6.2 Psychopharmacology Mechanisms
Key Takeaways
- SSRIs block SERT; SNRIs block SERT and NET; TCAs add muscarinic, histaminergic, and α1 blockade plus sodium-channel toxicity in overdose; MAOIs inhibit monoamine breakdown and risk tyramine hypertensive crisis and serotonin syndrome.
- Typical antipsychotics are high D2 antagonists with more EPS and hyperprolactinemia; atypicals add 5-HT2A antagonism with lower EPS risk but more metabolic adverse effects for several agents.
- Neuroleptic malignant syndrome is severe rigidity, hyperthermia, autonomic instability, and elevated CK from profound D2 blockade; serotonin syndrome features hyperreflexia and clonus with serotonergic excess.
- Lithium has a narrow therapeutic index with tremor, confusion, and seizures in toxicity; chronic use associates with hypothyroidism and nephrogenic diabetes insipidus.
- Benzodiazepines positively modulate GABA-A receptors; valproate, carbamazepine, and lamotrigine stabilize mood through distinct ion-channel and signaling actions with agent-specific toxicities (hepatotoxicity/teratogenicity, agranulocytosis/autoinduction, SJS/TEN rash).
Antidepressants: Transporters, Enzymes, and Toxicities
SSRIs (fluoxetine, sertraline, citalopram/escitalopram, paroxetine, fluvoxamine) selectively inhibit the serotonin transporter (SERT), increasing synaptic 5-HT. Early adverse effects include GI upset, sexual dysfunction, and anxiety/activation; hyponatremia via SIADH is a high-yield systemic risk, especially in older adults. SNRIs (venlafaxine, duloxetine) inhibit SERT and the norepinephrine transporter (NET); venlafaxine can raise blood pressure at higher doses through NE effects. Duloxetine also appears in pain and neuropathy vignettes because of descending monoamine analgesia pathways.
Tricyclic antidepressants (TCAs) inhibit SERT and NET but also block muscarinic (anticholinergic: dry mouth, constipation, urinary retention, delirium), H1 (sedation, weight gain), and α1-adrenergic (orthostasis) receptors. Overdose is lethal via cardiac sodium-channel blockade (wide QRS, ventricular arrhythmias) plus anticholinergic and antihistaminic toxicity—sodium bicarbonate is the classic overdose antidote framing.
MAOIs (phenelzine, tranylcypromine, selegiline) inhibit monoamine oxidase, reducing intracellular breakdown of 5-HT, NE, and DA. Two exam-critical interactions dominate: (1) tyramine crisis—dietary tyramine normally metabolized by gut MAO-A enters the circulation when MAO is inhibited, releasing NE and causing hypertensive emergency; (2) serotonin syndrome when combined with SSRIs/SNRIs/meperidine/linezolid/triptans or other serotonergic drugs.
| Class | Primary mechanism | Signature toxicity / pearl |
|---|---|---|
| SSRI | SERT inhibition | Sexual dysfunction; SIADH; serotonin syndrome risk |
| SNRI | SERT + NET inhibition | Hypertension (esp. venlafaxine); serotonin syndrome risk |
| TCA | SERT/NET + mACh/H1/α1 block | Wide-complex arrhythmia in overdose; anticholinergic effects |
| MAOI | MAO inhibition | Tyramine hypertensive crisis; serotonin syndrome |
| Bupropion | DA/NE reuptake effects | Seizure risk (dose/eating disorders); less sexual side effects |
| Mirtazapine | α2 antagonism → ↑5-HT/NE; H1 block | Sedation, weight gain |
Serotonin syndrome is excess 5-HT (often multi-drug): altered mental status, autonomic hyperactivity (hyperthermia, diaphoresis, tachycardia), and neuromuscular excitation with hyperreflexia and clonus (especially lower extremity). Contrast with NMS (below): NMS is bradyreflexic rigidity from dopamine blockade, not hyperreflexic clonus from serotonin excess.
Antipsychotics: D2, 5-HT2A, EPS, NMS, and Metabolic Effects
Typical (first-generation) antipsychotics (haloperidol, fluphenazine, chlorpromazine) primarily antagonize D2 receptors. High-potency agents (haloperidol) cause more extrapyramidal symptoms (EPS) and less H1/mACh/α1 blockade; low-potency agents (chlorpromazine, thioridazine) cause more sedation, anticholinergic effects, and orthostasis, with relatively less EPS. Atypical (second-generation) antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole, clozapine, ziprasidone) combine D2 antagonism (or partial agonism for aripiprazole) with 5-HT2A antagonism, generally reducing EPS at the cost of greater metabolic risk (weight gain, dyslipidemia, diabetes) for several agents—especially olanzapine and clozapine.
| Side-effect domain | Mechanism | Clinical pattern |
|---|---|---|
| Acute dystonia | Nigrostriatal D2 blockade | Hours–days: torticollis, oculogyric crisis |
| Akathisia | D2-related motor restlessness | Days–weeks: subjective need to move |
| Parkinsonism | Nigrostriatal D2 blockade | Weeks: bradykinesia, rigidity, tremor |
| Tardive dyskinesia | Chronic D2 blockade; receptor supersensitivity framing | Months–years: choreoathetoid orofacial movements |
| Hyperprolactinemia | Tuberoinfundibular D2 blockade | Galactorrhea, amenorrhea, sexual dysfunction (risperidone high-yield) |
| Metabolic syndrome | H1/5-HT2C and other receptors | Weight gain, insulin resistance (olanzapine, clozapine) |
| Agranulocytosis | Idiosyncratic (clozapine) | Mandatory ANC monitoring |
| QT prolongation | Cardiac K-channel effects | Arrhythmia risk (agent-dependent) |
Neuroleptic malignant syndrome (NMS) is a life-threatening reaction to dopamine antagonists: severe “lead-pipe” rigidity, hyperthermia, autonomic instability, altered mental status, and elevated CK with possible rhabdomyolysis and renal failure. It is a hypodopaminergic state; management framing includes stop the agent, supportive care, and sometimes dantrolene or dopaminergic agents in clinical layers. Do not confuse with serotonin syndrome’s hyperreflexia/clonus.
