CCS Integrated Cases

CCS case: outpatient depression with treatment initiation

Clinical Overview and When to Suspect Major Depressive Disorder

— Preferred screening tool: PHQ-2 (2 questions over past 2 weeks); if positive (≥3), administer PHQ-9

— PHQ-9 cutoffs: 5–9 mild, 10–14 moderate, 15–19 moderately severe, ≥20 severe

— SIGECAPS: Sleep change, Interest loss, Guilt/worthlessness, Energy loss, Concentration impairment, Appetite/weight change, Psychomotor change, Suicidal ideation

— Symptoms cause functional impairment and are not better explained by substance, medical condition, or bereavement

— Vague somatic complaints: fatigue, headache, GI upset, chronic pain without clear etiology

— Frequent no-shows, poor chronic disease control (e.g., uncontrolled diabetes, HTN)

— Postpartum window, post-MI, post-stroke, new cancer diagnosis, chronic pain

— Older adults presenting with "pseudodementia" or weight loss

Board pearl: A patient with depressive symptoms and prior "energetic, sleepless, spending sprees" lasting a week has bipolar I — starting an SSRI alone risks precipitating mania. Always ask before prescribing.

Major depressive disorder (MDD) is among the most common conditions in primary care, with a lifetime prevalence of ~17% in US adults and a 12-month prevalence near 8%

USPSTF (2023): screen all adults ≥18, including pregnant and postpartum patients, for depression when systems are in place to ensure diagnosis, treatment, and follow-up

DSM-5 criteria: ≥5 of 9 symptoms for ≥2 weeks, including at least one of depressed mood or anhedonia

When to suspect in clinic:

CCS case framing: 34-year-old woman presents to outpatient clinic for "fatigue and trouble sleeping for 2 months." On arrival, order PHQ-9, TSH, CBC, CMP, vitamin B12, vitamin D, urine pregnancy if reproductive age

Always rule out bipolar disorder before starting an antidepressant — screen with MDQ or directly ask about prior manic/hypomanic episodes

Co-screen for anxiety (GAD-7) and substance use (AUDIT-C, DAST-1) — comorbidity is the rule, not the exception

Presentation Patterns and Key History

— Mood: persistent sadness, tearfulness, hopelessness, irritability (especially in men, adolescents, elderly)

— Anhedonia: loss of interest/pleasure in previously enjoyed activities — often more specific than sadness

— Neurovegetative: insomnia (typically early-morning awakening) or hypersomnia; appetite/weight changes; fatigue out of proportion to activity

— Cognitive: poor concentration, indecisiveness, excessive guilt, worthlessness

— Psychomotor: retardation (slowed speech/movement) or agitation

— Use C-SSRS (Columbia Suicide Severity Rating Scale) or PHQ-9 item 9

— Ask explicitly: ideation, plan, intent, access to means (especially firearms), prior attempts, family history

— Risk factors: male, older age, white/Native American, prior attempt, substance use, recent loss, chronic pain, access to lethal means

— Symptom onset, duration, triggers, prior episodes

— Prior trials of antidepressants (drug, dose, duration, response, side effects)

— Manic/hypomanic screening: decreased need for sleep with high energy, grandiosity, racing thoughts, hypersexuality

— Psychotic features (mood-congruent delusions, hallucinations) → refer to psychiatry

— Substance use: alcohol, cannabis, stimulants, opioids

— Trauma history (PTSD overlap), recent loss (complicated grief)

— Medical: thyroid disease, anemia, OSA, chronic pain, recent steroid or interferon use

Step 3 management: A patient with PHQ-9 of 18 and item 9 positive for "thoughts of being better off dead, no plan" requires same-visit safety planning, means restriction counseling (firearms, medications), and rapid follow-up within 1 week — not automatic hospitalization.

Core symptom clusters to elicit on outpatient interview:

Suicide risk assessment is mandatory at every visit:

Key history elements:

Family history: MDD, bipolar disorder, completed suicide, response to specific antidepressants (pharmacogenomic clue)

Social history: housing, employment, relationships, intimate partner violence screen, social support

Physical Exam Findings and Mental Status Assessment

— Appearance: poor grooming, weight loss/gain, psychomotor slowing

— Skin: dry skin (hypothyroid), pallor (anemia), self-injury marks on forearms

— Thyroid: goiter, nodules

— Neuro: focal deficits (rule out stroke, especially in older "depressed" patient), tremor (Parkinson's), gait

— Cardiopulmonary: baseline before starting QT-prolonging agents

— Appearance/behavior: disheveled, poor eye contact, psychomotor retardation

— Speech: slowed, soft, decreased latency to respond

— Mood: patient's self-report ("sad," "empty," "numb")

— Affect: observer's assessment — restricted, blunted, tearful, congruent

— Thought process: linear, goal-directed (vs. tangential in mania, disorganized in psychosis)

— Thought content: hopelessness, guilt, worthlessness, SI/HI, delusions, hallucinations

— Cognition: orientation, attention (serial 7s), memory, executive function — formal MoCA if older adult

— Insight/judgment: typically preserved in MDD; impaired suggests psychosis or substance use

— Pseudodementia: acute onset, patient complains of memory loss, "I don't know" answers, mood symptoms precede cognitive

— Dementia: insidious, patient minimizes deficits, confabulates, cognitive symptoms first

Key distinction: Flat affect with intact orientation and "I don't know" responses in a 72-year-old with weight loss suggests depression-related pseudodementia — treat the depression and cognition often improves. Don't anchor on Alzheimer's.

