3.10 Psychopharmacology Foundations: Antidepressants, Anxiolytics, and Stimulants

Antidepressants

All antidepressants carry a Black Box Warning for increased risk of suicidal thinking and behavior in children, adolescents, and young adults up to age 24. Monitor closely for agitation, irritability, or worsening mood during the first 1-2 months of therapy or after any dose change.

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Mechanism: Inhibit the reuptake of serotonin at the presynaptic neuronal membrane, increasing serotonin in the synaptic cleft. First-line for major depressive disorder, GAD, panic disorder, OCD, PTSD, social anxiety disorder, and PMDD.
• Examples & Distinctions:
  • Fluoxetine (Prozac): Longest half-life (1-4 days; norfluoxetine 7-15 days) — activating, only SSRI approved for children ≥8 (with CBT), lowest discontinuation syndrome risk.
  • Sertraline (Zoloft): Best for cardiac patients (minimal QT effect); high GI protein binding.
  • Citalopram (Celexa) / Escitalopram (Lexapro): Most selective for SERT; minimal CYP drug interactions.
  • Paroxetine (Paxil): Most sedating, highest anticholinergic burden, worst discontinuation syndrome, and strong CYP2D6 inhibitor.
• Side Effects: GI upset (nausea, diarrhea — typically transient over 1-2 weeks), sexual dysfunction (decreased libido, anorgasmia, delayed ejaculation in up to 70% of patients), sleep disturbances, hyponatremia (SIADH — particularly in elderly), increased bleeding risk (platelet serotonin depletion; caution with NSAIDs, anticoagulants).
• QTc Prolongation: Citalopram carries a dose-dependent risk of QT prolongation (max dose 40 mg/day; 20 mg in elderly, hepatic impairment, or CYP2C19 poor metabolizers). Escitalopram max 20 mg/day (10 mg in elderly).

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Mechanism: Inhibit reuptake of both serotonin and norepinephrine.
• Examples: Venlafaxine (Effexor — strongest NE effect at doses >150 mg), Duloxetine (Cymbalta — also FDA-approved for diabetic peripheral neuropathy, fibromyalgia, chronic musculoskeletal pain), Desvenlafaxine (Pristiq), Levomilnacipran (Fetzima).
• Clinical Utility: Efficacious for depression with comorbid neuropathic pain (Duloxetine). Venlafaxine can cause dose-dependent hypertension due to its norepinephrine effects; monitor BP, especially at doses ≥225 mg/day.
• Discontinuation Syndrome: SNRIs (particularly venlafaxine with its short half-life) have notorious withdrawal ("brain zaps," dizziness, nausea, irritability); taper slowly over weeks.

Tricyclic Antidepressants (TCAs)

• Mechanism: Inhibit reuptake of serotonin and norepinephrine, but also aggressively block histaminic (H1), cholinergic (M1), and alpha-1 adrenergic receptors.
• Examples: Amitriptyline (Elavil), Nortriptyline (Pamelor — therapeutic window 50-150 ng/mL), Clomipramine (Anafranil — highly serotonergic, FDA-approved for OCD), Imipramine (Tofranil — used for enuresis).
• Toxicity: Highly lethal in overdose due to cardiotoxicity (sodium channel blockade → widened QRS complex >100 ms, prolonged QT, arrhythmias, hypotension). Anticholinergic side effects are severe (dry mouth, blurred vision, urinary retention, constipation, cognitive impairment).
• TCA Overdose Management: ABCs, continuous cardiac monitoring, IV sodium bicarbonate (1-2 mEq/kg boluses) for QRS widening >100 ms (sodium loading overcomes channel blockade + alkalosis increases protein binding), IV lipid emulsion in refractory cases. Avoid class Ia, Ic, III antiarrhythmics (amiodarone, procainamide, sotalol) which worsen toxicity.

Monoamine Oxidase Inhibitors (MAOIs)

• Mechanism: Irreversibly inhibit the enzyme monoamine oxidase, preventing the breakdown of serotonin, norepinephrine, and dopamine.
• Examples: Phenelzine (Nardil), Tranylcypromine (Parnate), Selegiline (Emsam — transdermal patch; at 6 mg/24 hr, no tyramine diet required).
• Hypertensive Crisis: Patients on MAOIs must strictly avoid foods containing tyramine (aged cheeses, cured meats, draft beer, fermented soy, fava beans, sauerkraut, Marmite) and certain medications (sympathomimetics, decongestants like pseudoephedrine, meperidine, dextromethorphan, tramadol). Tyramine releases norepinephrine; if MAO is inhibited, norepinephrine levels spike, causing a life-threatening hypertensive crisis (severe occipital headache, hypertension >180/120, chest pain, sweating, nausea).
• Treatment of Hypertensive Crisis: Phentolamine (alpha-blocker), nitroprusside, or labetalol.
• Washout Period: Minimum 14-day washout required when switching between an MAOI and another serotonergic agent. 5 weeks (35 days) required when switching FROM fluoxetine due to its long norfluoxetine half-life. Never combine MAOI with SSRIs/SNRIs/TCAs/meperidine/tramadol/dextromethorphan.

