintenance antidepressant only if the patient repeatedly relapses after stopping
- Need to carefully monitor mood symptoms and medication side effects, and titrate medication dose appropriately, including verifying therapeutic blood levels for certain medications (e.g., lithium, divalproex, carbamazepine)
- Patients who received ECT during the acute phase of treatment may also benefit from maintenance ECT.
Acute Treatment of Manic Episode or Depressive Episode
- The focus of psychotherapy during an acute manic or depressive episode is support and education.
- Education for the patient and family should emphasize that the patient’s mood symptoms are due to a treatable illness, that the patient must continue taking his/her medication and coming to appointments, and that suicide is not acceptable.
Improvement Phase of Treatment
- During the improvement phase, psychotherapy focuses on identifying and addressing stressors that can trigger mood symptoms, and dealing with damage to relationships, work, or finances that occurred during mood episodes.
Maintenance Phase of Treatment
- Psychotherapy during the maintenance phase can become more intensive.
- During the maintenance phase, psychotherapy focuses on medication adherence, education, lifestyle changes, and continuing to address the potentially devastating consequences of the illness.
- Medication adherence is an important focus of psychotherapy because patients often want to stop taking maintenance medication when they are feeling better, but medication nonadherence puts them at risk for recurrence.
- Education about the illness is important for both the patient and the family.
- Lifestyle changes are important in preventing recurrent episodes.
- The most important lifestyle change is good sleep hygiene, since sleep deprivation can impact mood and can often trigger mania -- patients need to get enough sleep on a regular basis.
- Avoiding alcohol and illicit substances is important.
- A healthy diet, regular exercise, and other stress reduction techniques are also helpful.
- Another focus of psychotherapy is continuing to address potentially devastating consequences of the illness, which can include suicide, violence, drug and alcohol use, divorce, job loss, and financial ruin.
WHEN TO REFER
- Patients with bipolar I disorder will need acute management of manic or depressive episodes, a potentially complex pharmacological regimen, psychotherapy, and management of common comorbidities including substance misuse and other psychiatric conditions.
- Referral to a psychiatrist is recommended if a bipolar I diagnosis is suspected, or a patient has a depressive episode and either past manic/hypomanic symptoms or a family history of bipolar disorder.
- Because patients with bipolar I disorder can have relatively poor health outcomes, and medications for bipolar I disorder can have serious side effects, it is important for primary care physicians and psychiatrists to work closely to coordinate care.
- Primary care physicians can be an invaluable resource for recognizing when a patient is experiencing breakthrough mood symptoms.
- Sportiche S, Geoffroy PA, Brichant-Petitjean C, et al. Clinical factors associated with lithium response in bipolar disorders. Aust N Z J Psychiatry. 2017;51(5):524-530. [PMID:27557821]
- Ahn SW, Baek JH, Yang SY, et al. Long-term response to mood stabilizer treatment and its clinical correlates in patients with bipolar disorders: a retrospective observational study. Int J Bipolar Disord. 2017;5(1):24. [PMID:28480482]
- Hunt GE, Malhi GS, Cleary M, et al. Comorbidity of bipolar and substance use disorders in national surveys of general populations, 1990-2015: Systematic review and meta-analysis. J Affect Disord. 2016;206:321-330. [PMID:27426694]
- Oedegaard KJ, Alda M, Anand A, et al. The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample. BMC Psychiatry. 2016;16:129. [PMID:27150464]
- Hou L, Heilbronner U, Degenhardt F, et al. Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. Lancet. 2016;387(10023):1085-93. [PMID:26806518]
- Gibbs M, Winsper C, Marwaha S, et al. Cannabis use and mania symptoms: a systematic review and meta-analysis. J Affect Disord. 2015;171:39-47. [PMID:25285897]
- Cohen BJ. Theory and Practice of Psychiatry. Oxford University Press. 2003.
- Connolly KR et al: The Clinical Management of Bipolar Disorder: A Review of Evidence-Based Guidelines. Prim Care Companion CNS Disord 13:PCC.10r01097, 2011.
- Das AK, Olfson M, Gameroff MJ, et al. Screening for bipolar disorder in a primary care practice. JAMA. 2005;293(8):956-63. [PMID:15728166]
- Goodwin FK & Jamison KR. Manic-Depressive Illness. Oxford University Press. 2007.
- Mondimore FM. Bipolar Disorder: A Guide for Patients and Families. Johns Hopkins University Press. 2006.
- Perlis RH: The Role of Pharmacological Treatment Guidelines for Bipolar Disorder. J Clin Psychiatry 66 (suppl 3): 37, 2005.
- Tohen M, Zarate CA, Hennen J, et al. The McLean-Harvard First-Episode Mania Study: prediction of recovery and first recurrence. Am J Psychiatry. 2003;160(12):2099-107. [PMID:14638578]