11.2 Antidepressant Pharmacotherapy & Treatment-Resistant Depression

ABIM Internal Medicine Exam

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1 Chapter 0: The ABIM Exam, Blueprint & Study Strategy

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2 Chapter 1: Cardiovascular Disease (14% of Exam)

1.1 Ischemic Heart Disease & Acute Coronary Syndromes 1.2 Antithrombotic Therapy, Secondary Prevention & Mechanical Complications of MI 1.3 Atrial Fibrillation, Atrial Flutter & Stroke Prevention 1.4 Supraventricular Tachycardias, Ventricular Arrhythmias & Bradycardias 1.5 Heart Failure: Classification, Staging & Guideline-Directed Medical Therapy 1.6 Device Therapy, HFpEF & the Cardiomyopathies 1.7 Valvular Heart Disease & Endocarditis Prophylaxis 1.8 Pericardial Disease & Acute Aortic Syndromes 1.9 Hypertension: Classification, Diagnosis & Secondary Causes 1.10 Hypertensive Crises & Dyslipidemia 1.11 Adult Congenital Heart Disease & Coarctation of the Aorta 1.12 Syncope: Reflex, Orthostatic & Cardiac Causes 1.13 Cardiac Physical Examination, Murmurs & Antithrombotic Selection

3 Chapter 2: Endocrinology, Diabetes & Metabolism (9% of Exam)

2.1 Diabetes Mellitus: Diagnosis, Glycemic Targets & Pharmacotherapy 2.2 Insulin Therapy, Hyperglycemic Emergencies & Chronic Complications 2.3 Thyroid Function Testing & Hypothyroidism 2.4 Thyrotoxicosis, Thyroid Storm & Thyroid Nodules 2.5 Adrenal & Pituitary Disorders 2.6 Hypercalcemia, Hypocalcemia & Disorders of Mineral Metabolism 2.7 Osteoporosis & Paget Disease of Bone 2.8 Ovarian, Testicular & Reproductive Endocrine Disorders 2.9 Hypoglycemia, Endocrine Tumors, Polyglandular Syndromes & Severe Hypertriglyceridemia

4 Chapter 3: Gastroenterology & Hepatology (9% of Exam)

3.1 Esophageal Disease 3.2 Stomach & Duodenal Disease and Gastrointestinal Hemorrhage 3.3 Inflammatory Bowel Disease 3.4 Celiac Disease & Irritable Bowel Syndrome 3.5 Diverticular Disease & Colorectal Cancer Screening 3.6 Viral Hepatitis, Steatotic & Alcohol-Associated Liver Disease 3.7 Cirrhosis & the Complications of Portal Hypertension 3.8 Acute Pancreatitis 3.9 Chronic Pancreatitis & Biliary Tract Disease 3.10 Inherited, Autoimmune & Drug-Induced Liver Disease 3.11 Small Intestinal Disease, Ischemia & Gastrointestinal Complications of HIV

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4.1 Lower Respiratory Tract Infections & Sepsis Syndromes 4.2 Viral Respiratory Pathogens & Tuberculosis 4.3 Central Nervous System Infections 4.4 Skin, Soft Tissue, Bone & Joint Infections 4.5 Infective Endocarditis & Cardiovascular Infection 4.6 Clostridioides difficile & Catheter-Related Bloodstream Infection 4.7 HIV Diagnosis, Antiretroviral Therapy & Prevention 4.8 Opportunistic Infections & Sexually Transmitted Infections 4.9 Fever of Unknown Origin, Neutropenic Fever & Toxic Shock 4.10 Travel-Related Illness, Vector-Borne Disease & Outbreaks 4.11 Infection Prevention, Nosocomial Infection & Postexposure Prophylaxis 4.12 Rheumatic Fever, Poststreptococcal Disease, Enteric & Hepatic Infections

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5.1 COPD: Diagnosis, GOLD Classification & Initial Pharmacotherapy 5.2 Interventions That Reduce COPD Mortality & Exacerbation Management 5.3 Asthma: Diagnosis, Stepwise Therapy & Status Asthmaticus 5.4 Interstitial Lung Disease & Idiopathic Pulmonary Fibrosis 5.5 Sarcoidosis, Hypersensitivity Pneumonitis & Occupational Lung Disease 5.6 Pulmonary Embolism: Diagnosis, Risk Stratification & Anticoagulation 5.7 Pulmonary Hypertension & Sleep-Disordered Breathing 5.8 Acute Respiratory Distress Syndrome & Mechanical Ventilation 5.9 Pleural Disease, Empyema & Pneumothorax 5.10 Bronchiectasis, Cystic Fibrosis & Restrictive Lung Disease 5.11 Evaluation of Cough, Dyspnea, Hemoptysis & the Solitary Pulmonary Nodule

