Bipolar Disorder (Depressive Episode)

The following figure provides a comprehensive overview of bipolar disorder, including the spectrum of manic and depressive symptoms, epidemiologic facts, and the cyclical nature of mood episodes.

• Onset and course: Age at first depressive episode, total number of prior depressive and manic/hypomanic episodes, duration of current episode, and time since last euthymic period [2-3]
• Symptom characterization: Persistent sad or irritable mood, anhedonia, changes in appetite/weight, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, worthlessness/guilt, poor concentration, recurrent thoughts of death or suicide [2]
• Atypical features suggestive of bipolarity: Hypersomnia, hyperphagia, psychomotor retardation, psychotic features, abrupt onset/offset of symptoms, mixed features (co-occurring manic symptoms) [2-3]
• Prior manic/hypomanic symptoms: Ask about prior periods of elevated energy, decreased need for sleep, increased goal-directed activity, grandiosity, impulsivity, increased sexuality — the defining diagnostic feature [2]
• Treatment history: Prior antidepressant response (or lack thereof), antidepressant-induced mania/hypomania, current medications, adherence [3]
• Substance use: Alcohol, cannabis (worsens mood cycling), stimulants, opioids — obtain a thorough substance use history [4]
• Suicidality: Active vs. passive ideation, plan, intent, prior attempts, access to lethal means [4-5]

• Active suicidal ideation with plan or intent — highest cause-specific elevated risk of premature mortality in bipolar disorder is death by suicide [5-6]
• Mixed features (co-occurring depressive and manic symptoms) — associated with markedly increased suicide risk [2][7]
• Psychotic symptoms (delusions, hallucinations, command auditory hallucinations)
• Catatonia (immobility, mutism, posturing, waxy flexibility)
• Severe functional decline: Inability to eat, drink, or perform self-care
• Rapid cycling (≥4 episodes/year) — indicates treatment complexity and higher relapse risk [4]
• Antidepressant-induced mood destabilization: New agitation, irritability, or mixed symptoms after starting an antidepressant [2-3]

FDA-approved for acute bipolar depression: [2][6]

Other key agents

• Lithium: Anti-suicidal properties; optimize to 0.6–0.8 mEq/L for depression; requires renal/thyroid monitoring [6]
• Lamotrigine: Effective for depressive relapse prevention; requires slow titration over 6 weeks to mitigate rash risk (5–10%); monotherapy may not be effective for acute bipolar depression per VA/DoD [2][8]
• Valproate: Second-line; monitor LFTs, CBC, levels

Contraindicated/caution

• Antidepressant monotherapy (especially in BD I) — risk of treatment-emergent mania (up to 12% in RCTs, 30% in retrospective studies); avoid in rapid cycling, mixed features, or prior antidepressant-induced destabilization [2-3]
• Tricyclics and SNRIs carry higher switch risk than SSRIs/bupropion [3]
• If antidepressants are used, they should be combined with a mood stabilizer or atypical antipsychotic [3][6]

• Alcohol avoidance: Worsens mood instability, interacts with mood stabilizers, and increases suicide risk
• Cannabis avoidance: Worsens mood swings in bipolar disorder [4]
• Caffeine moderation: Can disrupt sleep and exacerbate anxiety/agitation
• Lurasidone must be taken with food (≥350 kcal) for adequate absorption
• Metabolic monitoring: Many atypical antipsychotics cause weight gain and metabolic syndrome — dietary counseling and weight management are integral to long-term care [10-11]
• Lithium: Maintain consistent sodium and fluid intake; dehydration increases lithium toxicity risk

• Psychiatric: Mood, anhedonia, sleep pattern (hypersomnia vs. insomnia), appetite changes, energy, concentration, guilt, suicidal ideation, psychotic symptoms, anxiety, irritability, impulsivity
• Neurologic: Psychomotor retardation or agitation, tremor (lithium), headache
• Endocrine: Weight changes, menstrual irregularities (valproate, antipsychotics), cold intolerance (hypothyroidism from lithium)
• GI: Nausea, diarrhea (lithium), constipation (quetiapine)
• Cardiovascular: Palpitations, syncope (QTc-prolonging medications)
• Substance use: Screen for alcohol, cannabis, stimulants, opioids [4][12]