Depression is a clinical diagnosis, but exam serves to rule out medical mimics and document baseline

Vital signs: weight (track at follow-ups), BP (baseline before SNRI/bupropion), HR (bradycardia in hypothyroidism, tachycardia in hyperthyroid/anxiety)

General exam:

Mental Status Exam (MSE) — document explicitly:

Distinguishing pseudodementia from dementia in older adults:

Diagnostic Workup — Initial Labs and Screening

— TSH (with reflex free T4) — hypothyroidism is the classic mimic

— CBC — anemia presents with fatigue

— CMP — electrolytes, glucose (hypo/hyperglycemia), liver/renal function (baseline before drug therapy)

— Vitamin B12 (and folate if alcohol use or malabsorption) — deficiency causes fatigue, cognitive slowing, neuropsychiatric symptoms

— Vitamin 25-OH D — deficiency associated with depressive symptoms; replete if low

— Urine pregnancy test in reproductive-age women before prescribing

— HbA1c if risk factors — diabetes-depression bidirectional comorbidity

— Urine drug screen if substance use suspected

— HIV, RPR if risk factors — both can present with neuropsychiatric symptoms

— ANA, ESR/CRP if autoimmune features

— Cortisol/dexamethasone suppression only if Cushing's features (moon facies, central obesity, striae)

— Ferritin if menstruating, fatigue, restless legs symptoms

— PHQ-9: tracks treatment response; goal is ≥50% reduction at 6–8 weeks and remission (PHQ-9 <5) by 10–12 weeks

— GAD-7: comorbid anxiety, also tracks response

— MDQ or CIDI: bipolar screening before SSRI/SNRI initiation

— AUDIT-C / DAST-10: substance use

— C-SSRS: suicide risk

Board pearl: New-onset depression in a 65-year-old with apathy, gait change, and urinary incontinence — consider NPH or frontal pathology, not just MDD. Order MRI.

CCS pearl: On Day 1 of the outpatient visit, order PHQ-9 first to quantify severity, then a focused lab panel to rule out medical mimics — don't order a shotgun workup

Initial labs to order (same-visit or next-business-day):

Targeted labs based on history:

Validated rating scales (Day 1, re-administer at follow-up):

ECG: not routinely required; obtain baseline if starting citalopram (especially dose >20 mg in elderly), TCA, or in patients with cardiac disease or QT-prolonging polypharmacy

Do NOT order brain imaging routinely — only if focal neuro signs, new-onset late-life depression with cognitive change, or atypical features

Diagnostic Workup — Advanced and Confirmatory Studies

— First episode of depression after age 50 with cognitive changes

— Focal neurologic findings

— Sudden onset without psychosocial trigger

— History of head trauma, seizures, or stroke

— Findings that change management: tumors, NPH, white matter disease (vascular depression), MS

— Snoring, witnessed apnea, daytime sleepiness, refractory fatigue despite mood improvement

— OSA is highly comorbid with treatment-resistant depression; treating OSA can resolve depression

— Not recommended for first-line use by APA

— May guide therapy after ≥2 failed adequate trials (treatment-resistant depression)

— Helps explain ultra-rapid or poor metabolizer phenotypes affecting SSRI/TCA dosing

— Diagnostic uncertainty (bipolar vs unipolar, MDD vs PTSD vs adjustment disorder)

— Psychotic features

— Two or more failed adequate antidepressant trials

— Severe functional impairment, catatonia, or active SI with plan

Step 3 management: A 42-year-old with 3 failed SSRIs at adequate dose/duration meets criteria for treatment-resistant depression — next steps include psychiatric referral, augmentation (lithium, atypical antipsychotic, T3), or consideration of esketamine or ECT. Pharmacogenomic testing may be useful here, not at initial diagnosis.

MDD is a clinical diagnosis — there is no confirmatory imaging or biomarker. Advanced workup is reserved for atypical features, treatment resistance, or red flags

Brain MRI indications:

Sleep study (polysomnography) if:

EEG: rarely needed — consider if episodic mood symptoms with altered awareness (temporal lobe epilepsy mimicking depression)

Neuropsychological testing: useful when distinguishing pseudodementia from early dementia, or assessing cognitive deficits before vocational decisions

Pharmacogenomic testing (CYP2D6, CYP2C19):

Confirmatory diagnostic clarification — refer to psychiatry if:

Adequate trial definition: therapeutic dose for ≥6–8 weeks before declaring failure — premature switching is the most common outpatient error

Risk Stratification and First-Line Management Logic

— Mild (PHQ-9 5–9): psychotherapy alone (CBT or IPT) OR pharmacotherapy; behavioral activation, exercise prescription (150 min/week moderate aerobic), sleep hygiene

