Psychopharmacology
Psychopharmacology
What You'll Learn
- SSRIs are first-line antidepressants; key side effects include sexual dysfunction, GI upset, serotonin syndrome, and QTc prolongation (citalopram); paroxetine is the most anticholinergic and worst in pregnancy
- Serotonin syndrome vs NMS — serotonin syndrome: clonus + hyperreflexia (onset hours, treat with cyproheptadine); NMS: lead-pipe rigidity + elevated CK (onset days–weeks, treat with dantrolene + bromocriptine)
- Antipsychotic-induced movement disorders follow a time course: acute dystonia (hours) → akathisia (days) → parkinsonism (weeks) → tardive dyskinesia (months–years)
- PD psychosis: pimavanserin is FDA-approved (5-HT2A inverse agonist, no D2); clozapine has the strongest efficacy data but requires ANC monitoring for agranulocytosis; quetiapine is commonly used (low D2 affinity, practical ease) — mixed efficacy data, calling it "safest" is too strong. For DLB, all antipsychotics need caution (neuroleptic sensitivity + dementia mortality)
- Lithium has a narrow therapeutic index — causes tremor, hypothyroidism, nephrogenic DI, and Ebstein anomaly (teratogen); requires level/TSH/renal monitoring
- Benzodiazepines are GABA-A positive allosteric modulators (increase Cl− opening frequency); reversed by flumazenil; withdrawal seizures are a major concern
- Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) for mild–moderate AD; memantine (NMDA antagonist) for moderate–severe AD; anti-amyloid mAbs require ARIA monitoring
HighYield Pearls
- Citalopram QTc: max 40 mg/day overall, ≤20 mg/day if >60 yr or hepatic impairment — classic board trap dose
- Serotonin syndrome triggers: SSRI/SNRI + MAOI, tramadol, linezolid (reversible MAOI), methylene blue, MDMA, triptans, St John’s wort → clonus + hyperreflexia (lower-limb predominant) + autonomic instability; treat with cyproheptadine + supportive care
- Bupropion lowers seizure threshold → contraindicated in eating disorders, alcohol/BZD withdrawal, and seizure history; favored in elderly for low sexual SE and apathy
- Lithium toxicity: cerebellar signs + dysarthria + tremor + AMS ± seizures; SILENT syndrome (irreversible neurotoxicity) after severe/prolonged toxicity; avoid dehydration, NSAIDs, thiazides, ACE-i; treat severe toxicity with hemodialysis
- Antipsychotics in PD/DLB: AVOID haloperidol and high-D2 typicals. For PD psychosis: pimavanserin (5HT2A inverse agonist, no D2) is FDA-approved; clozapine has strongest efficacy but needs ANC monitoring; quetiapine commonly used (low D2 affinity, practical) — mixed efficacy. For DLB, all antipsychotics need caution (neuroleptic sensitivity + dementia mortality)
- Clozapine REMS: agranulocytosis (weekly ANC × 6 mo) + myocarditis + seizures (dose-dependent) + sialorrhea + metabolic syndrome — most effective for refractory schizophrenia
- BLACK BOX: all antipsychotics ↑ mortality in elderly with dementia; brexpiprazole (2023) is FDA-approved for agitation in Alzheimer dementia
- Lamotrigine + valproate: VPA inhibits LTG glucuronidation → ↑ SJS/TEN risk; titrate LTG even slower (halve the dose) when combined
- Zolpidem complex sleep behavior (sleep-driving, sleep-eating) + falls/delirium in elderly; benzodiazepines & Z-drugs on Beers list — avoid in NCD; flumazenil reverses BZD but may precipitate seizures
- Modafinil/armodafinil are CYP3A4 inducers → reduce efficacy of OCPs (counsel backup contraception); used for narcolepsy, OSA with residual sleepiness, shift-work disorder
🔍 Quick ReferenceMechanism · Adverse effects · Interactions / use
Mechanism
- Bupropion → NDRI (NE + DA reuptake inhibition)
- Mirtazapine → α2 antagonist + 5HT2/5HT3 antagonist (noradrenergic + specific serotonergic, NaSSA)
- Trazodone → 5HT2A antagonist + weak SERT inhibitor (SARI)
- Pimavanserin → selective 5HT2A inverse agonist with no D2 activity
- Aripiprazole / brexpiprazole → D2 partial agonist + 5HT1A partial agonist
- Buspirone → 5HT1A partial agonist (non-sedating anxiolytic)
- Varenicline → α4β2 nicotinic partial agonist
- Esketamine → NMDA antagonist (intranasal, S-enantiomer of ketamine)
- Modafinil → DA reuptake + histaminergic/orexin activation
- Atomoxetine → selective NE reuptake inhibitor (non-stimulant ADHD)
Adverse effects
- QTc prolongation → citalopram (dose-limited), ziprasidone, IV haloperidol, TCAs
- Hyponatremia / SIADH → SSRIs (esp. elderly), SNRIs, carbamazepine
- Priapism → trazodone
- Agranulocytosis → clozapine (weekly CBC monitoring)
- Tyramine crisis (aged cheese, cured meats, red wine) → MAOIs (phenelzine, tranylcypromine)
- Stevens-Johnson syndrome → lamotrigine (slow titration; worse with VPA)
- SILENT (syndrome of irreversible lithium-effectuated neurotoxicity) → lithium
- Nephrogenic DI + hypothyroidism + Ebstein anomaly → lithium
- Lowered seizure threshold → bupropion, clozapine, TCAs
- Metabolic syndrome / weight gain (worst) → olanzapine & clozapine
- Complex sleep behavior (sleep-driving) → zolpidem (Z-drugs)
- Smoking cessation: FDA REMOVED the neuropsychiatric boxed warning for varenicline and bupropion in December 2016 (after EAGLES trial) — monitoring for neuropsychiatric symptoms remains appropriate. Bupropion as an antidepressant still carries the class suicidality boxed warning in young patients (<24).
