Antidepressants — SSRIs, SNRIs, TCAs, MAOIs

• Monoamine Hypothesis and Synaptic Reuptake Inhibition: Depression is associated with functional deficiency of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) in key brain regions including prefrontal cortex, anterior cingulate, and limbic structures. Antidepressants increase synaptic concentrations of these neurotransmitters through competitive inhibition of presynaptic reuptake transporters. SSRIs selectively block the serotonin transporter (SERT), increasing 5-HT availability at postsynaptic receptors over weeks to months. SNRIs inhibit both SERT and norepinephrine transporter (NET), with varying selectivity depending on agent (venlafaxine more balanced at higher doses; duloxetine more 5-HT selective). TCAs nonselectively inhibit reuptake of 5-HT and NE with anticholinergic properties. MAOIs irreversibly inhibit monoamine oxidase enzymes (MAO-A and MAO-B), preventing degradation of 5-HT, NE, and DA throughout the nervous system, producing maximal monoamine elevation.

• Receptor Desensitization and Downstream Signaling: Acute reuptake inhibition increases synaptic monoamine concentration within hours, yet clinical antidepressant effects require 2-4 weeks, suggesting involvement of adaptive neural changes. Chronic antidepressant exposure causes desensitization of inhibitory autoreceptors (5-HT1A presynaptic somatodendritic autoreceptors and NE α2-autoreceptors), removing negative feedback and amplifying net neurotransmitter signaling. Enhanced G-protein coupled receptor signaling increases intracellular cAMP, activating protein kinase A (PKA) and CREB (cAMP response element binding protein), which upregulates brain-derived neurotrophic factor (BDNF) and other neurotrophic factors. BDNF signaling through tropomyosin receptor kinase B (TrkB) promotes neuroplasticity, synaptogenesis, and neuroprotection—potentially explaining the delayed therapeutic onset and sustained effects.

• Hypothalamic-Pituitary-Adrenal (HPA) Axis Normalization: Major depression involves hyperactivation of the HPA axis with elevated cortisol, ACTH, and CRH. Chronic antidepressant treatment normalizes HPA axis function through enhanced negative feedback at hippocampal glucocorticoid receptors (upregulated by BDNF and other mechanisms), reducing tonic cortisol elevation and blunting exaggerated stress responsiveness. Restoration of hippocampal BDNF, which is reduced in depression by chronic glucocorticoid excess, contributes to functional recovery of this critical memory and emotion regulation structure.

• Inflammatory and Immune Modulation: A subset of depressed patients exhibits elevated inflammatory cytokines (IL-6, TNF-α, CRP), suggesting neuroinflammatory pathways contribute to depression in some individuals. Antidepressants, particularly SSRIs, modulate immune function through effects on monoamine signaling in immune cells, reducing pro-inflammatory cytokine production and microglial activation. Restored serotonergic signaling enhances regulatory T cell differentiation, shifting immune balance toward anti-inflammatory states.

• Neurogenesis and Structural Neuroplasticity: Chronic stress and depression suppress adult hippocampal neurogenesis in the dentate gyrus through glucocorticoid-mediated mechanisms and reduced BDNF signaling. Antidepressants restore BDNF-dependent neurogenesis through enhanced 5-HT signaling (particularly via 5-HT1A receptors), increasing progenitor cell proliferation and neuronal survival. This neurogenic mechanism may contribute to mood improvement and cognitive recovery, particularly for memory function, over weeks to months of treatment.

• Glutamatergic Homeostasis: Emerging evidence suggests dysfunction in glutamate (Glu) homeostasis contributes to depression, with excessive Glu excitotoxicity in some brain regions and deficient Glu signaling in others. Chronic antidepressant treatment modulates Glu receptor function and astrocytic Glu reuptake through monoamine-dependent mechanisms, restoring balanced excitatory-inhibitory tone.

• Major Depressive Disorder (MDD) — The primary indication; characterized by persistent depressed mood, anhedonia, neurovegetative symptoms (sleep, appetite, energy), and cognitive/motor changes lasting ≥2 weeks. Both genetic factors (heritability ~40%) and environmental stressors (life events, trauma, chronic illness, social isolation) contribute to depression onset and perpetuation. Antidepressants are efficacious across all depression severity levels from mild to severe, though combined psychotherapy and pharmacotherapy yields superior outcomes to monotherapy.