— Moderate (PHQ-9 10–14): pharmacotherapy OR psychotherapy; combination is superior for sustained remission

— Moderately severe (PHQ-9 15–19): combination therapy (medication + psychotherapy) strongly preferred

— Severe (PHQ-9 ≥20) or with SI/psychosis: combination, psychiatric referral, consider ECT if catatonic, psychotic, or pregnant with severe symptoms

— Low risk (passive ideation, no plan, protective factors): outpatient with safety plan, 1-week follow-up, means restriction

— Moderate (ideation with vague plan, no intent): same-day psychiatric evaluation, intensive outpatient or partial hospitalization

— High (plan, intent, access, prior attempt): emergency department or direct admission; do not allow patient to leave alone

— Set expectations: 2–4 weeks for early response, 6–8 weeks for full effect

— Discuss side effects, especially sexual dysfunction, GI, and transient activation/SI in patients <25

— Black box warning: increased suicidality in patients <25 — closer monitoring, not avoidance

— Discuss duration: continue ≥6–12 months after remission for first episode; 2+ years or indefinite for recurrent

— Consider side-effect profile, comorbidities, prior response, cost, drug interactions, pregnancy status

Board pearl: Combination of pharmacotherapy + psychotherapy outperforms either alone for moderate-to-severe MDD and reduces relapse — on the exam, when severity is moderate+, choose both.

CCS pearl: On Day 1 after diagnosis, stratify severity by PHQ-9 and choose initial modality accordingly — document shared decision-making

Severity-based initial management:

Suicide risk triage:

Shared decision-making conversation (initial visit):

Choice of first-line agent: any SSRI is first-line for most patients

Pharmacotherapy — First-Line Drug Regimen

— Sertraline 50 mg daily (start 25 mg if anxious); titrate to 100–200 mg

— Escitalopram 10 mg daily; titrate to 20 mg (preferred in elderly; minimal interactions)

— Fluoxetine 20 mg daily; long half-life (good for nonadherent patients, no taper needed)

— Citalopram 20 mg daily; max 40 mg (max 20 mg if >60 yo) — QT prolongation dose-dependent

— Paroxetine — avoid in elderly (anticholinergic), avoid in pregnancy (cardiac defects, Category D)

— Duloxetine 30 mg → 60 mg; check BP, LFTs

— Venlafaxine XR 75 mg → 225 mg; dose-dependent BP elevation, difficult discontinuation syndrome

— Bupropion SR 150 mg BID or XL 300 mg daily — no sexual side effects, no weight gain, helps with smoking cessation; contraindicated in seizure disorder, eating disorders, active alcohol/benzo withdrawal

— Mirtazapine 15–45 mg qHS — sedating, increases appetite; ideal for elderly with insomnia and weight loss

— GI upset (transient, take with food)

— Sexual dysfunction (30–50%) — bupropion add/switch or sildenafil

— Activation, jitteriness in first 1–2 weeks — warn but continue

— Hyponatremia (SIADH) — especially elderly; check Na if symptomatic

— Bleeding risk with NSAIDs/anticoagulants — consider PPI

Step 3 management: Patient on SSRI with new sexual dysfunction limiting adherence — switch to bupropion or add bupropion 150 mg daily as augmentation; do not simply stop the SSRI.

SSRIs are first-line — equivalent efficacy across the class; choose by side-effect profile and interactions

Common SSRI starting doses (outpatient):

SNRIs (consider if comorbid chronic pain, neuropathy, fibromyalgia):

Atypicals:

CCS pearl: Day 1 — start sertraline 50 mg PO daily. Order labs. Schedule PHQ-9 recheck and side-effect review at week 2 by phone or telehealth, in-person visit at weeks 4 and 8. If <25 yo, weekly check-ins for first 4 weeks per FDA black box guidance

Common side effects to counsel:

Serotonin syndrome warning: avoid concurrent MAOIs, linezolid, tramadol, triptans, St. John's wort

Non-Pharmacologic and Adjunctive Management

— Cognitive Behavioral Therapy (CBT) — first-line; 12–20 sessions; identifies and modifies maladaptive thoughts/behaviors

— Interpersonal Therapy (IPT) — focuses on role transitions, grief, interpersonal conflict; well-suited for postpartum depression

— Behavioral Activation — structured scheduling of pleasurable/mastery activities; effective even in severe depression

— Problem-Solving Therapy — useful in primary care, brief format

— Mindfulness-Based Cognitive Therapy (MBCT) — relapse prevention

— Aerobic exercise 150 min/week moderate intensity — comparable to medication for mild-moderate MDD

— Sleep hygiene: fixed wake time, no screens 1 hr before bed, limit alcohol/caffeine

— Bright light therapy 10,000 lux × 30 min AM — first-line for seasonal pattern; adjunct for nonseasonal

— Mediterranean diet — modest benefit

— Reduce alcohol — bidirectional worsening

— Collaborative care model (PCP + care manager + psychiatric consultant) — strongest evidence base for primary care depression

— App-based CBT (e.g., FDA-cleared digital therapeutics) as adjuncts

— ECT: gold standard for severe, psychotic, catatonic, pregnant, suicidal, or refractory depression; response rate ~70–80%

— rTMS (repetitive transcranial magnetic stimulation): for patients who have failed ≥1 antidepressant; outpatient, no anesthesia

— Esketamine intranasal (Spravato): TRD; REMS program; 2-hour monitoring post-dose

— Vagus nerve stimulation: chronic, severe TRD

Board pearl: Pregnant patient with severe suicidal depression refusing medications — ECT is safe and effective in all trimesters and is the treatment of choice when rapid response is needed.

