Mood Disorders

• Definition: Mood (affective) disorders are DSM-5-TR conditions in which a sustained disturbance of internal emotional state — depressed, elevated, expansive, or irritable — drives the clinical picture, rather than a primary psychotic, anxiety, or substance disorder. The unipolar pole (major depressive disorder, persistent depressive disorder) is separated from the bipolar spectrum (bipolar I, bipolar II, cyclothymia) by the lifetime presence or absence of a manic or hypomanic episode.
• Why it matters: Mood disorders are among the leading causes of disability worldwide and are the psychiatric diagnoses most strongly linked to completed suicide. They also worsen outcomes in comorbid medical disease — post-MI depression and depression in diabetes are independently associated with poorer adherence and higher mortality — which is why the USPSTF gives a B recommendation to screening all adults, including pregnant and postpartum patients, for depression when systems are in place for accurate diagnosis and follow-up.

Epidemiology worth recalling

• Major depressive disorder: the most common mood disorder, with a lifetime prevalence in US adults on the order of one in six to one in five. Women are affected roughly twice as often as men, a gap that emerges at puberty. Median onset is in the twenties to thirties, but incidence spans adolescence to late life.
• Bipolar I disorder: roughly 1% lifetime prevalence, affecting men and women equally, with onset typically in the late teens to mid-twenties — considerably earlier than unipolar depression. Bipolar II is at least as common and is systematically under-recognized because patients present in the depressed phase.
• Course: MDD is recurrent in the majority of patients; each episode raises the risk of the next. Bipolar disorder is essentially lifelong, and untreated episodes tend to become more frequent over time.
• Demographics examiners plant: a postpartum woman, an adolescent with new irritability and falling grades, a college-aged patient with a first manic episode after an antidepressant was started, and an older adult whose depression masquerades as cognitive decline (pseudodementia).

Genetic / non-modifiable

• Heritability: Bipolar disorder is among the most heritable psychiatric conditions, substantially more so than MDD; a first-degree relative with bipolar disorder is the single strongest risk factor and the association examiners test. Inheritance is polygenic — no single locus is testable.
• Female sex for unipolar depression; equal sex distribution for bipolar I.
• Age of onset: early-onset depression (adolescence/early adulthood), a family history of bipolar illness, psychotic features, and hypersomnia/hyperphagia during depression all raise the probability that an apparently unipolar depression is actually bipolar.
• Early-life adversity: childhood abuse, neglect, or parental loss produce durable HPA-axis programming and lower the stress threshold for later episodes (the stress-diathesis model already outlined).

Modifiable / environmental

• Psychosocial stressors: bereavement, divorce, job loss, and social isolation precipitate first episodes more reliably than later ones (kindling — later episodes become increasingly autonomous).
• Substance use: alcohol, stimulants, and cannabis both mimic and precipitate mood episodes; alcohol use disorder markedly amplifies suicide risk. Stimulant intoxication and withdrawal are the classic mania and depression mimics.
• Sleep deprivation: a potent trigger for mania — the stem often mentions an overnight flight, shift change, or exam week preceding the episode.
• Medications: corticosteroids (mania or depression), interferon-alpha, isotretinoin (disputed), and dopamine agonists; antidepressant exposure can unmask mania in a bipolar-diathesis patient.

Medical and endocrine contributors

• Hypothyroidism — the mandatory TSH check in any new depression; also B12/folate deficiency, obstructive sleep apnea, and anemia.
• Neurologic disease: post-stroke depression (especially left frontal lesions), Parkinson disease, multiple sclerosis, epilepsy, traumatic brain injury, and dementia.
• Peripartum state: the abrupt postpartum fall in estrogen and progesterone, superimposed on sleep loss; a prior bipolar diagnosis is the dominant risk factor for postpartum psychosis.
• Chronic systemic illness: cancer, HIV, heart failure, and chronic pain — partly inflammatory (cytokine-driven), partly reactive.

