Anatomy Physiology Pharmacology Pathology

Psychopharmacology

What Do You Need to Know?

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)
Clozapine is most effective for refractory psychosis but requires ANC monitoring for agranulocytosis; quetiapine is safest for psychosis in PD/DLB
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

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)

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).

Serotonin Syndrome vs Neuroleptic Malignant Syndrome

Comparison Table

Feature	Serotonin Syndrome	NMS
Cause	Serotonergic excess (SSRI + MAOI, SSRI + triptan, SSRI + linezolid, SSRI + tramadol)	D2 blockade (antipsychotics) or rapid withdrawal of dopaminergic agents
Onset	Hours (within 24 hr of drug change)	Days to weeks after initiation or dose increase
Neuromuscular	Clonus (hallmark), hyperreflexia, myoclonus, tremor; lower extremities > upper	"Lead-pipe" rigidity (hallmark), bradyreflexia
Mental status	Agitation, confusion	Altered consciousness, stupor, catatonia
Autonomic	Hyperthermia, tachycardia, diaphoresis, mydriasis, diarrhea	Hyperthermia (≥40°C), autonomic instability (labile BP, tachycardia), diaphoresis
Labs	Usually normal CK; mild leukocytosis	Markedly elevated CK (rhabdomyolysis), leukocytosis, metabolic acidosis, renal failure
Treatment	Stop offending agent; cyproheptadine (5-HT2A antagonist); benzodiazepines; supportive cooling	Stop offending agent; dantrolene (muscle relaxant) + bromocriptine (DA agonist); supportive cooling
Resolution	Usually within 24–72 hours	Resolution over 1–2 weeks (longer if depot antipsychotic)

Board Pearl

The key differentiator: clonus with hyperreflexia = serotonin syndrome; lead-pipe rigidity with bradyreflexia = NMS. Both cause hyperthermia, but NMS typically produces higher temperatures with markedly elevated CK from rhabdomyolysis.

Antipsychotics

First-Generation (Typical) vs Second-Generation (Atypical)

Feature	Typical (First-Gen)	Atypical (Second-Gen)
Mechanism	Primarily D2 blockade	D2 blockade + 5-HT2A antagonism
Examples	Haloperidol, chlorpromazine, pimozide	Quetiapine, olanzapine, risperidone, clozapine, aripiprazole
EPS risk	High (especially haloperidol)	Lower (risperidone at high doses → EPS)
Metabolic	Lower	Higher (worst: olanzapine, clozapine)
QTc	Yes (haloperidol IV, chlorpromazine)	Ziprasidone highest risk
Prolactin	Elevated	Variable (risperidone highest; aripiprazole lowest)

High-Yield Individual Antipsychotics

Drug	Unique Features	Board-Yield Points
Clozapine	Most effective for refractory schizophrenia	Agranulocytosis (1–2%) — requires ANC monitoring (weekly × 6 mo, biweekly, monthly). Also: seizures (dose-dependent), metabolic syndrome, myocarditis, sialorrhea. Lowest EPS risk
Quetiapine	Low D2 affinity; sedating	Safest for PD/DLB psychosis (lowest EPS risk after clozapine)
Aripiprazole	D2 partial agonist	Lowest metabolic/prolactin risk; may cause akathisia
Pimozide	First-gen D2 antagonist	FDA-approved for Tourette syndrome; QTc risk, requires ECG
Haloperidol	High-potency D2 antagonist	Highest EPS/NMS risk; IV form → QTc/torsades
Chlorpromazine	Low-potency; anticholinergic	More sedation/orthostasis, lower EPS; retinal deposits, blue-gray skin

Board Pearl

Psychosis in PD/DLB requires careful selection — D2 blockade worsens parkinsonism. Quetiapine is most commonly used. Pimavanserin (selective 5-HT2A inverse agonist, no D2 activity) is FDA-approved specifically for PD psychosis. Never use haloperidol in PD/DLB.