Psychotherapy — evidence-based modalities for MDD:

CCS pearl: Day 1 — place referral to outpatient CBT or IPT, schedule first session within 2 weeks. Document modality preference and patient access (telehealth vs in-person, insurance coverage, language needs)

Lifestyle prescriptions (write as explicit orders):

Digital/collaborative care:

Advanced interventions (for treatment-resistant or severe):

Special Populations — Elderly and Renal/Hepatic Impairment

— Often presents as somatic complaints, cognitive slowing, irritability, anhedonia rather than sadness

— Use Geriatric Depression Scale (GDS-15) — less somatic items than PHQ-9

— Pseudodementia — improves with antidepressant treatment

— Higher suicide rate, especially in older white men with access to firearms

— Start at half the usual adult dose, titrate slowly

— Preferred agents: sertraline, escitalopram, mirtazapine (for insomnia/weight loss)

— Avoid: paroxetine (anticholinergic), TCAs (anticholinergic, orthostasis, cardiac), benzodiazepines (falls, delirium) — all on Beers list

— Citalopram max 20 mg/day in patients >60 due to QT prolongation

— Monitor hyponatremia (SIADH) — check Na at 2 and 4 weeks; risk highest in first month

— Monitor falls — orthostatic vitals at every visit

— Monitor bleeding — SSRIs + NSAIDs/antiplatelets/anticoagulants → add PPI

— Sertraline, citalopram, escitalopram: generally safe; no dose adjustment typically required, but go slow if CrCl <30

— Venlafaxine, duloxetine: reduce dose if CrCl <30; avoid duloxetine if CrCl <30

— Bupropion: active metabolites accumulate — reduce dose

— Lithium (augmentation): renally cleared, narrow window — avoid or reduce significantly in CKD

— Avoid duloxetine (hepatotoxicity, contraindicated in chronic liver disease/heavy alcohol use)

— Sertraline, citalopram preferred — lower doses

— Avoid nefazodone (black box hepatotoxicity)

— Monitor LFTs at baseline and 3 months in chronic liver disease

Step 3 management: 78-year-old with depression, BPH, and chronic kidney disease (eGFR 35) — start sertraline 25 mg daily, avoid paroxetine and TCAs, check Na at 2 and 4 weeks, screen for falls, and counsel on firearm safety.

Geriatric depression — clinical pearls:

Pharmacology adjustments in elderly:

Renal impairment:

Hepatic impairment:

Special Populations — Pregnancy, Postpartum, and Adolescents

— Untreated depression carries risks: preterm birth, low birth weight, postpartum depression, impaired bonding, suicide

— Risk-benefit discussion with patient is documented at every visit

— First-line SSRIs in pregnancy: sertraline, citalopram, escitalopram — most safety data

— Avoid paroxetine — associated with cardiac malformations (Ebstein-like, septal defects)

— Late third trimester: counsel about neonatal adaptation syndrome (jitteriness, feeding difficulty, transient) and small risk of PPHN

— Do not abruptly stop antidepressants in pregnancy — relapse risk high; continue effective regimen

— ECT safe in all trimesters for severe/refractory cases

— Screen with Edinburgh Postnatal Depression Scale (EPDS) at well-child visits and 6-week postpartum visit

— Onset within 12 months of delivery; distinguish from baby blues (resolves by 2 weeks) and postpartum psychosis (psychiatric emergency, hospitalize)

— Sertraline is preferred for breastfeeding (minimal milk transfer)

— Zuranolone (oral) and brexanolone (IV) — neurosteroids approved for postpartum depression, rapid onset

— Refer postpartum psychosis to ED immediately; high infanticide and suicide risk

— Fluoxetine is FDA-approved first-line (>8 years) — strongest evidence

— Escitalopram approved age ≥12

— Black box warning for increased suicidality in patients <25 — weekly contact for first 4 weeks, then biweekly until 12 weeks

— Combination CBT + fluoxetine superior to either alone (TADS trial)

— Avoid paroxetine, venlafaxine in adolescents (efficacy/safety concerns)

— Screen for bullying, family conflict, substance use, gender identity concerns

Board pearl: Pregnant patient with stable MDD on paroxetine for 3 years asks about continuing — switch electively to sertraline before conception if possible; if already pregnant, weigh relapse risk vs cardiac teratogen risk in shared decision.