• Collateral from family/significant others is essential — hypomanic and manic symptoms are often more obvious to others than to the patient [2]
• Family history of bipolar disorder is one of the strongest predictors; first-degree relative with BD significantly increases diagnostic probability [2-3]
• Family history of suicide increases risk [5]
• Childhood maltreatment is a recognized risk factor for bipolar disorder [2]
• Social context: Living situation, employment, relationship stability, social support, access to lethal means [4]

• Family history of bipolar disorder or extensive psychopathology [3]
• Early age of onset (<25 years) [3][13]
• Multiple prior depressive episodes (≥3) [3]
• Atypical depression (hyperphagia, hypersomnia) [3]
• Treatment-resistant depression or antidepressant non-response [2-3]
• Comorbid substance use disorders (~56%), anxiety disorders (~71%), personality disorders (~36%), ADHD (~10–20%) [2]
• Childhood trauma/maltreatment [2]
• Suicide risk factors: Male sex, living alone, divorced, younger age (<35) or elderly (>75), prior suicide attempt, predominant depressive polarity, mixed episodes [5]

The following table from a JAMA review summarizes the key differential diagnoses and distinguishing features:

• Major depressive disorder (MDD): Most common misdiagnosis; at least 7% of patients treated for MDD in primary care may have unrecognized bipolar disorder; the diagnostic distinction requires eliciting a history of mania/hypomania [3][14]
• Borderline personality disorder: Affective dysregulation is enduring and reactive to psychosocial triggers, not episodic [2]
• ADHD: Symptoms are chronic and non-episodic, unlike the clear breaks in function seen with hypomania [2]
• Substance-induced mood disorder: Cocaine, amphetamines, corticosteroids can mimic mania; symptoms should resolve after drug discontinuation [2]
• Schizoaffective disorder / schizophrenia: Psychotic symptoms occur outside of mood episodes in schizophrenia [13]
• Anxiety disorders: Anxious ruminations may mimic racing thoughts; assess episodicity [13]
• Medical causes: Hypothyroidism, Cushing disease, multiple sclerosis, delirium [13][15]

• Prior manic, hypomanic, depressive, and mixed episodes — number, severity, hospitalizations
• Prior suicide attempts (strongest predictor of future attempts) [5]
• Medication trials and responses (including adverse effects and switches)
• Comorbid medical conditions: Cardiovascular disease (2× risk), diabetes, obesity, thyroid disease, migraine [2][16]
• Comorbid psychiatric conditions: Anxiety, PTSD, substance use, eating disorders, ADHD [2]
• Surgical history (relevant for ECT candidacy)
• Reproductive history in women: Pregnancy status, contraception (teratogenicity of valproate, lithium, carbamazepine) [4]

• Vital signs: Blood pressure, heart rate, temperature, weight/BMI (baseline for metabolic monitoring)
• General appearance: Psychomotor retardation (slowed speech, movement, latency) or agitation; poor hygiene/self-care suggesting severity
• Mental status exam: Mood, affect (flat, constricted, tearful), thought content (suicidal/homicidal ideation, delusions), thought process, cognition, insight, judgment
• Neurologic: Tremor (lithium), extrapyramidal symptoms (antipsychotics), akathisia, tardive dyskinesia [11]
• Thyroid: Goiter (lithium-induced hypothyroidism)
• Skin: Rash (lamotrigine — Stevens-Johnson syndrome risk)
• Abdominal: Hepatomegaly (valproate)

Per the VA/DoD guidelines and AAFP recommendations: [4][16]

• Baseline labs:
  • TSH (rule out thyroid disease; baseline before lithium)
  • CBC
  • CMP (renal function for lithium; hepatic function for valproate)
  • Fasting glucose and lipid panel (metabolic baseline before antipsychotics)
  • Urine drug screen
  • Pregnancy test (if applicable)
  • Prolactin (if starting antipsychotics, especially risperidone)
• Medication-specific monitoring:
  • Lithium level (target 0.6–0.8 mEq/L for depression), renal function, thyroid function q6–12 months
  • Valproate level, LFTs, CBC, ammonia if mental status changes
  • Lamotrigine: No routine labs, but monitor for rash
  • Antipsychotics: Fasting glucose, HbA1c, lipids at baseline, 3 months, then annually; weight/BMI monthly for first 3 months [11]
• Rule out medical mimics: Vitamin B12, folate, RPR, HIV as clinically indicated [15]