• Anxiety Disorders — Generalized Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), Panic Disorder (PD), and Agoraphobia share hyperactivity in amygdala and threat-processing circuits with insufficient serotonergic inhibition. SSRIs and SNRIs are first-line agents; sertraline, paroxetine, and venlafaxine have the strongest evidence base. Neurobiologically, enhanced serotonergic and noradrenergic tone reduces amygdala reactivity and enhances prefrontal regulatory control.

• Obsessive-Compulsive Disorder (OCD) — Characterized by hyperactivity in orbitofrontal-striatal circuits with serotonin insufficiency. SSRIs uniquely show efficacy for OCD (paroxetine, fluoxetine, sertraline) at doses higher than those for depression (typically 40-80 mg for SSRIs). The mechanism involves both acute reuptake inhibition and chronic normalization of aberrant orbitofrontal-striatal connectivity.

• Post-Traumatic Stress Disorder (PTSD) — Results from dysregulated fear conditioning and extinction learning due to amygdala hyperactivity and impaired ventromedial prefrontal cortex inhibition. Sertraline and paroxetine are FDA-approved; SSRIs reduce hyperarousal and re-experiencing symptoms through restored serotonergic inhibition of amygdala and enhanced prefrontal regulation.

• Chronic Pain and Neuropathic Pain Syndromes — SNRIs (duloxetine, venlafaxine) and TCAs (amitriptyline, nortriptyline) are efficacious for diabetic peripheral neuropathy, fibromyalgia, chronic low back pain, and migraine prevention. Dual NE/5-HT effects enhance descending pain inhibitory pathways in the spinal cord (monoamine-dependent gate control mechanisms) and reduce central sensitization. TCAs additionally provide anticholinergic effects, though this limits tolerability.

• Eating Disorders — Fluoxetine is FDA-approved for bulimia nervosa; SSRIs reduce binge-purge cycles through serotonergic effects on satiety, impulse control, and mood regulation. Antidepressants are less effective for anorexia nervosa and primarily treat comorbid depression and anxiety.

• Menopausal Vasomotor Symptoms — SSRIs and SNRIs (particularly venlafaxine at higher doses) reduce hot flushes and night sweats through effects on thermoregulatory centers in the hypothalamus, independent of mood effects. Mechanism involves serotonergic modulation of TRPV1 (transient receptor potential) channels in thermoregulatory neurons.

• Attention-Deficit/Hyperactivity Disorder (ADHD) — While not first-line, atomoxetine (selective NE reuptake inhibitor) and some SNRIs (duloxetine) show modest efficacy, particularly when depression or anxiety coexist. Mechanism involves enhanced prefrontal NE signaling, improving executive function and impulse control.

Initial Period (Days 1-2 weeks) — Pharmacodynamic Onset

• Gastrointestinal Effects: Nausea, vomiting, diarrhea, or constipation occur in 10-30% of SSRI initiates, likely from enhanced serotonergic signaling in GI smooth muscle and chemoreceptor trigger zone. Typically resolves within 1-2 weeks with continued use as tolerance develops. Taking SSRIs with food or switching between formulations (e.g., liquid vs. tablet) may improve tolerability.
• Activation/Anxiety: Paradoxical anxiety, insomnia, restlessness, or "jitteriness" occurs in 10-15% of patients, particularly early in treatment, reflecting acute serotonergic overstimulation before autoreceptor desensitization. More common with stimulating agents (fluoxetine, sertraline) and less common with sedating agents (paroxetine). May respond to dose reduction or temporary adjunctive benzodiazepine.
• Sexual Dysfunction: Delayed or absent orgasm, erectile dysfunction, or decreased libido emerge within days to weeks (SSRI-induced sexual dysfunction [SISD] affects 40-60% of patients on chronic therapy). Mechanism involves serotonergic inhibition of nitric oxide signaling in genital tissues and reduced dopaminergic tone in mesolimbic reward circuits. Typically persists without intervention; management includes dose reduction, switching agents, timed dosing (e.g., taking medication after intercourse), or addition of phosphodiesterase inhibitors or buspirone.

Early Therapeutic Window (Weeks 2-4)

• Reduced Insomnia/Sleep Fragmentation: Sedating agents (paroxetine, mirtazapine, TCAs) improve sleep architecture through 5-HT2A antagonism and H1 receptor blockade, improving sleep onset within 1-2 weeks. Activating agents (fluoxetine, sertraline) may paradoxically worsen sleep initially.
• Reduced Anxiety Symptoms: In anxiety disorders, SSRIs/SNRIs begin reducing anticipatory anxiety and hyperarousal through enhanced amygdala inhibition.
• Appetite and Weight Changes: SSRIs may cause initial weight loss (fluoxetine, sertraline) or delayed weight gain (paroxetine) through effects on appetite-regulating neurons in the hypothalamus. Mechanism of SSRI-induced weight gain involves serotonin-induced upregulation of orexigenic neuropeptide Y (NPY) and agouti-related peptide (AgRP) in lateral hypothalamus, paradoxically increasing hunger.