Interactions / use
- Linezolid + SSRI/SNRI → serotonin syndrome (linezolid is a reversible MAOI)
- Cyproheptadine → antidote for serotonin syndrome (5HT2A antagonist)
- Hemodialysis → severe lithium toxicity (level ≥4.0 or symptomatic ≥2.5)
- Modafinil / CBZ CYP3A4 induction → OCP failure (counsel backup contraception)
- PD psychosis: pimavanserin FDA-approved; clozapine strongest efficacy (needs ANC monitoring); quetiapine commonly used but mixed efficacy — not "safest"; DLB → all antipsychotics need caution (neuroleptic sensitivity + dementia mortality); AVOID haloperidol
- Brexpiprazole → FDA-approved (2023) for agitation in Alzheimer dementia
- Duloxetine → diabetic peripheral neuropathy + fibromyalgia + depression
- Sertraline → preferred SSRI in pregnancy and breastfeeding (paroxetine worst — cardiac teratogen)
- Fluoxetine → 5-week washout before starting MAOI (long half-life)
- Methylphenidate / amphetamines → ADHD + narcolepsy + apathy in dementia (off-label)
- Naltrexone → μ-opioid antagonist for alcohol craving (avoid in active opioid use — precipitates withdrawal)
- Flumazenil → reverses BZD overdose (caution: may precipitate seizures in chronic users)
Antidepressants
Antidepressant Classes
| Class | Examples | Mechanism | Key Side Effects | Board-Yield Points |
|---|---|---|---|---|
| SSRIs | Fluoxetine, sertraline, paroxetine, citalopram, escitalopram | Selective serotonin reuptake inhibition | Sexual dysfunction; GI (nausea, diarrhea); serotonin syndrome (with MAOIs, triptans, tramadol, linezolid) | Citalopram: QTc prolongation (max 40 mg/day, 20 mg if >60 yr). Paroxetine: most anticholinergic SSRI, shortest half-life, worst in pregnancy. Fluoxetine: longest half-life, strong CYP2D6 inhibitor |
| SNRIs | Venlafaxine, duloxetine | 5-HT + NE reuptake inhibition | Hypertension (venlafaxine); discontinuation syndrome | Duloxetine: FDA-approved for diabetic neuropathic pain and fibromyalgia. Venlafaxine: SSRI-like at low doses, NE effect at higher doses |
| TCAs | Amitriptyline, nortriptyline, desipramine, imipramine | 5-HT + NE reuptake + anticholinergic, antihistaminic, α1-blocking | Anticholinergic (dry mouth, urinary retention). Cardiac: Na+ channel blockade → QRS widening. Seizures in overdose | Nortriptyline: less sedating than amitriptyline; used for neuropathic pain. TCA overdose: treat with sodium bicarbonate. Amitriptyline: migraine prophylaxis |
| MAOIs | Phenelzine, tranylcypromine | Irreversible MAO-A/B inhibition → ↑ 5-HT, NE, DA | Tyramine crisis (aged cheese, red wine, cured meats); serotonin syndrome with SSRIs/meperidine | 2-week washout when switching to/from SSRIs (5 weeks for fluoxetine). Selegiline: MAO-B selective at low doses (used for PD) |
| Bupropion | Bupropion (Wellbutrin, Zyban) | NDRI (norepinephrine/dopamine reuptake inhibitor) | Lowers seizure threshold; insomnia, agitation; less sexual dysfunction | Contraindicated in bulimia/anorexia and seizure history; useful for smoking cessation; less sexual dysfunction than SSRIs |
| Trazodone | Trazodone | 5-HT2A antagonist; SARI | Sedation, orthostasis, priapism (rare but emergent) | Frequently used off-label for insomnia; low risk of dependence |
| Nefazodone | Nefazodone | 5-HT2A antagonist + weak SNRI | Boxed warning hepatotoxicity | Largely abandoned due to hepatotoxicity |
| Mirtazapine | Mirtazapine | Alpha-2 antagonist + H1 antagonist (NaSSA) | Sedation, weight gain, appetite stimulation | Useful in cachexia, anorexia, insomnia; minimal sexual dysfunction |
Board Pearl
TCA overdose is a medical emergency: altered mental status, seizures, and cardiac arrhythmias (widened QRS from Na+ channel blockade). First-line treatment is IV sodium bicarbonate. QRS >100 ms predicts seizures; QRS >160 ms predicts ventricular arrhythmias. Never use class IA/IC antiarrhythmics (further Na+ channel blockade).
Board Pearl
MAOI + tyramine interaction: MAOIs prevent intestinal/hepatic degradation of dietary tyramine → massive catecholamine release → hypertensive crisis (severe headache, hypertension, risk of intracerebral hemorrhage). Patients must avoid aged cheeses, cured meats, red wine, soy sauce, and draft beer. A 2-week washout is required when switching between MAOIs and serotonergic drugs (5 weeks for fluoxetine due to its long half-life and active metabolite norfluoxetine).
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