• Routine neuroimaging is not indicated for typical bipolar depression presentations [4]
• Reserve MRI brain or CT for: new-onset psychosis, focal neurologic findings, atypical presentations, or suspicion of organic etiology (e.g., CNS lesion, demyelinating disease) [4][16]
• EEG: Consider if seizure disorder is suspected [4]

• Screening tools:
  • Mood Disorder Questionnaire (MDQ): 13 yes/no items; ≥7 concurrent symptoms with moderate disability = positive screen; sensitivity ~73–80%, specificity ~70–90%; useful for excluding bipolar disorder but not sufficient to confirm diagnosis [3][12][16]
  • Hypomania Checklist 32 (HCL-32): Sensitivity ~82%, specificity ~57% [3]
  • PHQ-9: Useful for tracking depressive symptom severity; item 9 screens for suicidal ideation [4][14]
  • Columbia-Suicide Severity Rating Scale (C-SSRS): Structured suicide risk assessment [4][7]
• Point-of-care: Urine drug screen, fingerstick glucose, pregnancy test

• Indications: Baseline ECG recommended for patients >40 years, those with cardiac risk factors, or before starting QTc-prolonging medications (olanzapine, quetiapine, ziprasidone, lumateperone) [16-17]
• QTc monitoring: A risk score–based approach can guide whether baseline ECG is needed; patients with ≥2 risk factors for QTc prolongation should have ECG before starting a potentially QTc-prolonging agent [17]
• Dangerous patterns: QTc >500 ms warrants medication change or dose reduction; monitor for torsades de pointes risk [17]
• Lithium: Can cause sinus node dysfunction, T-wave flattening/inversion; ECG at baseline is reasonable

• Bipolar depression is the predominant mood state — patients spend significantly more time depressed than manic/hypomanic, and depression is typically the index presentation [2-3]
• Severity stratification: Mild (functional, no SI) → Moderate (impaired function, passive SI) → Severe (unable to function, active SI, psychotic features, catatonia, inability to eat/drink)
• Mixed features (co-occurring hypomanic symptoms during depression) significantly increase suicide risk and treatment complexity [2]
• Comorbidity is the rule: ~65% have ≥1 comorbid psychiatric disorder [2]
• Complications: Suicide (20–30× general population risk), substance abuse, cardiovascular disease, metabolic syndrome, functional impairment, cognitive decline [2][5]

Initial stabilization (ED/acute setting)

• Immediate safety assessment and suicide risk stratification [4]
• Lethal means counseling and restriction
• If severe SI, catatonia, or inability to maintain oral intake → consider ECT (response rate ~77% in bipolar depression) [2][4]

Pharmacotherapy: [2][6][8]

• First-line monotherapy: Quetiapine (per VA/DoD guidelines)
• Second-line options: Lurasidone, cariprazine, lumateperone (favorable metabolic profiles); olanzapine/fluoxetine (highest efficacy but significant metabolic burden)
• If already on lithium: Optimize to 0.6–0.8 mEq/L and add lamotrigine or quetiapine, or add lurasidone/lumateperone [4]
• If already on valproate/carbamazepine/lamotrigine: Add quetiapine, lurasidone, or cariprazine [4]
• Treatment-resistant: Consider ECT; ketamine if ECT is unacceptable, unsuccessful, or unavailable [2][4]
• Avoid antidepressant monotherapy in BD I [2-3]

Psychotherapy (adjunctive): [18]

• Psychoeducation, CBT, interpersonal and social rhythm therapy (IPSRT), family-focused therapy
• Emphasis on sleep hygiene, circadian rhythm stabilization, and medication adherence

Admission criteria

• Active suicidal ideation with plan or intent
• Psychotic features
• Catatonia or inability to maintain oral intake
• Severe functional impairment with inability to care for self
• Need for ECT or acute medication titration requiring monitoring
• Involuntary admission when impaired judgment affects capacity to consent [2]

Observation indications

• Passive suicidal ideation without plan, with adequate safety plan and supports
• Medication initiation requiring short-term monitoring

Discharge criteria

• No active suicidal ideation with plan/intent
• Safety plan in place with identified supports
• Outpatient psychiatric follow-up arranged
• Medication plan established with clear instructions
• Lethal means restriction addressed