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6.1 Rheumatoid Arthritis: Diagnosis & Systemic Manifestations 6.2 Antirheumatic Pharmacotherapy & the Spondyloarthropathies 6.3 Gout: Pathophysiology & Acute Management 6.4 Urate-Lowering Therapy & Calcium Pyrophosphate Deposition Disease 6.5 Osteoarthritis 6.6 Systemic Lupus Erythematosus 6.7 Systemic Sclerosis, Sjogren Syndrome & Inflammatory Myopathies 6.8 The Vasculitides 6.9 Regional Musculoskeletal Syndromes, Back Pain & Sports Injuries 6.10 Other Primary Rheumatic Disorders & Mixed Connective Tissue Disease 6.11 Osteonecrosis & Metabolic Bone Disease

8 Chapter 7: Hematology (6% of Exam)

7.1 Approach to Anemia & the Microcytic Anemias 7.2 Macrocytic, Normocytic & Hemolytic Anemias 7.3 Hemoglobinopathies, Thalassemias & Paroxysmal Nocturnal Hemoglobinuria 7.4 Platelet Disorders, Thrombocytopenia & the Bleeding Patient 7.5 Coagulation Factor Disorders, Thrombophilia & Anticoagulant Reversal 7.6 Acute Leukemias, Chronic Leukemias & Myeloproliferative Neoplasms 7.7 Lymphomas & Plasma Cell Disorders 7.8 Myelodysplastic Syndrome, Myeloproliferative Neoplasms & Porphyria 7.9 Transfusion Medicine & Late Complications of Transplantation

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10 Chapter 9: Nephrology & Urology (6% of Exam)

9.1 Acute Kidney Injury: Staging, Etiology & Urine Microscopy 9.2 Glomerular Disorders & Nephrotic Syndrome 9.3 Nephritic Syndromes, RPGN & Indications for Renal Replacement Therapy 9.4 Chronic Kidney Disease: Staging & Progression Retardation 9.5 Complications of Chronic Kidney Disease: Anemia, CKD-MBD & Acidosis 9.6 Hyponatremia, Hypernatremia & Water Balance 9.7 Potassium Disorders & Systematic Acid-Base Analysis 9.8 Renal Tubular Acidosis & Nephrolithiasis 9.9 Prostate Disorders, Urinary Incontinence & Other Urologic Conditions 9.10 Cystic Kidney Disease, Obstructive Uropathy, Tubulointerstitial Disease & Hematuria

11 Chapter 10: Neurology (4% of Exam)

10.1 Acute Ischemic Stroke: Syndromes & Reperfusion 10.2 Transient Ischemic Attack, Secondary Prevention & Hemorrhagic Stroke 10.3 Headache & Facial Pain 10.4 Seizures, Epilepsy & Movement Disorders 10.5 Multiple Sclerosis & Neuromuscular Junction Disorders 10.6 Motor Neuron Disease & Acute Peripheral Neuropathy 10.7 Cranial Neuropathies & Neuro-Ophthalmology 10.8 Peripheral Neuropathies, CNS Tumors & Other Neurologic Disorders

12 Chapter 11: Psychiatry & Behavioral Health (4% of Exam)

11.1 Major Depressive Disorder & Medical Mimics 11.2 Antidepressant Pharmacotherapy & Treatment-Resistant Depression 11.3 Bipolar Disorder, Mood Stabilizers & Lithium Toxicity 11.4 Anxiety, Stress-Related & Obsessive-Compulsive Disorders 11.5 Alcohol Use Disorder & Withdrawal 11.6 Pharmacotherapy for Alcohol & Opioid Use Disorder 11.7 Toxidromes, Psychiatric Emergencies & Suicide Risk Assessment 11.8 Psychotic, Somatic Symptom, Factitious & Personality Disorders 11.9 Eating Disorders, Sleep Disorders & Sexual Health

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12.1 Dermatitis, Papulosquamous & Inflammatory Dermatoses 12.2 Acne, Rosacea & Cutaneous Infections 12.3 Herpes Zoster & Autoimmune Blistering Diseases 12.4 Nodules, Tumors & Cutaneous Oncology 12.5 Dermatologic Emergencies & Severe Cutaneous Adverse Reactions 12.6 Pigment Disorders, Alopecia, Nail Disease & Photosensitivity 12.7 Vascular Dermatoses, Environmental Injury & Cutaneous Signs of Systemic Disease