Plateau Phase (Weeks 4-12) — Peak Therapeutic Effect

• Mood Normalization: Gradual restoration of euthymia with improved motivation, interest in activities (anhedonia resolution), and emotional reactivity. Neurobiologically reflects BDNF-dependent neuroplastic changes.
• Neurovegetative Improvement: Normalized sleep-wake cycle, restored appetite, increased energy, and improved concentration. Reflects normalization of hypothalamic and brainstem monoamine circuits.
• Anxiety Reduction: In anxiety disorders, substantial reduction in worry frequency, intensity, and physiological arousal (reduced heart rate, muscle tension). Reflects amygdala desensitization and enhanced prefrontal inhibitory control.
• Pain Relief (in pain syndromes): Progressive analgesic effect in neuropathic pain through enhanced descending inhibition and reduced central sensitization.

Chronic Phase (>12 weeks)

• Sexual Dysfunction becomes prominent as noted above—one of the most common reasons for SSRI discontinuation despite mood improvement.
• Weight Gain: Sustained weight gain may occur with chronic SSRI use (particularly paroxetine), averaging 2-5 kg over months to years. Mechanism involves both pharmacological effects on appetite regulation and behavioral changes (reduced activity, increased carbohydrate seeking).
• Emotional Blunting (apathy syndrome): Some patients develop diminished emotional responsiveness, reduced motivation, or "flat" affect despite mood improvement—potentially dose-related and more common with SSRIs than SNRIs.
• Hyponatremia/SIADH: Can develop insidiously over weeks to months, particularly in elderly patients.

Physical Examination Findings

• Vital Signs: TCAs cause tachycardia (anticholinergic effects, direct cardiac effects); MAOIs may cause hypertensive episodes. SSRIs/SNRIs typically do not substantially affect resting vital signs.
• Tremor: Fine postural tremor may develop, particularly with SSRIs and SNRIs, reflecting enhanced monoamine signaling in cerebellar circuits.
• Mydriasis: TCAs and MAOIs cause pupillary dilation through anticholinergic mechanisms.
• Decreased Lacrimation/Dry Mouth: Anticholinergic effects of TCAs and some older agents (paroxetine has modest anticholinergic activity).
• Neurological Findings: Serotonin syndrome presents with hyperreflexia, clonus (particularly ankle), rigidity, and altered mental status (see Complications section).

Atypical Presentations

• TCA Overdose: Presents with cardiac arrhythmias (QRS widening, torsades de pointes), seizures, coma, and hypotension—more dangerous than SSRI overdose. Anticholinergic toxidrome (dilated pupils, dry mouth, ileus, urinary retention, agitation, hallucinations) may predominate.
• MAOI Hypertensive Crisis: Acute severe hypertension with occipital headache, chest or abdominal pain, neck stiffness, and risk of intracranial hemorrhage or myocardial infarction triggered by dietary tyramine or sympathomimetic drugs.

Clinical History and Diagnostic Criteria

• DSM-5 Criteria for Major Depressive Episode: Requires ≥5 symptoms during a 2-week period with at least one being either depressed mood or anhedonia. Symptoms include: depressed mood (most of the day, nearly every day), markedly diminished interest or pleasure in activities (anhedonia), significant weight loss/gain or appetite changes, insomnia/hypersomnia, psychomotor agitation or retardation (observable by others), fatigue/loss of energy, feelings of worthlessness or inappropriate guilt, diminished ability to concentrate or make decisions, or recurrent thoughts of death/suicidal ideation. Symptoms must cause clinically significant distress or functional impairment and not be attributable to substance use or medical conditions.
• Severity Assessment: Mild (minimal functional impairment), moderate (moderate functional impairment), or severe (substantial functional impairment) depression. Psychotic features (mood-congruent delusions/hallucinations) indicate need for antipsychotic augmentation or higher-dose monotherapy.
• Temporal Pattern: Assess age of onset, episode duration, frequency of episodes, seasonal pattern (seasonal affective disorder [SAD]), and relationship to menses (premenstrual dysphoric disorder [PMDD]).