Drug-Induced Movement Disorders

Antipsychotic-Induced Movement Disorders by Time Course

Disorder	Onset	Features	Treatment
Acute dystonia	Hours–days	Torticollis, oculogyric crisis, trismus, laryngospasm. Young males, high-potency agents	Diphenhydramine or benztropine IM/IV
Akathisia	Days–weeks	Subjective restlessness, inability to sit still; often misdiagnosed as worsening psychosis	Propranolol (first-line), benzodiazepines
Parkinsonism	Weeks–months	Bradykinesia, rigidity, tremor — bilateral/symmetric (vs. asymmetric PD). DaT scan normal	Reduce dose; benztropine or amantadine
Tardive dyskinesia	Months–years	Oro-bucco-lingual choreiform movements: lip smacking, tongue protrusion. May be irreversible. Risk: older, female	VMAT2 inhibitors: valbenazine, deutetrabenazine (FDA-approved). Anticholinergics worsen TD

Clinical Pearl

Anticholinergics (benztropine) treat acute dystonia and drug-induced parkinsonism but worsen tardive dyskinesia. VMAT2 inhibitors (valbenazine, deutetrabenazine) are the only FDA-approved TD treatments — distinguish from tetrabenazine, which is approved for Huntington chorea. Drug-induced parkinsonism is typically bilateral and symmetric (unlike asymmetric idiopathic PD), and DaT scan is normal (vs. abnormal in PD), helping differentiate the two.

Mood Stabilizers

Lithium

First-line for bipolar disorder (mania + maintenance); anti-suicidal properties
Narrow therapeutic index (0.6–1.2 mEq/L); toxicity at >1.5 mEq/L
Neurologic: fine postural tremor (therapeutic); coarse tremor, ataxia, irreversible cerebellar damage (toxic)
Endocrine: hypothyroidism (up to 20%), hyperparathyroidism
Renal: nephrogenic diabetes insipidus (ADH resistance at collecting duct)
Teratogenicity: Ebstein anomaly (tricuspid valve malformation)
Monitoring: lithium levels, TSH, creatinine, calcium
Interactions: NSAIDs, thiazides, ACE inhibitors ↑ lithium levels; dehydration precipitates toxicity

Other Mood Stabilizers

Drug	Bipolar Use	Board-Yield Points
Valproate	Acute mania	Neural tube defects (highest teratogenicity); hepatotoxic (children <2); contraindicated in mitochondrial disease; tremor, weight gain, hyperammonemia
Carbamazepine	Mania; maintenance	Autoinduction CYP3A4; SIADH; SJS/TEN (screen HLA-B*1502); aplastic anemia
Lamotrigine	Bipolar depression	SJS/TEN (slow titration); valproate doubles levels; NOT for acute mania; no weight gain

Board Pearl

Lithium toxicity is precipitated by dehydration, NSAIDs, thiazides, and ACE inhibitors. Coarse tremor with ataxia and confusion signals toxicity. Severe toxicity causes seizures, coma, and irreversible cerebellar damage. Hemodialysis if levels >2.5 mEq/L or severe neurologic symptoms.

Anxiolytics & Sedatives

Benzodiazepines

Mechanism: GABA-A positive allosteric modulators — increase frequency of Cl− channel opening (require GABA; ceiling effect → safer than barbiturates)
Examples: diazepam (long-acting), lorazepam (no active metabolites — preferred in liver disease), midazolam (ultra-short), clonazepam (anxiety/seizures)
Reversal: flumazenil — caution: can precipitate withdrawal seizures in chronic users
Dependence: withdrawal can be life-threatening (seizures, delirium); requires gradual taper

Buspirone

5-HT1A partial agonist; used for GAD; takes 2–4 weeks for effect
No sedation, no dependence, no withdrawal; does not impair cognition
Ineffective for panic disorder; does not work if already tolerant to benzodiazepines

Dementia Medications

Cholinesterase Inhibitors & NMDA Antagonist

Drug	Mechanism	Indication	Key Points
Donepezil	Reversible AChE inhibitor	Mild–severe AD	Most widely used; cholinergic side effects (nausea, diarrhea, bradycardia, vivid dreams)
Rivastigmine	AChE + BuChE inhibitor	Mild–moderate AD; PD dementia	Only ChEI with PD dementia indication; transdermal patch reduces GI side effects
Galantamine	AChE inhibitor + nicotinic allosteric modulator	Mild–moderate AD	Dual mechanism; similar side effects to donepezil
Memantine	NMDA antagonist	Moderate–severe AD	Blocks excitotoxicity; can combine with ChEIs; fewer GI effects