Positive-symptom efficacy tracks mesolimbic D2 blockade. Worsening of negative symptoms or cognitive dulling can reflect mesocortical dopamine reduction—another reason pathway thinking beats “dopamine bad” heuristics.
Lithium: Efficacy, Toxicity, Thyroid, and Kidney
Lithium is a first-line mood stabilizer for mania and maintenance in bipolar disorder. Cellular mechanisms include inositol signaling modulation and effects on GSK-3 and second-messenger systems—exam items more often test pharmacokinetics and toxicity than every molecular target. Lithium is renally cleared, has a narrow therapeutic index, and toxicity is precipitated by dehydration, NSAIDs, ACE inhibitors, and thiazides that increase lithium levels.
Toxicity spectrum: tremor → ataxia, dysarthria, confusion → seizures and coma; ECG changes may appear. Chronic adverse effects include hypothyroidism (and goiter) and nephrogenic diabetes insipidus (downregulation of aquaporin-2 responsiveness to ADH → polyuria/polydipsia). Monitoring themes: serum levels, renal function, TSH, and pregnancy counseling (Ebstein anomaly risk is the classic teratogenicity association).
Benzodiazepines and GABA-A
Benzodiazepines bind an allosteric site on GABA-A receptors, increasing the frequency of chloride channel opening in the presence of GABA (positive allosteric modulation). Clinical effects: anxiolysis, sedation, muscle relaxation, anticonvulsant action. Risks include tolerance, dependence, respiratory depression especially with alcohol/opioids, and withdrawal seizures when stopped abruptly after chronic use. Flumazenil is a competitive antagonist used in select overdose settings but can precipitate seizures in dependent patients—mechanism awareness matters more than protocol memorization.
Stimulants
Amphetamines promote release and block reuptake of DA and NE; methylphenidate primarily blocks reuptake. They enhance prefrontal catecholamine signaling in ADHD. Adverse effects: appetite suppression, insomnia, tachycardia/hypertension, anxiety; misuse potential via mesolimbic reward activation. Atomoxetine (NET inhibitor) and α2 agonists (guanfacine, clonidine) are non-stimulant alternatives with different adverse-effect profiles (e.g., atomoxetine hepatotoxicity rare warning; α2 agonists cause sedation and hypotension).
Mood Stabilizers Beyond Lithium: Valproate, Carbamazepine, Lamotrigine
| Agent | Core mechanism framing | Key toxicities / pearls |
|---|---|---|
| Valproate | Na+ channel effects; ↑GABA; histone deacetylase inhibition themes | Hepatotoxicity, pancreatitis, neural-tube defects (↓folate), weight gain, tremor, thrombocytopenia |
| Carbamazepine | Voltage-gated Na+ channel blockade | Agranulocytosis/aplastic anemia, SIADH/hyponatremia, CYP3A4 autoinduction, SJS risk (HLA-B*1502 in at-risk ancestry) |
| Lamotrigine | Na+ channel modulation; glutamate release dampening | Slow titration to avoid SJS/TEN; safer in pregnancy than valproate for many bipolar depression contexts |
Valproate is highly effective for acute mania and mixed features; lamotrigine is more associated with bipolar depression maintenance than acute mania. Carbamazepine’s enzyme induction creates drug–drug interaction vignettes. Always link rash timelines and titration speed for lamotrigine to immune-mediated severe cutaneous reactions.
Integrating Toxidromes for Exam Discrimination
| Syndrome | Trigger class | Motor findings | Other anchors |
|---|---|---|---|
| Serotonin syndrome | Serotonergic combos | Hyperreflexia, clonus | Hyperthermia, diarrhea, agitation |
| NMS | Dopamine antagonists | Lead-pipe rigidity, bradyreflexia | High CK, days after start/increase |
| Anticholinergic toxicity | TCAs, low-potency APs, antihistamines | Normal reflexes; dry skin | “Mad as a hatter…,” mydriasis, urinary retention |
| Lithium toxicity | Lithium + renal clearance drop | Coarse tremor, ataxia | GI symptoms early; confusion, seizures |
Psychopharmacology items reward receptor-level reasoning: if the vignette shows galactorrhea after risperidone, think tuberoinfundibular D2 blockade; if wide QRS after TCA overdose, think cardiac Na+ channels; if hypertensive crisis after cheese and an MAOI, think tyramine and peripheral NE; if hyperthermia with clonus after an SSRI plus MAOI, think serotonin syndrome rather than NMS.
A patient on phenelzine eats aged cheese and develops severe headache, diaphoresis, and blood pressure of 220/120 mm Hg. Which mechanism best explains this crisis?
Two days after starting high-potency haloperidol, a patient develops fever, lead-pipe rigidity, fluctuating blood pressure, and CK of 8,000 U/L. Deep tendon reflexes are reduced. Which diagnosis and mechanism pairing is most accurate?
A bipolar patient stable on lithium develops polyuria and polydipsia with dilute urine that does not concentrate appropriately after desmopressin. Which mechanism best explains this adverse effect?