Section 6.1: Depressive and Bipolar Disorders

Why Bipolar and Depressive Disorders Matter for the PANCE

Depressive and bipolar disorders represent a substantial portion of the Psychiatry and Behavioral Science section on the PANCE blueprint. These conditions carry high morbidity and mortality risks, particularly through suicide. The PANCE heavily tests the precise Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) criteria, specific symptom timelines (e.g., 2 weeks for Major Depressive Disorder, 1 week for mania, and 4 consecutive days for hypomania), first-line pharmacotherapeutic choices, drug-drug interactions, and life-threatening adverse drug reactions such as Serotonin Syndrome and lithium toxicity. Additionally, a critical clinical competency is distinguishing between unipolar depression, Bipolar I, and Bipolar II, as misdiagnosis can lead to inappropriate antidepressant monotherapy and precipitate a manic switch.

Major Depressive Disorder (MDD)

Pathophysiology and Risk Factors

Major Depressive Disorder is a highly prevalent mood disorder. The primary pathophysiology centers on the monoamine hypothesis, which posits a deficiency in synaptic concentrations of neurotransmitters, specifically serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Risk factors include female gender (approximately a 2:1 ratio compared to males), family history of depressive disorders (the strongest genetic risk factor), chronic medical illnesses, adverse childhood experiences, and stressful life events.

Clinical Presentation and Diagnostic Criteria

To diagnose MDD under DSM-5-TR criteria, a patient must exhibit five or more of the following symptoms during the same 2-week period, representing a change from previous functioning. Crucially, at least one symptom must be either (1) depressed mood or (2) anhedonia (loss of interest or pleasure). The high-yield mnemonic SIGECAPS summarizes these criteria:

• Sleep disturbance: Insomnia (typically terminal insomnia/early morning awakening) or hypersomnia.
• Interest deficit: Anhedonia.
• Guilt: Feelings of worthlessness or excessive/inappropriate guilt.
• Energy deficit: Fatigue or loss of energy nearly every day.
• Concentration difficulties: Diminished ability to think, concentrate, or make decisions.
• Appetite changes: Significant weight loss or gain, or decrease/increase in appetite.
• Psychomotor agitation or retardation: Observable by others, not just subjective feelings.
• Suicidal ideation: Recurrent thoughts of death, suicidal ideation with or without a plan, or a suicide attempt.

Diagnostic Workup

MDD is primarily a clinical diagnosis, but clinicians must rule out organic and metabolic causes of depressive symptoms. Essential workup includes:

1. Thyroid Function Tests (TSH, Free T4): To rule out hypothyroidism, which commonly mimics depression (e.g., fatigue, weight gain, psychomotor slowing).
2. Complete Blood Count (CBC): To evaluate for anemia, which can cause severe fatigue.
3. Basic Metabolic Panel (BMP): To assess electrolytes and renal function.
4. Urine Drug Screen (UDS): To rule out substance-induced mood disorders.
5. Vitamin B12 and Folate Levels: Particularly in elderly patients, as deficiencies can cause cognitive changes and depressive symptoms.

Pharmacotherapy and Management

First-line pharmacotherapy for MDD consists of Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g., sertraline, escitalopram, fluoxetine). They act by inhibiting the presynaptic serotonin transporter (SERT), thereby increasing synaptic cleft serotonin. Common side effects include gastrointestinal upset (nausea, diarrhea), sexual dysfunction (delayed ejaculation, anorgasmia), weight changes, headache, and sleep disturbances. Black box warning: increased risk of suicidal ideation and behavior in children, adolescents, and young adults (under 25).

Alternative antidepressants are selected based on the patient's symptom profile and comorbid conditions:

• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) (e.g., duloxetine, venlafaxine): Useful for patients with comorbid chronic pain or neuropathy (duloxetine). Side effects include dose-dependent hypertension due to noradrenergic effects.
• Bupropion: A norepinephrine-dopamine reuptake inhibitor (NDRI). It is highly favored because it lacks serotonergic side effects (no sexual dysfunction or weight gain). However, it is strictly contraindicated in patients with a history of seizure disorders, anorexia nervosa, or bulimia nervosa, as it lowers the seizure threshold.
• Mirtazapine: An alpha-2 antagonist that increases serotonin and norepinephrine release. Highly sedating and causes weight gain; useful for depressed patients with severe insomnia and anorexia.

Serotonin Syndrome

Serotonin Syndrome is a life-threatening crisis resulting from excessive synaptic serotonin, typically caused by the co-administration of two or more serotonergic agents (e.g., SSRIs, SNRIs, MAOIs, TCAs, tramadol, linezolid, dextromethorphan, triptans, and St. John's Wort).