Anti-Amyloid Monoclonal Antibodies

Drug	Target	Key Points
Lecanemab	Amyloid-beta protofibrils	Early AD; IV q2 weeks; requires amyloid PET/CSF confirmation; ~27% slowing of decline
Donanemab	Pyroglutamate amyloid-beta	Early AD; dosing ends when amyloid cleared on PET
Aducanumab	Aggregated amyloid plaques	Controversial approval; largely withdrawn from market

ARIA-E: vasogenic edema/sulcal effusions (FLAIR hyperintensity) — ARIA-H: microhemorrhages/superficial siderosis (SWI/GRE)
ApoE4 homozygotes: significantly higher ARIA risk (>35%); genotyping recommended before treatment
Monitoring: serial brain MRIs required; most ARIA is asymptomatic

Clinical Pearl

Rivastigmine is the only ChEI FDA-approved for PD dementia in addition to AD. Its dual AChE + BuChE inhibition may provide additional benefit in DLB/PDD where BuChE activity increases as AChE decreases. The transdermal patch formulation significantly reduces the cholinergic GI side effects that limit oral dosing.

Clinical Pearl

Anti-amyloid mAbs and anticoagulation: Patients on anticoagulants were excluded from clinical trials. ARIA-H (microhemorrhages) can occur in up to 17% of treated patients, and concurrent anticoagulation may increase the risk of symptomatic intracerebral hemorrhage. ApoE4 genotyping is recommended before treatment — homozygotes have >35% ARIA risk and require careful risk-benefit discussion.

Quick Reference

Psychopharmacology — At a Glance

Drug / Class	Key Association	Board-Yield Feature
Citalopram	QTc prolongation	Max 40 mg/day; 20 mg if >60 years
Paroxetine	Most anticholinergic SSRI	Worst in pregnancy; worst withdrawal
Duloxetine	Neuropathic pain SNRI	Diabetic neuropathy, fibromyalgia
TCA overdose	QRS widening + seizures	Sodium bicarbonate
MAOIs	Tyramine crisis; cheese/wine	2-week washout; serotonin syndrome with SSRIs
Serotonin syndrome	Clonus + hyperreflexia	Hours onset; cyproheptadine
NMS	Rigidity + elevated CK	Days–weeks; dantrolene + bromocriptine
Clozapine	Agranulocytosis; ANC monitoring	Most effective for refractory schizophrenia
Quetiapine	PD/DLB psychosis	Safest available antipsychotic in PD
Pimozide	Tourette syndrome	QTc risk; requires ECG
Tardive dyskinesia	Months–years; oro-bucco-lingual	Valbenazine, deutetrabenazine (VMAT2 inhibitors)
Lithium	Narrow index; tremor	Hypothyroidism, nephrogenic DI, Ebstein anomaly
Lamotrigine	Bipolar depression	SJS/TEN; valproate doubles levels
Benzodiazepines	GABA-A; ↑ frequency	Flumazenil reversal; withdrawal seizures
Buspirone	5-HT1A partial agonist	No sedation, no dependence; GAD only
Donepezil	AChE inhibitor	Most widely used ChEI; mild–severe AD
Memantine	NMDA antagonist	Moderate–severe AD; blocks excitotoxicity
Lecanemab	Anti-amyloid mAb	ARIA-E/H monitoring; ApoE4 increases risk

References

Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology. 12th ed. McGraw-Hill; 2023.
Stahl SM. Stahl’s Essential Psychopharmacology. 5th ed. Cambridge University Press; 2021.
Bhatt A. Ultimate Review for the Neurology Boards. 3rd ed. Demos Medical; 2016.
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112–1120.
Hauser RA, et al. KINECT 3: valbenazine for tardive dyskinesia. Am J Psychiatry. 2017;174(5):476–484.
van Dyck CH, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21.
Aminoff MJ, Greenberg DA, Simon RP. Clinical Neurology. 11th ed. McGraw-Hill; 2021.