• Monoamine deficiency and its limits: Reduced serotonergic, noradrenergic, and dopaminergic transmission in prefrontal–limbic circuits explains the symptom triad — serotonin with mood, anxiety, and rumination; norepinephrine with energy, concentration, and vigilance; dopamine with anhedonia and psychomotor slowing (mesolimbic reward hypofunction). The theory's key exam corollary is the therapeutic lag: synaptic monoamine levels rise within hours of an SSRI, yet clinical response takes weeks, because benefit requires downregulation/desensitization of presynaptic 5-HT1A autoreceptors and downstream transcriptional change, not simple reuptake blockade.
• HPA-axis dysregulation: Chronic stress drives CRH and cortisol excess with loss of glucocorticoid-receptor negative feedback — the basis of the historical dexamethasone non-suppression finding in melancholic depression. Sustained hypercortisolemia is toxic to hippocampal neurons and helps explain the impaired concentration, memory complaints, and, in older adults, pseudodementia.
• Neurotrophic and structural change: Reduced BDNF signaling and impaired hippocampal neurogenesis accompany depression; antidepressants and ECT increase BDNF, matching the timeline of recovery. Imaging correlates include reduced hippocampal volume and hypometabolism of the dorsolateral prefrontal cortex with hyperactivity of the subgenual cingulate and amygdala — a top-down control failure that makes negative affect self-sustaining.
• Glutamatergic mechanism: NMDA-receptor antagonism (ketamine/esketamine) produces an AMPA-mediated burst of synaptogenesis via mTOR signaling, which is why antidepressant effect appears within hours rather than weeks — the mechanistic counterexample to the monoamine model.
• Circadian and sleep architecture: Depression classically shows shortened REM latency, increased REM density, and reduced slow-wave sleep, with early-morning awakening and diurnal mood variation in melancholia — the phenotypic output of a phase-advanced circadian system. In mania, circadian collapse manifests as a decreased need for sleep (distinct from insomnia: the patient is not tired).
• Bipolar intracellular signaling: Dysregulated PKC and GSK-3β cascades and mitochondrial/energetic abnormalities underlie mood instability; lithium inhibits GSK-3β and inositol monophosphatase, depleting the phosphoinositide second-messenger pool and dampening the excessive signaling that generates manic drive.

Depressive episode — mechanism-linked findings

• Anhedonia and depressed mood: mesolimbic dopaminergic hypofunction; the patient describes loss of reactivity even to previously reliable pleasures. Anhedonia is the more specific of the two cardinal symptoms.
• Neurovegetative signs: early-morning awakening, diurnal variation (worse in the morning), weight loss, and profound psychomotor retardation define the melancholic subtype and track with HPA/circadian dysfunction. The atypical subtype reverses this — hypersomnia, hyperphagia with weight gain, leaden paralysis, mood reactivity, and rejection sensitivity — and is enriched in bipolar depression.
• Cognitive findings: poor concentration and indecisiveness; in an older adult, prominent memory complaints with poor effort on testing that improve with antidepressant treatment suggest pseudodementia rather than Alzheimer disease.
• Somatic presentation: fatigue, vague pain, and GI complaints are how depression frequently presents in primary care and in many cultural contexts.
• Psychotic features: mood-congruent delusions of guilt, poverty, nihilism, or somatic decay (Cotard delusion) — always ask, because it changes treatment.
• Catatonia: mutism, negativism, waxy flexibility, echolalia — a mood-disorder complication, not exclusively schizophrenic.

Manic episode

• Decreased need for sleep with preserved or increased energy — the discriminator from insomnia and the earliest prodromal sign.
• Pressured speech, flight of ideas, distractibility, and grandiosity reflect disinhibited frontal control; goal-directed hyperactivity and reckless behavior (spending sprees, sexual indiscretion, impulsive travel) generate the functional and legal consequences that define severity.
• Psychosis occurs only in mania, never in hypomania, and its presence mandates a bipolar I diagnosis regardless of episode duration.
• Mixed features: simultaneous depressive and manic symptoms — agitated, dysphoric, sleepless — carry the highest suicide risk of any mood state.

Step 1 — screen

• PHQ-2 then PHQ-9: a positive two-item screen prompts the full nine-item PHQ-9, which maps directly onto DSM-5-TR criteria. Scores stratify severity (roughly: 5–9 mild, 10–14 moderate, 15–19 moderately severe, ≥20 severe), and a score of ≥10 is the usual threshold for clinically significant depression. USPSTF endorses screening in all adults and in adolescents 12–18.
• Perinatal screening: the Edinburgh Postnatal Depression Scale is the standard instrument; ACOG recommends screening at least once during pregnancy and at the postpartum visit, with a full mood assessment rather than a score alone.
• Bipolar screening before prescribing: every depressed patient must be asked about prior manic/hypomanic symptoms; the Mood Disorder Questionnaire is the named screening tool. Missing this is the classic path to an antidepressant-induced switch.

Step 2 — apply DSM-5-TR criteria

• Diagnosis is clinical; there is no confirmatory laboratory or imaging test. Symptoms must cause distress or functional impairment and must not be attributable to a substance or another medical condition.
• Specifiers change management: with anxious distress, with mixed features, melancholic, atypical, psychotic features, catatonia, peripartum onset, and seasonal pattern.
• DSM-5 removed the bereavement exclusion; DSM-5-TR added prolonged grief disorder as a separate entity.
• A manic episode emerging during antidepressant treatment and persisting beyond the physiologic effect of that treatment counts toward a bipolar I diagnosis.