Atypical/Novel Antidepressants

• Bupropion (Wellbutrin): Dopamine and norepinephrine reuptake inhibitor (DNRI). No sexual side effects (often used to counter SSRI-induced sexual dysfunction or as adjunct). Contraindicated in eating disorders and seizure disorders (lowers seizure threshold). Also FDA-approved for smoking cessation (Zyban) and ADHD (off-label).
• Mirtazapine (Remeron): Alpha-2 antagonist (increases NE/5-HT release) and 5-HT2/5-HT3 antagonist. Highly sedating (H1 block) and appetite-stimulating — useful in depressed patients with insomnia and weight loss. Less sexual dysfunction than SSRIs. Rare agranulocytosis.
• Trazodone (Desyrel): SARI (serotonin antagonist and reuptake inhibitor). Highly sedating — primarily used off-label for insomnia at low doses (25-100 mg). Rare but serious side effect: priapism (medical emergency; can cause permanent erectile dysfunction).
• Vortioxetine (Trintellix): Serotonin modulator with multi-modal serotonergic receptor activity; some pro-cognitive effects and lower sexual dysfunction burden.

Comparison Table: Common Antidepressants

Serotonin Syndrome

A life-threatening condition caused by excessive serotonergic activity. Often results from combining serotonergic agents (e.g., SSRI + MAOI, SSRI + tramadol, SSRI + St. John's Wort, SSRI + triptans, linezolid, dextromethorphan).

• Symptoms (Triad):
  1. Mental Status Changes: Agitation, confusion, hallucinations.
  2. Autonomic Hyperactivity: Diaphoresis, tachycardia, hyperthermia, shivering, mydriasis, diarrhea.
  3. Neuromuscular Abnormalities: Hyperreflexia, clonus (especially lower extremities), rigidity. (Note: NMS presents with lead-pipe rigidity and hyporeflexia/bradyreflexia, distinguishing it from Serotonin Syndrome.)
• Onset: Rapid, usually within 24 hours of initiation, dose change, or addition of a second serotonergic agent.
• Treatment: Discontinue all serotonergic agents, supportive care (cooling, benzodiazepines for agitation and rigidity), Cyproheptadine (a 5-HT2A antagonist; 12 mg initial dose, then 2 mg QH up to 32 mg/day). Severe cases require ICU, intubation, and neuromuscular paralysis.

SSRI Discontinuation Syndrome

Abrupt cessation of SSRIs (especially those with short half-lives like paroxetine, venlafaxine) can cause discontinuation syndrome: dizziness, "brain zaps" (paresthesias), nausea, headache, insomnia, irritability, vivid dreams. Onset within 1-3 days; resolution within 1-2 weeks. Prevent by tapering over several weeks; fluoxetine is self-tapering due to long half-life.

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Anxiolytics

Benzodiazepines

• Mechanism: Potentiate the action of GABA, an inhibitory neurotransmitter, by increasing the frequency of chloride channel openings (vs barbiturates, which increase the duration).
• Examples & Half-lives: Alprazolam (Xanax, 6-12 hr), Clonazepam (Klonopin, 18-50 hr), Lorazepam (Ativan, 10-20 hr), Diazepam (Valium, 20-100 hr with multiple active metabolites), Chlordiazepoxide (Librium, 5-30 hr plus active metabolites).
• Clinical Use: Highly effective for acute management of panic attacks, severe anxiety, alcohol withdrawal, status epilepticus (lorazepam IV — first-line), and procedural sedation. Due to risks of tolerance, dependence, and abuse, they are not recommended for long-term treatment of generalized anxiety.
• Withdrawal: Abrupt cessation can precipitate life-threatening withdrawal symptoms, including seizures, hallucinations, and delirium tremens-like syndrome. They must be tapered slowly (5-10% per week for long-term users; consider phenobarbital conversion for severe dependence).
• Elderly: Increased risk of falls, cognitive impairment, paradoxical agitation, and respiratory depression. Beer's Criteria recommends avoiding. If required, use "LOT" drugs (Lorazepam, Oxazepam, Temazepam) — metabolized only by glucuronidation (no CYP450 metabolism, no active metabolites) — safe in hepatic impairment and elderly.
• Overdose Reversal: Flumazenil (Romazicon) — competitive GABA-A antagonist. Use with caution; can precipitate seizures, especially in chronic benzodiazepine users, mixed overdoses with TCAs, or those with seizure disorder.

