Psychopharmacology Overview — Viva

Q1: The four drug classes and their mechanisms (2 min)

Examiner: Take me through the four pillars of psychopharmacology. For each, name the receptor target, the first-line agent, and the signature side-effect. ^[1]

Expected answer: The four classes are antidepressants, antipsychotics, mood stabilisers, and anxiolytics. ^[1]

Antidepressants — first-line are the SSRIs (sertraline, fluoxetine, escitalopram). They block the serotonin transporter (SERT), raising synaptic 5-HT. Clinical effect takes 2 to 6 weeks (5-HT1A autoreceptor desensitisation and BDNF-mediated neuroplasticity). Signature side effects: nausea, sexual dysfunction, hyponatraemia (SIADH, especially in the elderly), GI bleed, QT with citalopram. The named emergency is serotonin syndrome (hyperreflexia, clonus, autonomic instability). ^[2]

Antipsychotics — first-line are the second-generation (atypical) antipsychotics (olanzapine, risperidone, quetiapine, aripiprazole). Mechanism: D2 receptor blockade (response emerges above about 65 percent D2 occupancy, EPS above about 78 percent — Kapur 2000 PET study), with atypicals also blocking 5-HT2A (which restores nigrostriatal dopamine tone and reduces EPS). The four dopamine pathways are key: mesolimbic (efficacy against positive symptoms), mesocortical (cognition and negative symptoms), nigrostriatal (motor — D2 blockade causes EPS), tuberoinfundibular (prolactin inhibition — D2 blockade causes hyperprolactinaemia). Signature side effects: the EPS quartet (acute dystonia, akathisia, parkinsonism, tardive dyskinesia), metabolic syndrome (weight, glucose, lipids), hyperprolactinaemia, sedation, QT. The named emergency is NMS (fever, lead-pipe rigidity, CK high, altered consciousness). ^[2]

Mood stabilisers — gold standard is lithium (multiple targets — GSK-3β inhibition, inositol cycle modulation, BDNF enhancement); narrow therapeutic window — maintenance 0.6 to 0.8 mmol/L (0.8 to 1.0 for acute mania under specialist care). Signature ADRs: fine tremor, polyuria (nephrogenic DI), hypothyroidism, weight gain. The named emergency is lithium toxicity (coarse tremor, ataxia, confusion, seizures — dialysis per EXTRIP: impaired renal function with level over 4.0, or decreased consciousness, seizures or life-threatening dysrhythmias irrespective of level). Valproate (teratogenic), lamotrigine (SJS), carbamazepine (HLA-B*1502 SJS) are the alternatives. ^[3]

Anxiolytics — short-term benzodiazepines (diazepam, lorazepam) — positive allosteric modulators of GABA-A, increasing the frequency of chloride channel opening. Signature ADRs: sedation, dependence, withdrawal (seizures), falls in the elderly. The named emergency is withdrawal seizures (managed by tapering and IV lorazepam acutely; flumazenil reverses overdose cautiously). ^[12]

Q2: Differentiating the toxidromes (3 min)

Examiner: A patient on psychiatric medication presents febrile, confused, and rigid. How do you distinguish NMS from serotonin syndrome, and what would you do? ^[4]

Expected answer: The discriminating features are tempo, tone, reflexes, autonomic pattern, and trigger. ^[6]

NMS: triggered by an antipsychotic, evolves over hours to days, has lead-pipe rigidity with bradyreflexia, normal pupils, reduced or normal bowel sounds, marked CK elevation, leukocytosis, low serum iron. Treatment: stop the antipsychotic, IV dantrolene 1 to 2.5 mg/kg bolus then 1 mg/kg every 6 hours (maximum 10 mg/kg/day), bromocriptine (2.5 mg two or three times daily titrated to 45 mg/day), aggressive cooling, IV fluids, ICU. Mortality was over 30 percent in early reports and is closer to 10 percent now. ^[4]

Serotonin syndrome: triggered by a serotonergic agent (SSRI, SNRI, TCA, MAOI, tramadol, triptan, linezolid, methylene blue, dextromethorphan, St John's wort), evolves over hours, has hyperreflexia with clonus (especially lower limbs), mydriasis, hyperactive bowel sounds, diarrhoea, agitation, autonomic instability. Treatment: stop all serotonergics, benzodiazepines for agitation/myoclonus, aggressive cooling, cyproheptadine 12 mg PO/NG initially, then 2 mg every 2 hours if symptoms continue, then 8 mg every 6 hours once stabilised (5-HT2A antagonist), ICU if severe. Antipyretics are ineffective because the heat is generated by muscle activity. ^[4]

I would also consider the mimics: malignant hyperthermia (triggered by inhaled anaesthetic or succinylcholine, intraoperative, treated with the same dantrolene), anticholinergic toxicity ('dry as a bone, red as a beet, hot as a hare, blind as a bat, mad as a hatter' — dry flushed skin, mydriasis, urinary retention, absent bowel sounds, treated with physostigmine in severe cases), and meningitis/encephalitis/sepsis — which must be excluded with cultures, LP if indicated, and empirical antibiotics if the diagnosis is unclear. ^[4]