Clinical Triad of Serotonin Syndrome

1. Neuromuscular Excitation: Hyperreflexia, spontaneous or inducible clonus, ocular clonus, tremors, and rigidity (typically more pronounced in the lower extremities).
2. Autonomic Instability: Hyperthermia, diaphoresis, tachycardia, tachypnea, mydriasis, and labile blood pressure.
3. Altered Mental Status: Agitation, confusion, anxiety, and delirium.

Management

The primary intervention is the immediate discontinuation of all serotonergic agents. Treatment is supportive, involving intravenous fluids, oxygen, and aggressive management of agitation and hyperthermia using benzodiazepines (e.g., diazepam). For moderate-to-severe cases refractory to supportive care, the gold-standard antidote is cyproheptadine, a histamine and serotonin (5-HT1A/5-HT2A) receptor antagonist.

Bipolar I vs. Bipolar II Disorder

The fundamental distinction between Bipolar I and Bipolar II lies in the severity and duration of the elevated mood episodes.

Bipolar I Disorder

Bipolar I requires the occurrence of at least one manic episode. While major depressive episodes and hypomanic episodes are common, they are not required for diagnosis.

• Manic Episode Criteria: A distinct period of abnormally and persistently elevated, expansive, or irritable mood, and abnormally and persistently increased goal-directed activity or energy, lasting at least 1 week (or any duration if hospitalization is necessary).
• Symptom Mnemonic (DIG FAST): Distractibility, Indiscretion (hedonistic behaviors with high risk), Grandiosity (inflated self-esteem), Flight of ideas (racing thoughts), Activity increase (goal-directed or psychomotor agitation), Sleep need decreased (feeling rested after only 2-3 hours), Talkativeness (pressured speech).
• Impairment: Must cause marked impairment in social or occupational functioning, require hospitalization to prevent harm, or involve psychotic features (delusions/hallucinations).

Bipolar II Disorder

Bipolar II is characterized by at least one hypomanic episode AND at least one major depressive episode. There must never have been a manic episode.

• Hypomanic Episode Criteria: A distinct period of elevated, expansive, or irritable mood lasting at least 4 consecutive days. The episode must match the symptoms of mania (DIG FAST) but is less severe.
• Impairment: The episode is associated with an unequivocal change in functioning, but it does not cause marked impairment in social or occupational functioning, does not require hospitalization, and contains no psychotic features.

Mood Stabilizers: Lithium and Valproate

First-line maintenance therapy for Bipolar Disorder involves mood stabilizers.

Lithium Carbonate

Lithium is the classic mood stabilizer and is unique for its proven ability to reduce suicide risk.

• Adverse Effects: Acne, weight gain, cognitive slowing, hypothyroidism, nephrogenic diabetes insipidus (polyuria and polydipsia due to resistance to ADH), hyperparathyroidism, and chronic kidney disease.
• Monitoring: Lithium has a narrow therapeutic range (0.6–1.2 mEq/L). Levels must be drawn 12 hours post-dose. Prior to initiation and periodically during therapy, clinicians must monitor renal function (BUN/creatinine), thyroid function (TSH), calcium levels, pregnancy status, and electrolytes.
• Toxicity: Acute toxicity causes gastrointestinal distress, coarse tremors, ataxia, slurred speech, confusion, seizures, and EKG changes.
• Drug Interactions (PANCE Trap): Lithium clearance is reduced by NSAIDs, Thiazide diuretics, and ACE inhibitors/ARBs, which can precipitate life-threatening lithium toxicity. Loop diuretics and aspirin are safer alternatives.

Valproic Acid (Divalproex Sodium)

Valproic acid is highly effective for acute mania, mixed episodes, and rapid cycling.

• Adverse Effects: Hepatotoxicity (elevated transaminases), acute pancreatitis, thrombocytopenia (easy bruising), significant weight gain, and alopecia.
• Teratogenicity: Extremely teratogenic, causing neural tube defects (e.g., spina bifida). Contraindicated in pregnancy and women of childbearing age unless no other options exist and strict contraception is used.
• Monitoring: Requires baseline and routine liver function tests (LFTs), complete blood counts (CBC) for platelets, and serum valproate level monitoring (therapeutic range: 50–125 mcg/mL).

Classic PANCE Traps & Clinical Pearls

• The Antidepressant Trap: Never prescribe antidepressant monotherapy (such as SSRIs) to a patient with a history of Bipolar Disorder. This can precipitate acute mania. Always co-prescribe a mood stabilizer (e.g., lithium) or atypical antipsychotic.
• The Lithium Clearance Trap: Remember that dehydration, NSAIDs, thiazides, and ACE inhibitors increase lithium levels. A classic vignette describes a bipolar patient taking lithium who develops arthritis, starts ibuprofen, and presents with coarse tremors and confusion.
• Ebstein's Anomaly: Lithium exposure in the first trimester of pregnancy is associated with Ebstein's anomaly, a congenital cardiac defect characterized by the apical displacement of the tricuspid valve leaflets, leading to atrialization of the right ventricle.