Pregnancy:

Postpartum depression:

Adolescents (age 12–17):

Complications and Adverse Outcomes

— Lifetime suicide risk in MDD ~5–8%; higher in those hospitalized

— Risk peaks early in treatment as energy returns before mood improves — counsel and monitor closely in first 2–4 weeks

— Adolescents and young adults <25: FDA black box for increased SI

— Means restriction (firearms, lethal medications) is the single most effective intervention

— Serotonin syndrome: triad of mental status change, autonomic instability (HTN, tachycardia, hyperthermia), neuromuscular hyperactivity (clonus, hyperreflexia, rigidity); occurs with SSRI + MAOI/linezolid/tramadol/triptan/St. John's wort

— Management: stop offending agent, supportive care, cyproheptadine for moderate-severe

— SIADH/hyponatremia: elderly, first 4 weeks; presents as fatigue, confusion, seizure

— GI bleeding: SSRI + NSAID/anticoagulant — add PPI

— QT prolongation: citalopram >40 mg, TCAs — baseline ECG if risk factors

— Antidepressant discontinuation syndrome: FINISH (Flu-like, Insomnia, Nausea, Imbalance, Sensory disturbances "brain zaps," Hyperarousal); worst with short half-life (paroxetine, venlafaxine); taper over 2–4 weeks minimum

— Treatment-emergent mania/hypomania: switch suggests bipolar; stop SSRI, refer

— Sexual dysfunction: 30–50%; bupropion add/switch

— Weight gain: paroxetine, mirtazapine

— Bupropion: seizure risk dose-dependent; contraindicated if eating disorder or seizure history

— Job loss, relationship breakdown, substance use

— Worse outcomes in comorbid CAD, CHF, diabetes (depression is independent CV risk factor post-MI)

— Pediatric school failure, suicide

CCS pearl: Patient on venlafaxine for 18 months stops abruptly; presents with dizziness, nausea, "brain zaps." Diagnosis: discontinuation syndrome. Management — restart venlafaxine, taper over 4+ weeks. Educate patient never to stop abruptly.

Suicide:

Medication adverse effects:

Functional consequences of untreated depression:

When to Escalate Care — Referral and Inpatient Triage

— Active suicidal ideation with plan and intent

— Recent attempt, especially with high-lethality method

— Inability to commit to safety plan or no protective factors

— Severe MDD with psychotic features (mood-congruent delusions, hallucinations)

— Catatonia (mutism, posturing, waxy flexibility) — needs benzodiazepine challenge, ECT

— Severe self-neglect, dehydration, malnutrition

— Postpartum psychosis

— Acute mania (if antidepressant precipitated switch)

— Encourage voluntary first

— Involuntary hold (varies by state, often 72 hours): danger to self/others or grave disability

— Document the criteria met; preserve the therapeutic alliance

— Diagnostic uncertainty (bipolar suspicion, PTSD, personality disorder)

— Two failed adequate antidepressant trials

— Need for augmentation (lithium, atypical antipsychotic, T3, esketamine)

— Severe symptoms with marginal response

— Comorbid severe anxiety, OCD, eating disorder, substance use disorder

— Patients needing more structure than weekly therapy but not requiring 24/7 care

— Step-down from inpatient

— Care manager performs PHQ-9 follow-ups, medication adherence checks

— Curbside psychiatric consultation

— Strong evidence base, particularly for moderate depression

— Severe MDD with SI, psychotic depression, catatonia, pregnancy with severe MDD, treatment resistance

Step 3 management: Patient with PHQ-9 of 24, auditory hallucinations telling her she is worthless, and a stockpiled bottle of acetaminophen at home — this is MDD with psychotic features and high suicide risk: arrange direct psychiatric admission, not outpatient follow-up.

CCS pearl: Escalation decisions hinge on safety, severity, and treatment response — document the rationale every time

Psychiatric emergency / immediate ED or admission:

Voluntary vs involuntary admission:

Outpatient psychiatric referral (urgent, within 1–2 weeks):

Partial hospitalization / intensive outpatient program (PHP/IOP):

Collaborative care referral within primary care:

ECT consultation:

Key Differentials — Other Mood and Psychiatric Disorders

— Lifetime history of mania (BPI) or hypomania (BPII)

— Starting an SSRI alone risks precipitating mania — always screen with MDQ

— Treatment: mood stabilizer (lithium, valproate, lamotrigine) ± atypical antipsychotic

— Lamotrigine is preferred for bipolar depression

— Depressed mood most days for ≥2 years (≥1 year in children/adolescents)

— Less severe than MDD but chronic; "double depression" = MDD episode superimposed

— Treatment same as MDD

— Mood symptoms in luteal phase only, resolving with menses

— First-line: SSRI (continuous or luteal-phase dosing); combined OCPs (drospirenone)

— Symptoms within 3 months of identifiable stressor, do not meet full MDD criteria, resolve within 6 months of stressor resolution

— Treatment: supportive psychotherapy, problem-solving; medications usually unnecessary

— DSM-5 removed bereavement exclusion; if full MDD criteria met during grief, diagnose and treat

— Prolonged grief disorder: intense grief >12 months in adults

— Worry, restlessness, muscle tension; high overlap with MDD

— Treatment: SSRI/SNRI + CBT (same first-line agents)

— Trauma exposure, intrusions, avoidance, hyperarousal, negative cognitions

— First-line: sertraline, paroxetine (FDA-approved), trauma-focused CBT, EMDR

Key distinction: Patient endorses 2 weeks of depressed mood after a layoff, no anhedonia, no SI, functioning at 70% — this is adjustment disorder, not MDD; supportive therapy is first-line, not an SSRI.