14 Chapter 13: Obstetrics & Gynecology / Women's Health (3% of Exam)

13.1 Contraception, Preconception Care & Teratogenicity 13.2 Hypertensive Disorders of Pregnancy & Gestational Diabetes 13.3 Thyroid Disease & Venous Thromboembolism in Pregnancy 13.4 Menopause & Menopausal Hormone Therapy 13.5 Abnormal Uterine Bleeding, Endometrial Disease & Gynecologic Cancer Screening 13.6 Breast Disorders & Diseases of the Vulva and Vagina 13.7 Menstrual Disorders, Fibroids, Endometriosis & Early Pregnancy Complications

15 Chapter 14: Geriatric Syndromes (3% of Exam)

14.1 Comprehensive Geriatric Assessment & Frailty 14.2 Falls, Gait Assessment & Polypharmacy 14.3 Urinary Incontinence & Pressure Injuries in Older Adults 14.4 Mild Cognitive Impairment, Dementia & Its Subtypes 14.5 Delirium & the Pharmacotherapy of Cognitive Disorders 14.6 Palliative Care, Hospice & Advance Care Planning 14.7 Chronic Wounds, Nutrition, Swallowing, Constipation & Hip Fracture 14.8 Sensory Impairment, Dizziness, Elder Mistreatment & Care Settings

16 Chapter 15: Allergy & Immunology (2% of Exam)

15.1 Anaphylaxis: Recognition & Emergency Management 15.2 Urticaria & Angioedema 15.3 Drug Allergy, Desensitization & Adult Immunodeficiency 15.4 Food Allergy, Insect Venom Hypersensitivity, Serum Sickness & Contrast Reactions 15.5 Rhinitis, Conjunctivitis, Eosinophilic & Mast Cell Disorders

17 Chapter 16: Preventive Medicine, Immunization & Clinical Epidemiology

16.1 The USPSTF Framework & Evidence-Based Cancer Screening 16.2 Cardiovascular & Metabolic Screening and Primary Prevention 16.3 Adult Immunization & Vaccines in Special Populations 16.4 Clinical Epidemiology, Biostatistics & Study Design

18 Chapter 17: Miscellaneous - Ethics, Patient Safety & Quality Improvement (2% of Exam)

17.1 Principles of Bioethics & Decisional Capacity 17.2 Informed Consent, Treatment Refusal & Special Scenarios 17.3 Surrogate Decision-Making, Advance Directives & Confidentiality 17.4 Patient Safety Science, Medical Error & Diagnostic Reasoning 17.5 Quality Improvement Methods, Health Disparities & Health Equity

19 Chapter 18: Perioperative Medicine & Medical Consultation

18.1 Preoperative Cardiovascular Risk Assessment 18.2 Preoperative Pulmonary Risk & Perioperative Medication Management 18.3 Perioperative Anticoagulation, Bridging & Postoperative Complications

20 Chapter 19: Ophthalmology (1% of Exam)

19.1 The Acute Red Eye & Ophthalmic Emergencies 19.2 Painless Vision Loss & Chronic Ophthalmic Disease 19.3 Uveitis, Scleritis & Orbital Disease

21 Chapter 20: Otolaryngology & Dental Medicine (1% of Exam)

20.1 Dizziness, Vertigo & Epistaxis 20.2 Ear Disorders, Hearing Loss & Upper Respiratory Infections 20.3 Oral Cavity, Salivary Gland, Laryngeal & Taste and Smell Disorders

11.2 Antidepressant Pharmacotherapy & Treatment-Resistant Depression

Key Takeaways Explain This Topic AI

Selective serotonin reuptake inhibitors are first-line, and class efficacy is broadly similar so selection turns on tolerability and interactions.

An adequate trial requires four to eight weeks at a therapeutic dose before concluding that a drug has failed.

Bupropion lowers the seizure threshold and is avoided in seizure disorders and in active eating disorders with purging.

Selective serotonin reuptake inhibitors increase bleeding risk, particularly when combined with antiplatelet or anticoagulant therapy.

After a first episode remits, treatment continues for at least four to nine months, with longer maintenance after recurrent episodes.