Step 3 — exclude medical mimics (the labs the stem expects)

• TSH (hypothyroidism), CBC, comprehensive metabolic panel, B12 and folate, and a urine drug screen; consider HIV and RPR when risk factors are present, and a pregnancy test before starting valproate or lithium in a person of childbearing potential.
• Neuroimaging only for atypical features: first episode after age 50, focal neurologic signs, or abrupt personality change.

Step 4 — risk stratify

• Direct suicide inquiry is mandatory; the Columbia-Suicide Severity Rating Scale is the commonly named structured tool. Document intent, plan, means, and protective factors — this determines disposition before any prescription is written.

Immediate stabilization

• Assess suicide and homicide risk first. Active intent, a plan with available means, psychosis, or inability to care for self warrants inpatient admission — involuntarily if the patient refuses and statutory criteria are met. Restricting access to firearms and lethal medication quantities is part of the plan, not an afterthought.
• Acute mania: ensure safety, stop antidepressants and stimulants, correct sleep deprivation, and treat agitation with a benzodiazepine (e.g., lorazepam) while a mood stabilizer or atypical antipsychotic takes effect. Postpartum psychosis is a psychiatric emergency requiring hospitalization.

Maintaining and escalating unipolar therapy (per the APA Practice Guideline for MDD)

• Allow an adequate trial: 4–8 weeks at a therapeutic dose before declaring failure; partial response at 4 weeks predicts eventual response.
• If inadequate response: optimize the dose, then either switch within or across class (SSRI → SNRI, bupropion, mirtazapine) or augment — atypical antipsychotics (aripiprazole, quetiapine), lithium, or thyroid hormone (T3) are the classic augmentation agents. Combine with evidence-based psychotherapy (CBT, interpersonal therapy) at every step.
• Treatment-resistant depression: intranasal esketamine may be added to an oral antidepressant and, per FDA labeling, is available only through a restricted REMS program with post-dose observation for sedation and dissociation. Repetitive transcranial magnetic stimulation is an option for patients who have failed antidepressant trials.
• Electroconvulsive therapy is the definitive treatment and the best next step for depression with psychotic features, catatonia, food/fluid refusal, imminent suicidality, or failure of multiple medication trials — and it is the preferred somatic therapy in pregnancy.

Bipolar maintenance

• Lithium has the best evidence for reducing suicide risk; monitor serum level, renal function, TSH, and calcium. Standard maintenance levels are approximately 0.6–1.2 mEq/L.
• Lamotrigine requires slow titration to reduce the risk of serious rash.

Contraindicated / avoid

• Valproate in pregnancy and generally in persons of childbearing potential without reliable contraception (neural tube defects, impaired neurodevelopment); carbamazepine is likewise teratogenic.
• MAOIs with SSRIs/SNRIs/triptans/linezolid — 2-week washout, 5 weeks after fluoxetine; MAOIs plus tyramine-rich foods cause hypertensive crisis.
• NSAIDs, thiazides, and ACE inhibitors raise lithium levels.

Disease complications

• Suicide — the emergency. Highest in mixed states, psychotic depression, comorbid substance use, and early in recovery when psychomotor retardation lifts before mood does (the patient regains the energy to act). Bipolar disorder carries a particularly high lifetime suicide risk.
• Catatonia: mutism, immobility, negativism; risk of dehydration, aspiration, pressure ulcers, and venous thromboembolism. A lorazepam challenge is both diagnostic and therapeutic; ECT is definitive.
• Manic sequelae: financial ruin, sexual and legal consequences, and injury from reckless behavior — the functional impairment that separates mania from hypomania.
• Medical comorbidity: elevated cardiovascular mortality, poorer adherence in diabetes and post-MI care, and substance use disorders layered onto self-medication.