Bipolar disorder (I or II):

Persistent Depressive Disorder (dysthymia):

Premenstrual Dysphoric Disorder (PMDD):

Adjustment Disorder with Depressed Mood:

Bereavement / Prolonged Grief Disorder:

Generalized Anxiety Disorder (GAD):

Post-Traumatic Stress Disorder (PTSD):

Schizoaffective disorder: psychotic symptoms ≥2 weeks without mood symptoms

Substance-induced mood disorder: alcohol, cocaine withdrawal, sedative withdrawal, stimulant intoxication/withdrawal

Key Differentials — Medical and Substance-Induced Mimics

— Hypothyroidism — fatigue, weight gain, cold intolerance, bradycardia, dry skin, constipation; check TSH

— Hyperthyroidism — can present with anxiety/depression mixed picture

— Cushing's syndrome — depression in 60%, central obesity, striae, HTN

— Addison's disease — fatigue, weight loss, hyperpigmentation, hyponatremia/hyperkalemia

— Hyperparathyroidism — "stones, bones, abdominal groans, psychiatric overtones"

— Diabetes — depression-diabetes bidirectional; poor glycemic control worsens mood

— Parkinson's disease — depression precedes motor symptoms in 30%; treat with SSRI (avoid TCAs anticholinergic)

— Stroke — post-stroke depression in 30%; left frontal lesions classic association

— Multiple sclerosis — depression in up to 50%; check for relapse if new mood symptoms

— Dementia — early Alzheimer's, frontotemporal, vascular dementia

— NPH — gait, incontinence, cognitive decline; "wet, wobbly, wacky"

— Subdural hematoma in elderly with falls

— Brain tumor (frontal especially)

— HIV (especially CNS involvement), neurosyphilis, Lyme, mononucleosis, COVID-19 post-infection

— B12 deficiency — fatigue, paresthesias, megaloblastic anemia, neuropsychiatric

— Folate deficiency

— Vitamin D deficiency

— Iron deficiency

— Corticosteroids, interferon-α, beta-blockers (less than thought), isotretinoin, levetiracetam, varenicline (controversial), hormonal contraceptives, opioids, GnRH agonists, efavirenz

— Alcohol (depressant; withdrawal also depressogenic)

— Cannabis (chronic heavy use)

— Cocaine/stimulant withdrawal — "crash" mimics severe depression

— Opioid withdrawal

— Sedative-hypnotic withdrawal

— OSA, chronic insomnia, restless legs syndrome — all can mimic or worsen depression

Board pearl: Patient on interferon-α for hepatitis C develops new SI — interferon-induced depression is well-documented; consider switching antiviral regimen and start SSRI; psychiatric consult.

Endocrine:

Neurologic:

Infectious:

Nutritional:

Medications causing depression:

Substance-related:

Sleep:

Secondary Prevention, Maintenance, and Long-Term Plan

— First episode: continue at full therapeutic dose for 6–12 months after symptom remission (acute + continuation phase) to prevent relapse

— Second episode: continue 1–3 years, especially if severe or with risk factors

— Third episode or recurrent: consider indefinite maintenance

— Risk factors favoring longer treatment: severe episodes, psychotic features, suicide attempt, chronic stressors, family history, residual symptoms

— Response: ≥50% PHQ-9 reduction from baseline

— Remission: PHQ-9 <5

— Recovery: remission sustained ≥4 months

— Relapse: return of symptoms during continuation phase

— Recurrence: new episode after recovery

— Never stop abruptly (except fluoxetine — long half-life self-tapers)

— Taper over 2–4 weeks minimum, longer for paroxetine and venlafaxine (4–8 weeks)

— Educate patient about discontinuation symptoms ("brain zaps," dizziness, flu-like)

— Continue psychotherapy (especially MBCT for relapse prevention) even after medication taper

— Maintain exercise, sleep, social engagement

— Address modifiable risk factors: alcohol, substance use, untreated OSA, chronic pain

— Patient awareness of early warning signs ("relapse signature": insomnia, withdrawal, irritability)

— Cardiovascular disease: depression doubles post-MI mortality; treat aggressively (sertraline is safe post-MI)

— Diabetes: collaborative care improves both A1c and depression

— Chronic pain: SNRI (duloxetine) or TCA (amitriptyline)

Step 3 management: Patient with 3rd lifetime MDD episode, now in remission for 4 months on escitalopram — recommend indefinite maintenance therapy at current dose with annual reassessment, plus continued MBCT or CBT.