Q3: Clozapine, lithium, and the high-yield monitoring (3 min)

Examiner: When would you use clozapine, and what monitoring does it need? And how do you start and monitor lithium? ^[7]

Expected answer:

Clozapine is indicated for treatment-resistant schizophrenia — failure of two adequate antipsychotic trials (different drugs, 6 weeks each at therapeutic dose). It is the only drug with proven superiority, with response in 30 percent of refractory patients in the pivotal Kane 1988 trial and 40.1 percent in the Siskind 2017 meta-analysis. Clozapine also has a role in schizophrenia with suicidal behaviour (the only antipsychotic with an FDA indication for suicide reduction) and in psychosis in Parkinson's disease (low EPS liability). ^[7]

Monitoring: mandatory full blood count (absolute neutrophil count) — weekly for the first 18 weeks, fortnightly until week 52, then monthly for as long as treatment continues (UK protocol; US: weekly for 6 months, fortnightly for the second 6 months, then monthly). Stop if ANC under 1.5 × 10⁹/L (or under 1.0 in the US "general" category — depends on local protocol), and do not re-challenge. Register with a clozapine monitoring service. Warn about and monitor for: myocarditis (first 2 months — flu-like then chest pain, fever, tachycardia; troponin and echocardiogram diagnostic; stop and do not re-challenge), cardiomyopathy, seizure (1.3 percent of 5,629 registry patients — during titration even at low dose and at 600 mg/day or more in maintenance), severe constipation and gastrointestinal hypomotility (a recognised cause of clozapine-related death — reported case fatality 18 percent — bowel regimen, regular laxatives), hypersalivation (sublingual atropine, terazosin), and metabolic syndrome. ^[7]

Lithium — baseline: U&E, eGFR, TFTs, calcium, pregnancy test, ECG if cardiac risk, weight/BMI. Start 400 to 600 mg nocte. Check the 12-hour trough level (drawn 12 hours after the last dose — this is critical; a level taken too early will be falsely high) at 5 to 7 days. Titrate to a maintenance level of 0.6 to 0.8 mmol/L (acute mania may target 0.8 to 1.0 under specialist care). Recheck weekly until stable, then 3-monthly. U&E, eGFR, TFTs, calcium 6-monthly. Counsel on: maintain normal fluid intake; omit the dose and seek review if unwell with vomiting/diarrhoea/fever/dehydration; avoid NSAIDs, diuretics, ACE-i/ARB; report coarse tremor, ataxia, confusion immediately; reliable contraception; carry a lithium alert card; do not stop abruptly. ^[11]

Q4: Special populations — pregnancy and the elderly (2 min)

Examiner: A pregnant woman with severe bipolar disorder and a young woman of childbearing potential with epilepsy — how do you approach psychotropic prescribing? ^[9]

Expected answer: In pregnancy, untreated psychiatric illness itself harms mother and fetus (relapse, suicide, substance use, poor antenatal care, postpartum relapse), so the question is not 'avoid all drugs' but 'choose the safest effective option'. SSRIs — sertraline preferred (lowest fetal transfer); avoid paroxetine (first-trimester cardiac defects) and high-dose citalopram (QT). Lithium — cardiac malformation risk (adjusted RR 1.65; right-sided outflow tract defects including Ebstein anomaly 0.60 percent vs 0.18 percent unexposed, dose-dependent); in stable patients, weigh continuation against relapse; if continued, monitor levels closely (clearance rises through pregnancy then falls acutely postpartum — risk of toxicity in the puerperium, reduce the dose immediately post-delivery). Valproate and carbamazepine are TERATOGENIC — avoid; use a pregnancy prevention programme if essential. Lamotrigine is relatively safer; clearance rises in pregnancy, dose may need to rise. Antipsychotics — olanzapine and quetiapine are reasonably safe; avoid high-dose typicals in the third trimester (extrapyramidal signs in neonate). Benzodiazepines — third-trimester use causes neonatal floppy-baby syndrome and withdrawal. ECT is safe in pregnancy for severe illness (catatonia, suicidal depression, psychotic depression). ^[9]

Breastfeeding: most SSRIs (sertraline, paroxetine) have minimal transfer and are preferred; lithium is contraindicated (high milk transfer); valproate and carbamazepine are compatible; olanzapine and quetiapine considered compatible. ^[9]

In a woman of childbearing potential, the Pregnancy Prevention Programme for valproate is mandatory: reliable contraception, regular pregnancy testing, specialist review, and signed informed consent documenting the teratogenic risk. The same care applies to carbamazepine. Always discuss family planning at the time of initiation, not after conception. ^[10]

References12ShowHide

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