Last updated: August 2026

1. Antidepressant Pharmacotherapy: Drug Classes, Selection & Monitoring

Selecting the optimal antidepressant requires matching the drug's pharmacology and adverse effect profile to the patient's individual clinical presentation and medical comorbidities.

Comprehensive Antidepressant Pharmacotherapy Matrix

Drug Class & Generic Name Typical Starting & Target Doses Mechanism of Action Clinical Indications & Board Pearls Key Adverse Effects & Critical Contraindications

SSRI: Sertraline 50 mg/day (start 25 mg in anxiety); target 100-200 mg/day Selective serotonin reuptake inhibitor Drug of choice in cardiovascular disease & post-myocardial infarction (proven cardiac safety in SADHART trial); safe in breastfeeding GI disturbances (nausea, diarrhea), sexual dysfunction (30-40%: delayed ejaculation, anorgasmia), insomnia/agitation

SSRI: Escitalopram 10 mg/day; target 10-20 mg/day Highly selective 5-HT reuptake inhibitor Cleanest pharmacokinetic profile; minimal CYP450 drug-drug interactions; highly predictable dose-response Mild nausea, headache, low risk of QT prolongation compared to citalopram

SSRI: Citalopram 20 mg/day; target 20-40 mg/day Racemic selective 5-HT reuptake inhibitor Effective first-line agent FDA Black Box Warning for QTc Prolongation: Maximum dose is 40 mg/day in adults; Capped at 20 mg/day in patients >=60 years old , hepatic impairment, or CYP2C19 poor metabolizers

SSRI: Fluoxetine 20 mg/day; target 20-60 mg/day 5-HT reuptake inhibitor + weak 5-HT2C antagonism Activating profile (useful in psychomotor retardation/fatigue); longest half-life (parent drug 2-4 days, active metabolite norfluoxetine 7-15 days -> lowest risk of discontinuation syndrome) Insomnia, jitteriness, anorexia; potent CYP2D6 inhibitor; mandates a 5-week washout period before starting an MAOI (vs 2 weeks for other SSRIs)

SSRI: Paroxetine 20 mg/day; target 20-50 mg/day Potent 5-HT reuptake inhibitor + anticholinergic Highly sedating; approved for panic disorder and social anxiety Highest rate of weight gain, sedation, and sexual dysfunction ; anticholinergic effects (dry mouth, constipation, urinary retention); highest risk of discontinuation syndrome due to short half-life; teratogenic (cardiac ventricular septal defects)

SNRI: Venlafaxine 375 mg/day (XR start 37.5-75 mg; target 150-225 mg) 5-HT reuptake inhibitor at low doses; Norepinephrine reuptake inhibitor at >=150 mg/day Effective for MDD with comorbid severe generalized anxiety disorder, panic disorder, or social phobia Dose-dependent diastolic hypertension (monitor BP at doses >=225 mg); severe discontinuation syndrome with missed doses (dizziness, electric shock-like "brain zaps", nausea)

SNRI: Duloxetine 30 mg/day for 1 week, then target 60 mg/day (max 120 mg) Balanced 5-HT and NE reuptake inhibitor FDA-approved dual indications for: Diabetic peripheral neuropathic pain, Fibromyalgia, and Chronic musculoskeletal low back / osteoarthritis pain Nausea, dry mouth, constipation, diaphoresis; Avoid in severe hepatic impairment, chronic liver disease, heavy alcohol use (hepatotoxicity risk), or severe renal failure (eGFR <30 mL/min)

Atypical (NDRI): Bupropion 150 mg XL/day; target 300 mg XL/day (max 450 mg) Norepinephrine-Dopamine Reuptake Inhibitor (NDRI) No sexual dysfunction; promotes mild weight loss; aids smoking cessation (Zyban) ; highly activating (ideal for fatigue, hypersomnia, psychomotor slowing, ADHD comorbidity) ABSOLUTE CONTRAINDICATIONS: History of seizures, active eating disorders ( Bulimia nervosa, Anorexia nervosa — high seizure risk from electrolyte shifts), abrupt discontinuation of alcohol or benzodiazepines; can worsen acute anxiety/insomnia

Atypical: Mirtazapine 15 mg at bedtime; target 15-45 mg at bedtime Central presynaptic alpha-2 adrenergic antagonist + 5-HT2 and 5-HT3 antagonist + potent H1 histamine antagonist Ideal for depressed geriatric patients with severe insomnia, marked anorexia, and cachexia/weight loss ; potent antiemetic properties (via 5-HT3 blockade) Sedation and significant weight gain / increased appetite (note: lower doses [7.5-15 mg] are more sedating due to unopposed H1 blockade; higher doses [30-45 mg] increase noradrenergic transmission and are less sedating); rare agranulocytosis