Buspirone (Buspar)

• Mechanism: Partial agonist at the 5-HT1A receptor and some D2 antagonism.
• Clinical Use: Used for Generalized Anxiety Disorder (GAD). Not effective for acute anxiety or panic attacks because it takes 2-4 weeks to achieve clinical efficacy. No potential for abuse, dependence, or withdrawal — ideal for patients in recovery from substance use disorders. Does not potentiate alcohol. No significant interaction with CNS depressants.

Other Anxiolytic Strategies

• Hydroxyzine (Vistaril, Atarax): Antihistamine (H1 blocker) used for short-term anxiety; non-habit-forming. Side effects: sedation, dry mouth, anticholinergic. Often used as an adjunct in alcohol withdrawal.
• Propranolol: Beta-blocker used for performance anxiety (somatic symptoms like tachycardia, tremor); not for generalized anxiety.
• Gabapentin / Pregabalin: Off-label for GAD and social anxiety; useful in patients with substance use history. Pregabalin is approved for GAD in some European countries.

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Stimulants and ADHD Medications

Stimulants

• Mechanism: Block the reuptake of dopamine and norepinephrine (DAT/NET inhibition); amphetamines also promote the release of these neurotransmitters from presynaptic vesicles.
• Methylphenidate-based: Ritalin (IR), Concerta (OROS long-acting), Focalin (dexmethylphenidate — the d-enantiomer), Daytrana (transdermal patch), Quillichew (chewable).
• Amphetamine-based: Adderall (mixed amphetamine salts), Vyvanse (lisdexamfetamine — a prodrug activated by intestinal hydrolysis, lower abuse/diversion potential), Dexedrine, Mydayis.
• Side Effects: Insomnia, decreased appetite, weight loss, headaches, irritability, exacerbation of tics, dry mouth, GI upset, bruxism.
• Cardiovascular Risk: Can cause elevations in heart rate and blood pressure. Careful cardiac history is required before initiation; avoid in structural heart defects, cardiomyopathy, arrhythmias, uncontrolled hypertension. Black Box Warning for high abuse potential (Schedule II) and cardiovascular events. Baseline and periodic BP and HR.
• Growth Concerns: Monitor height in pediatric patients; may slow growth velocity (catch-up growth occurs after discontinuation). FDA recommends drug holidays if growth suppression noted.

Non-Stimulant ADHD Medications

• Atomoxetine (Strattera): Selective Norepinephrine Reuptake Inhibitor (NRI specific to ADHD). Ideal for patients with personal or strong family history of substance abuse, severe anxiety, or tics. Takes 4-6 weeks for full effect (vs hours for stimulants). Black Box Warning: increased risk of suicidal ideation in children/adolescents. Liver injury is a rare but severe risk. May cause GI upset, fatigue, mood swings.
• Alpha-2 Adrenergic Agonists: Guanfacine ER (Intuniv) and Clonidine ER (Kapvay). Activate presynaptic alpha-2A receptors in the prefrontal cortex, improving attention and reducing hyperactivity/impulsivity. Particularly useful for comorbid tics, oppositional defiant behavior, sleep onset difficulty, and impulsivity. Often used as adjuncts to stimulants. Side effects: sedation, hypotension, bradycardia, dry mouth; taper to avoid rebound hypertension.
• Viloxazine (Qelbree): Norepinephrine reuptake inhibitor, newer non-stimulant option approved 2021. Avoid with MAOIs; monitor for BP/HR elevation and suicidal ideation.

Clinical Vignette

A 32-year-old woman with MDD and chronic neuropathic leg pain from a prior L4 herniation has failed an SSRI trial (sertraline 200 mg × 10 weeks). She reports low energy, anhedonia, and 3 AM terminal insomnia. BMI is 19. She has a remote history of opioid use disorder (in remission 5 years on buprenorphine). Plan: Switch to duloxetine (SNRI — addresses both depression and neuropathic pain; FDA-approved for both indications). Avoid bupropion (seizure threshold concern if eating disorder history ever emerges; not contraindicated by SUD history itself but caution with active eating disorders). Avoid TCAs (cardiotoxicity in overdose risk given suicidality history). Avoid benzodiazepines given SUD history — consider hydroxyzine or CBT-I for insomnia. Augment with CBT and consider mirtazapine at night if sleep remains refractory (sedating, appetite-stimulating). Monitor for suicidality during the transition (Black Box Warning).