Duration of antidepressant therapy after remission:

Defining response and remission:

Tapering antidepressants:

Relapse prevention strategies:

Comorbidity management:

Vaccinations, cancer screening, lifestyle counseling: don't neglect preventive care; depressed patients are less likely to receive USPSTF-recommended services

Follow-Up, Monitoring, and Outpatient Cadence

— Week 1–2: phone or telehealth check — tolerability, side effects, adherence, suicide screen (especially <25 yo)

— Week 4: in-person — PHQ-9, side effects, dose titration if partial response

— Week 6–8: in-person — assess full response; if <50% PHQ-9 reduction, optimize dose, switch, or augment

— Week 12: assess for remission (PHQ-9 <5); if not achieved, escalate (psychiatry referral, augmentation)

— After remission: visits every 3 months during continuation phase; every 6 months in maintenance

— PHQ-9 score (measurement-based care)

— Side effects

— Adherence

— Substance use (AUDIT-C)

— Suicide risk (C-SSRS or PHQ-9 item 9)

— Functional status (work, relationships, ADLs)

— Sleep, appetite, energy

— No response (<25% improvement): switch antidepressant (different SSRI or different class)

— Partial response (25–49%): optimize dose to maximum tolerated; if still partial, augment (bupropion add-on, atypical antipsychotic like aripiprazole 2–5 mg, lithium, T3)

— Response (≥50%) but not remission: continue, reassess in 4 weeks; consider augmentation

— Remission: continue continuation phase 6–12 months

— Exercise prescription, sleep hygiene

— Limit alcohol

— Reinforce psychotherapy attendance

— Means restriction

— Stigma normalization, treatment expectations

— Communicate with therapist (signed release)

— Coordinate with psychiatrist if co-managed

— Update medication reconciliation across all clinicians

Board pearl: Measurement-based care — using serial PHQ-9 to guide treatment decisions — significantly improves remission rates over usual care. Always re-administer PHQ-9 at follow-up visits.

CCS pearl: Build the visit schedule explicitly into the case — depression care is defined by measurement-based follow-up, not just prescriptions

Standard outpatient follow-up cadence:

At each visit, document:

Decision rules at week 6–8:

Counseling at every visit:

Care team handoffs:

Ethical, Legal, and Patient Safety Considerations

— Discuss expected onset (2–4 weeks for early effect, 6–8 weeks for full)

— Side effects, including sexual dysfunction, weight changes, GI

— Black box warning for patients <25 — discuss explicitly and document

— Discontinuation syndrome — never stop abruptly

— Pregnancy and breastfeeding implications for reproductive-age patients

— Document the conversation in the chart

— Depression itself does not equal lack of capacity — most depressed patients retain decision-making capacity

— Severe depression with psychosis or active SI may impair capacity for treatment refusal — assess formally

— Adolescents: confidentiality is generally protected, but imminent danger to self/others requires parental notification

— Inform patient of limits at first visit

— Child abuse, elder abuse, intimate partner violence in many states — know your state's requirements

— Tarasoff duty — duty to warn/protect identifiable third parties if patient expresses credible threat (state-dependent)

— Ask all depressed patients about access; counsel removal or safe storage (locked, separate from ammunition)

— Means restriction is ethically and medically appropriate — not a Second Amendment violation in clinical care

— Document the counseling

— Risk of suicide is highest in 30 days after psychiatric hospitalization discharge — ensure follow-up within 7 days of discharge, ideally within 48–72 hours by phone

— Reconcile medications carefully — avoid duplicates or unintended discontinuation

— Provide crisis line (988 Suicide and Crisis Lifeline) in writing

— Counsel on sedating side effects (mirtazapine, TCAs); avoid driving until tolerance established

— Pilots, commercial drivers, military: profession-specific reporting requirements

Step 3 management: Discharge from psychiatric inpatient for suicide attempt — schedule face-to-face follow-up within 7 days, phone contact within 48 hours, provide 988 number, ensure means restriction with collateral (family removed firearms), and provide limited-quantity prescriptions (no >2 weeks at a time).

Informed consent for antidepressants:

Capacity and consent:

Confidentiality and limits:

Mandatory reporting:

Firearm safety counseling:

Patient safety in care transitions:

Driving and work:

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: "Brain zaps" + flu-like illness 3 days after stopping an antidepressant = discontinuation syndrome, not a relapse — restart and taper slowly.

SSRI sexual dysfunction → add or switch to bupropion

Depression + chronic neuropathic pain → duloxetine or TCA

Depression + insomnia + low weight in elderly → mirtazapine

Depression + smoking → bupropion (dual indication)

Seasonal pattern depression → bright light therapy 10,000 lux × 30 min AM

Postpartum depression + breastfeeding → sertraline

Pregnancy + MDD → sertraline, citalopram, escitalopram; avoid paroxetine

Adolescent MDD → fluoxetine (FDA-approved age ≥8)

Treatment-resistant depression → augment with aripiprazole, lithium, T3, or refer for ECT/esketamine/rTMS

Psychotic depression → SSRI + atypical antipsychotic OR ECT

Catatonia → lorazepam challenge; ECT if refractory

Post-MI depression → sertraline (cardiac safety data)

Citalopram >40 mg → QT prolongation (>20 mg in elderly)

SSRI + tramadol/triptan/MAOI/linezolid → serotonin syndrome

Sudden discontinuation of paroxetine/venlafaxine → discontinuation syndrome with "brain zaps"