Tricyclics (TCAs): Amitriptyline, Nortriptyline Nortriptyline: 25 mg qhs; target 50-150 mg (trough level 50-150 ng/mL) Non-selective 5-HT and NE reuptake inhibitor + alpha-1, H1, and muscarinic blockade Second/third-line for MDD; neuropathic pain, migraine prophylaxis Fatal in overdose (3 Cs: Coma, Convulsions, Cardiac arrhythmias from sodium-channel blockade causing QRS widening >100 ms); anticholinergic toxicity; orthostatic hypotension; avoid in elderly and CAD

MAOIs: Phenelzine, Tranylcypromine, Selegiline Phenelzine 15 mg TID; Selegiline transdermal patch 6-12 mg/24h Irreversible inhibition of Monoamine Oxidase (MAO-A and MAO-B) Treatment-resistant depression, atypical depression (mood reactivity, leaden paralysis, hypersomnia) Hypertensive Crisis if combined with dietary tyramine (aged cheeses, cured meats, red wine, draft beer); Serotonin Syndrome if combined with SSRIs/SNRIs/TCAs/meperidine/tramadol/dextromethorphan; requires 14-day washout (5 weeks for fluoxetine)

Inadequate Response Algorithm & Treatment Duration Rules

Adequate Trial Definition: An adequate antidepressant trial requires 6 to 8 consecutive weeks at the target therapeutic dose. Evaluating efficacy at 1 to 2 weeks is premature (except to monitor adverse effects and initial behavioral activation).

Management of Inadequate Response:

No Response (<25% improvement after 6-8 weeks): Confirm medication adherence; cross-taper and switch to another first-line agent (either within the same class [e.g., switch sertraline to escitalopram] or switch classes [e.g., switch SSRI to SNRI, Bupropion, or Mirtazapine]).

Partial Response (25% to 50% improvement): Optimize dose to the maximum approved/tolerated level. If still partial response, utilize pharmacologic augmentation :

Atypical Antipsychotic Augmentation: Low-dose Aripiprazole (2 to 5 mg/day), Quetiapine XR (150 to 300 mg/day), or Brexpiprazole (1 to 2 mg/day) has the strongest randomized trial evidence for augmenting SSRI/SNRIs.

Bupropion Augmentation: Adding Bupropion (150-300 mg XL) to an SSRI/SNRI targets residual fatigue, low energy, and reverses SSRI-induced sexual dysfunction.

Lithium Augmentation: Adding Lithium Carbonate (target serum level 0.6 to 0.8 mEq/L) reduces suicide risk and augments serotonergic neurotransmission.

Liothyronine (T3) Augmentation: Adding T3 (25 to 50 mcg/day) accelerates and enhances antidepressant response even in euthyroid patients.

Psychotherapy Augmentation: Initiating evidence-based Cognitive Behavioral Therapy (CBT) or Interpersonal Psychotherapy (IPT).

Treatment Duration Guidelines:

First Single Unipolar Episode: Continue full-dose antidepressant therapy for 6 to 9 months after achieving full clinical remission (continuation phase) before considering a gradual taper over 1-2 months. Stopping early drastically increases relapse rates.

Recurrent Depressive Episodes (>=2 to 3 lifetime episodes), Chronic Depression (duration >=2 years), or Severe/Psychotic/Suicidal Episodes: Maintain long-term maintenance pharmacotherapy for at least 2 to 3 years or indefinitely at the full therapeutic dose that induced remission.

Electroconvulsive Therapy (ECT):

Efficacy: Most effective acute treatment for severe depression (response rates 70-90%).

First-Line Board Indications:

Severe Major Depression with Psychotic Features (delusional guilt, auditory hallucinations).

Catatonia (stupor, mutism, waxy flexibility, negativism).

Acute Life-Threatening Suicidal Crisis requiring immediate clinical stabilization.

Severe Malnutrition / Acute Food and Fluid Refusal causing medical decompensation.

Severe refractory depression in pregnancy (where pharmacotherapy carries fetal risks).

Adverse Effects: Post-ictal confusion, retrograde and anterograde amnesia (typically resolves within weeks to months); no absolute medical contraindications (relative contraindication: increased intracranial pressure / intracranial mass).