Treatment complications

• Serotonin syndrome (emergency): acute onset of clonus, hyperreflexia (lower > upper limbs), hyperthermia, agitation, mydriasis, diarrhea after adding a second serotonergic agent. Stop all serotonergic drugs, cool aggressively, give benzodiazepines; cyproheptadine is the antidote. Contrast with the lead-pipe rigidity, bradyreflexia, and slower onset of neuroleptic malignant syndrome.
• Lithium toxicity (emergency): coarse tremor, ataxia, vomiting, confusion, seizures — precipitated by dehydration, NSAIDs, thiazides, ACE inhibitors, or acute kidney injury. Hemodialysis for severe toxicity. Chronic use causes nephrogenic diabetes insipidus, hypothyroidism, and hyperparathyroidism/hypercalcemia.
• Valproate: hepatotoxicity, pancreatitis, hyperammonemic encephalopathy, thrombocytopenia, weight gain, and teratogenicity (neural tube defects).
• Carbamazepine: agranulocytosis and aplastic anemia, hyponatremia/SIADH, hepatic enzyme induction, and **SJS/TEN associated with HLA-B*1502** in patients of Asian ancestry (test before starting).
• Lamotrigine: Stevens-Johnson syndrome/TEN with rapid titration — any rash is an emergency until proven otherwise.
• Antipsychotics: metabolic syndrome, extrapyramidal symptoms, tardive dyskinesia, hyperprolactinemia, and NMS.
• Antidepressants: sexual dysfunction (the leading cause of nonadherence), SIADH/hyponatremia in older adults, GI bleeding when combined with NSAIDs, QT prolongation with citalopram (FDA dose limits, lower in patients over 60), discontinuation syndrome with abrupt cessation of paroxetine or venlafaxine, and the FDA boxed warning for increased suicidal ideation in patients under 25. Bupropion lowers the seizure threshold — avoid in bulimia, anorexia, and seizure disorder.

• Before prescribing any antidepressant, ask about prior mania or hypomania. A depressed patient with a family history of bipolar disorder, early onset, hypersomnia/hyperphagia, or psychotic features is the stem's setup for an antidepressant-induced manic switch. The best next step is a mood-stabilizer-based regimen, not an SSRI alone.
• **Decreased need for sleep is not insomnia.** The manic patient sleeps three hours and feels energized; the depressed patient sleeps three hours and feels exhausted. This single distinction sorts most mood-disorder vignettes.
• The best next step in a newly depressed patient is almost always a suicide risk assessment plus TSH. Examiners reward direct questioning about suicidal ideation and reward excluding hypothyroidism before attributing symptoms to primary psychiatric illness.
• ECT is the answer for psychotic depression, catatonia, refusal of food and fluids, imminent suicidality, refractory illness, and depression or mania in pregnancy. The expected adverse effect is transient anterograde and retrograde amnesia — not brain damage.
• Lithium is the mood stabilizer with the best anti-suicide evidence, and it is the one requiring monitoring of level, renal function, TSH, and calcium. When a stable lithium patient becomes tremulous and ataxic, look in the stem for a new NSAID, thiazide, ACE inhibitor, or dehydration.
• Any rash on lamotrigine is Stevens-Johnson until proven otherwise — the reason for the slow titration schedule. Do not confuse this with carbamazepine's agranulocytosis/aplastic anemia or valproate's hepatotoxicity and neural tube defects.
• Serotonin syndrome has clonus and hyperreflexia; NMS has lead-pipe rigidity and bradyreflexia. Onset is hours for serotonin syndrome and days for NMS. Cyproheptadine versus dantrolene/bromocriptine.
• The common distractor: mistaking postpartum blues (peaks within the first week, self-limited, no functional impairment) for postpartum depression, and mistaking either for postpartum psychosis — the one that is a true emergency, is strongly associated with underlying bipolar disorder, and requires hospitalization because of infanticide and suicide risk.

• Major Depressive Disorder (MDD): 5+ symptoms for ≥2 weeks including depressed mood or anhedonia (one must be present)
• Bipolar Disorder Type I: ≥1 manic episode (manic episodes are pathognomonic); Type II has hypomanic + depressive episodes
• Mania vs. Hypomania: Mania lasts ≥7 days with marked functional impairment or psychosis; hypomania lasts ≥4 days without severe impairment
• Persistent Depressive Disorder (Dysthymia): Depressed mood ≥2 years (≥1 year in children) with fewer symptoms than MDD
• Postpartum mood disorders: Postpartum blues (normal, transient); postpartum depression (MDD within 4 weeks); postpartum psychosis (rare, medical emergency)

• MDD: Patient reports "nothing brings me joy anymore" (anhedonia), poor sleep/appetite, low energy, feels worthless, concentration problems for >2 weeks
• Bipolar I (Manic): Decreased need for sleep (feels rested after 3 hours), racing thoughts, flight of ideas, increased talkativeness, reckless spending/behavior, grandiosity
• Bipolar II: Periods of high energy/productivity (hypomania) alternating with depression; less severe than Type I
• Dysthymia: "I've been down for years" – chronic, low-grade depressed mood

• Antidepressant monotherapy in Bipolar Disorder: Can precipitate manic episode; must combine with mood stabilizer (lithium, valproate, lamotrigine, atypical antipsychotics)
• Missing Hypomania in Bipolar II: Patients often present in depressive episodes; always ask about periods of increased energy, decreased sleep need, reckless behavior—don't misdiagnose as unipolar depression
• Not screening for suicide: Standard of care in all depressed patients—ask directly ("Do you have thoughts of harming yourself?"); high-risk patients need safety assessment and may require hospitalization