SIADH from SSRI — most common in elderly women in first month

MAOI + tyramine-rich foods (aged cheese, wine, cured meat) → hypertensive crisis

MAOI + meperidine → fatal serotonin syndrome

Bupropion contraindicated in seizure disorder, eating disorders, MAOI use

Mirtazapine 5-HT2/H1 antagonist — sedation and appetite stimulation

TCA overdose triad — wide QRS, anticholinergic, seizures → sodium bicarbonate

Lithium augmentation — narrow therapeutic window 0.6–1.2 mEq/L; monitor renal, thyroid, calcium

Duration after first episode: 6–12 months continuation; recurrent episodes: indefinite

Adequate trial: therapeutic dose × 6–8 weeks before declaring failure

PHQ-9 ≥10 is conventional threshold for treatment

Collaborative care model — strongest evidence in primary care depression

988 — Suicide and Crisis Lifeline (national)

USPSTF recommends screening all adults, including pregnant and postpartum

Board Question Stem Patterns

Step 3 management: When the stem features both a stable response and patient adherence, the next question is almost always about continuation duration — for a first episode, the answer is 6–12 months after remission.

Stem 1 — Initiation decision: 32-year-old woman, PHQ-9 of 16, no prior treatment, no SI, no manic history → start sertraline 50 mg + refer to CBT, follow-up in 2 weeks

Stem 2 — Bipolar unmasking: Patient started on SSRI develops 5 days of decreased need for sleep, grandiosity, impulsive spending → stop SSRI, refer to psychiatry; consider mood stabilizer; this is BPI

Stem 3 — Adequate trial: Patient on sertraline 50 mg × 8 weeks with minimal improvement → answer is increase dose to therapeutic range (100–200 mg), not switch

Stem 4 — Sexual dysfunction: Patient improved on paroxetine but reports anorgasmia → add or switch to bupropion

Stem 5 — Elderly + hyponatremia: 75-year-old started on citalopram 2 weeks ago, now confused, Na 126 → SSRI-induced SIADH; stop SSRI, fluid restriction, switch class

Stem 6 — Serotonin syndrome: Patient on fluoxetine, given tramadol, develops clonus, hyperreflexia, hyperthermia → discontinue offending agents, supportive care, cyproheptadine

Stem 7 — Discontinuation syndrome: Patient out of paroxetine for 5 days, dizzy, "brain zaps," flu-like → restart and taper slowly

Stem 8 — Pregnancy: 28-year-old at 8 weeks gestation on paroxetine asks about safety → discuss switching to sertraline given paroxetine cardiac teratogen risk; do not abruptly stop

Stem 9 — Postpartum: 4 weeks postpartum, mother reports SI, hearing voices telling her to harm baby → postpartum psychosis, emergency admission

Stem 10 — Suicide risk: PHQ-9 of 22, plan to overdose, stockpiled pills at home → hospitalize (voluntary or involuntary)

Stem 11 — Pseudodementia: 70-year-old with subacute cognitive decline, complains of memory, "I don't know" responses, weight loss → treat depression first; cognition often improves

Stem 12 — Hypothyroidism mimic: 45-year-old with fatigue, weight gain, depression, TSH 22 → levothyroxine, not SSRI

Stem 13 — Treatment-resistant: 2 failed SSRI trials at adequate dose × 8 weeks each → augment with aripiprazole 2–5 mg or refer for ECT

Stem 14 — Black box pediatric: 16-year-old started on fluoxetine → counsel family on increased SI monitoring, weekly contact × 4 weeks

Stem 15 — Adjustment disorder: 2 weeks of low mood after a job loss, no anhedonia, functioning → supportive therapy, not SSRI

One-Line Recap

Outpatient MDD is diagnosed by DSM-5 criteria and PHQ-9 severity, managed with first-line SSRIs plus evidence-based psychotherapy (especially CBT/IPT), monitored using measurement-based care with PHQ-9 at structured intervals, and continued for at least 6–12 months after remission — with vigilant suicide assessment, bipolar screening, and means restriction at every visit.

Board pearl: When the case gives you a depressed patient with any hint of past mania/hypomania, the right answer is never "start an SSRI" — it is mood stabilizer and psychiatric referral. This single decision rule wins many Step 3 stems.

Diagnosis: ≥5 DSM-5 symptoms × 2 weeks including depressed mood or anhedonia; PHQ-9 quantifies severity (10+ treatment threshold, 20+ severe); always rule out bipolar, thyroid, B12, substance use before starting an antidepressant

Initiation: Sertraline/escitalopram first-line for most adults; fluoxetine for adolescents; sertraline in pregnancy/breastfeeding; mirtazapine for elderly with insomnia/anorexia; bupropion for sexual side effects or smoking cessation; avoid paroxetine in elderly and pregnancy

Follow-up cadence: phone at 1–2 weeks, in-person at 4 and 8 weeks with PHQ-9, decide at 6–8 weeks whether to optimize dose, switch, or augment; weekly check-ins × 4 weeks for patients <25 due to FDA black box; psychiatric follow-up within 7 days after inpatient discharge

Long-term: continue 6–12 months after remission for first episode, indefinite maintenance for ≥3 episodes or severe features; taper slowly to avoid discontinuation syndrome; never stop abruptly; means restriction (firearms, medication stockpiles) is the single most effective suicide prevention intervention