Specialist consultation triggers: [4]

• All suspected new diagnoses of bipolar disorder → psychiatry referral
• Mania, psychosis, or safety concerns → immediate ED evaluation
• Treatment-resistant depression → specialty mental health
• Pregnancy in a patient with bipolar disorder → high-risk OB and psychiatry co-management

Follow-up timing

• Psychiatry follow-up within 1–2 weeks of ED discharge or medication initiation
• PCP follow-up for metabolic monitoring within 4–6 weeks of starting antipsychotics
• Lithium level check within 5–7 days of dose change, then q3–6 months when stable
• Most patients require lifelong treatment to reduce relapse rates [2]

Return precautions — instruct patient and family to return immediately for:

• Worsening suicidal thoughts, new plan or intent to harm self
• New psychotic symptoms (hearing voices, paranoia, delusions)
• Signs of mania/hypomania (decreased need for sleep, racing thoughts, impulsive behavior, grandiosity)
• Inability to eat, drink, or care for self
• Signs of medication toxicity: lithium (tremor, vomiting, confusion, ataxia), lamotrigine (any new rash), antipsychotics (muscle rigidity, fever → NMS)

Patient counseling

• Bipolar disorder is a chronic, relapsing illness — medication adherence is critical even when feeling well [2]
• Avoid alcohol, cannabis, and recreational drugs [4]
• Maintain regular sleep-wake schedule and daily routines (circadian rhythm stabilization) [18]
• Engage family/support system in monitoring for mood changes
• 988 Suicide & Crisis Lifeline (call or text 988) for crisis support

1. The 2020 Royal Australian and New Zealand College of psychiatrists clinical practice guidelines for mood disorders: Bipolar disorder summary. — Malhi GS, Bell E, Boyce P, et al. Bipolar Disorders. 2020.

2. Diagnosis and Treatment of Bipolar Disorder: A Review. — Nierenberg AA, Agustini B, Köhler-Forsberg O, et al. The Journal of the American Medical Association. 2023.

3. Bipolar Disorders. — McIntyre RS, Berk M, Brietzke E, et al. Lancet. 2020.

4. Management of Bipolar Disorder (BD) (2023). — Thad Abrams MD MS, Jennifer Bell MD, Paulette Cazares MD MPH, et al Department of Veterans Affairs. 2023.

5. Bipolar Disorder and Suicide: A Review. — Miller JN, Black DW. Current Psychiatry Reports. 2020.

6. Bipolar Disorder. — Singh B, Swartz HA, Cuellar-Barboza AB, et al. Lancet. 2025.

7. Suicide and Suicidal Behaviour. — Turecki G, Brent DA. Lancet. 2016.

8. Management of Bipolar Disorder: Guidelines From the VA/­DoD. — Arnold MJ. American Family Physician. 2024.

9. FDA Orange Book. — FDA Orange Book. 2026.

10. Efficacy and Safety Profiles of Mood Stabilizers and Antipsychotics for Bipolar Depression: A Systematic Review. — Cai L, Chen G, Yang H, Bai Y. International Clinical Psychopharmacology. 2023.

11. Collaborative Care in the Identification and Management of Psychosis in Adolescents and Young Adults. — Hua LL. Pediatrics. 2021.

12. Bipolar Disorder — A Focus on Depression. — Frye MA. The New England Journal of Medicine. 2011.

13. Diagnostic and Statistical Manual of Mental Disorders. — Dilip V. Jeste, Jeffrey A. Lieberman, David Fassler, et al American Psychiatric Association (2022). 2022.

14. Management of Depression in Adults: A Review. — Simon GE, Moise N, Mohr DC. The Journal of the American Medical Association. 2024.

15. Depression in the Primary Care Setting. — Park LT, Zarate CA. The New England Journal of Medicine. 2019.

16. Bipolar Disorders: Evaluation and Treatment. — Marzani G, Price Neff A. American Family Physician. 2021.

17. QTc Monitoring in Adults With Medical and Psychiatric Comorbidities: Expert Consensus From the Association of Medicine and Psychiatry. — Xiong GL, Pinkhasov A, Mangal JP, et al. Journal of Psychosomatic Research. 2020.

18. Bipolar Disorder. — Carvalho AF, Firth J, Vieta E. The New England Journal of Medicine. 2020.