Targeted History Elements Guiding Agent Selection

• Comorbid Conditions: Anxiety disorders benefit from SSRIs/SNRIs (especially paroxetine, sertraline, duloxetine); chronic pain syndromes favor SNRIs or TCAs;

Class-wide and SSRI/SNRI effects

• Serotonin syndrome: excess 5-HT1A/2A stimulation from combining serotonergic agents (SSRI + MAOI, linezolid, tramadol, meperidine, triptans, dextromethorphan, St. John's wort). Hunter criteria emphasize inducible/spontaneous clonus, hyperreflexia (lower > upper limbs), tremor, agitation, diaphoresis, and hyperthermia. Treat by stopping all serotonergic drugs, giving benzodiazepines and cooling; cyproheptadine, a 5-HT2A antagonist, is the antidote in refractory cases.
• Bleeding: SSRIs deplete platelet serotonin stores, impairing aggregation; risk of GI bleeding rises with concurrent NSAIDs, aspirin, or anticoagulants (consider PPI cover).
• Hyponatremia/SIADH: most common in elderly, female, low-body-weight, and diuretic-treated patients; check sodium if confusion or falls develop early in therapy.
• QT prolongation: citalopram is the offender; FDA labeling caps the daily dose and lowers the cap in patients over 60, hepatic impairment, CYP2C19 poor metabolizers, or with CYP2C19 inhibitors.
• Discontinuation syndrome: flu-like symptoms, dizziness, insomnia, and "brain zaps" with abrupt stop of short half-life agents (paroxetine, venlafaxine); fluoxetine's long-lived norfluoxetine metabolite makes it least prone. Taper rather than stop.
• Boxed warning: increased suicidal ideation in patients under 25 — FDA mandates close monitoring during the first weeks and after dose changes.
• SNRI-specific: dose-dependent hypertension (venlafaxine — monitor BP); duloxetine hepatotoxicity, avoid in significant hepatic disease or heavy alcohol use.

TCAs

• Three C's of overdose: convulsions, coma, cardiotoxicity from fast sodium-channel blockade — QRS widening, terminal R wave in aVR, hypotension, and ventricular arrhythmia. Give IV sodium bicarbonate for QRS widening; avoid class IA/IC antiarrhythmics and physostigmine.
• Receptor blockade effects: muscarinic (dry mouth, urinary retention, delirium), α1 (orthostasis), H1 (sedation, weight gain). Contraindicated after recent MI and listed as potentially inappropriate in older adults by the AGS Beers Criteria; narrow therapeutic index warrants level monitoring.

MAOIs

• Tyramine hypertensive crisis: aged cheese, cured meats, wine; treat with phentolamine or nitroprusside. Require a 2-week washout from other antidepressants (about 5 weeks after fluoxetine).

• Serotonin syndrome vs. neuroleptic malignant syndrome: serotonin syndrome develops within hours, features clonus and hyperreflexia, and follows a serotonergic drug combination; NMS evolves over days with lead-pipe rigidity, bradyreflexia, and a dopamine antagonist in the history. Cyproheptadine treats the former; dantrolene/bromocriptine the latter.
• TCA overdose — single best next step is an ECG, not a drug level. QRS prolongation predicts seizures and arrhythmia and is the trigger for IV sodium bicarbonate, which both alkalinizes and increases extracellular sodium to overcome channel blockade. A terminal R wave in aVR is the classic finding.
• Wash out fluoxetine for about 5 weeks before an MAOI because of its active metabolite norfluoxetine; two weeks suffices for other SSRIs. This is the most frequently tested drug-interaction fact in this class.
• Screen for prior mania or hypomania before prescribing, per APA guidance — antidepressant monotherapy in bipolar disorder can precipitate a manic switch. A stem describing decreased need for sleep after starting an SSRI is testing this.
• Allow an adequate trial: 4–6 weeks at a therapeutic dose before declaring failure. The common distractor is switching agents or adding a second drug after one to two weeks of "no response."
• Sexual dysfunction is the leading cause of nonadherence; the tested workaround is switching to bupropion or mirtazapine, neither of which inhibits serotonin reuptake. Bupropion is contraindicated with seizure disorder and eating disorders.
• Fluoxetine and paroxetine are potent CYP2D6 inhibitors — avoid with tamoxifen, which needs CYP2D6 to form active endoxifen; sertraline, citalopram, and escitalopram have cleaner interaction profiles.
• Confusion plus lethargy weeks after starting an SSRI in an elderly patient: check a serum sodium for SIADH before invoking dementia or a new stroke.