Psychopharmacology accounts for approximately 22% of Paper A marks — roughly 33 of 150 questions. This makes it the second-largest section after neurosciences. Unlike neurosciences, however, pharmacology is fundamentally logical. If you understand mechanisms, you can deduce side effects and interactions without memorising every fact in isolation.
Antidepressants: Mechanism-First Learning
There are eight classes of antidepressants, but the underlying mechanisms reduce to three core strategies: increase monoamine availability, modulate receptor sensitivity, or alter intracellular signalling.
SSRIs
Mechanism: Inhibit serotonin reuptake via SERT. First-line for moderate-severe depression due to favourable side-effect profile and safety in overdose. Key difference between SSRIs: fluoxetine has the longest half-life (4–6 days), paroxetine has the highest anticholinergic burden and worst withdrawal, sertraline has a favourable GI profile and some dopamine reuptake inhibition at higher doses.
SNRIs
Venlafaxine and duloxetine inhibit both serotonin and noradrenaline reuptake. Dose-dependent effect: at lower doses (venlafaxine <150mg), serotonergic effects dominate. At higher doses, noradrenergic effects emerge. Venlafaxine requires blood pressure monitoring. Duloxetine is licensed for diabetic neuropathic pain and stress incontinence as well as depression.
NaSSAs (Mirtazapine)
Mirtazapine blocks presynaptic α2-adrenoceptors, increasing noradrenaline and serotonin release. It also blocks 5-HT2 and 5-HT3 receptors (reducing anxiety and GI side effects) and H1 receptors (causing sedation). It has the lowest seizure risk of any antidepressant and the lowest sexual dysfunction rate — making it first-line in patients with epilepsy or pre-existing sexual dysfunction.
TCAs
Amitriptyline, nortriptyline, clomipramine, imipramine, dosulepin. Block serotonin and/or noradrenaline reuptake, but also block histamine, acetylcholine, and α1-adrenoceptors — hence the side-effect burden (sedation, dry mouth, constipation, postural hypotension, cardiac toxicity). Nortriptyline has the best evidence in post-stroke depression. Clomipramine is the TCA evidence-based for OCD.
MAOIs
Phenelzine, tranylcypromine, moclobemide (reversible MAO-A inhibitor). Irreversible MAOIs require dietary tyramine restriction to avoid hypertensive crisis. Exam classic: cheese reaction = tyramine + MAOI-A = hypertensive emergency. Moclobemide does not require dietary restriction.
Other Classes
Agomelatine: MT1/MT2 agonist + 5-HT2C antagonist. No sexual dysfunction, no discontinuation syndrome. Liver function monitoring required.
Bupropion: NDRI. Contraindicated in epilepsy and eating disorders. Used for smoking cessation and as augmentation.
Vortioxetine: Multimodal serotonergic agent. May improve cognitive function in depression.
Antipsychotics: The Receptor Profile Method
The key insight for antipsychotic pharmacology is that every effect — therapeutic and adverse — can be predicted from the receptor-binding profile.
| Receptor | Blockade effect |
|---|---|
| D2 | Antipsychotic effect (mesolimbic) | Extrapyramidal side effects (nigrostriatal) | Prolactin elevation (tuberoinfundibular) |
| 5-HT2A | Reduced EPS (atypical advantage) | Weight gain |
| H1 | Sedation | Weight gain |
| M1 | Anticholinergic (dry mouth, blurred vision, constipation, cognitive dulling) |
| α1 | Postural hypotension | Sedation |
Key Antipsychotics to Know
Clozapine: The gold standard for treatment-resistant schizophrenia. Unique mechanism: weak D2 blockade but strong D4, 5-HT2A, and adrenergic effects. Mandatory FBC monitoring due to 1% risk of agranulocytosis. Also causes sialorrhoea, tachycardia, constipation, and myocarditis (especially in the first 2 months).
Olanzapine: High affinity for histamine and 5-HT2C receptors = significant weight gain and metabolic syndrome. D2 occupancy drops below therapeutic threshold at 24 hours — hence once-daily dosing is sufficient for psychosis but twice-daily may improve control for some patients.
Risperidone: Active metabolite (9-hydroxyrisperidone). Prolactin elevation is dose-dependent and more prominent than with other atypicals. Paliperidone is the active metabolite itself, formulated as an extended-release preparation.
Aripiprazole: Partial D2 agonist. Unique profile: low EPS, low prolactin, low sedation, but can cause akathisia and nausea. Useful for patients with metabolic syndrome or hyperprolactinaemia from other antipsychotics.
Amisulpride: Selective D2/D3 antagonist. Low doses (<400mg) preferentially block presynaptic D2 receptors (disinhibiting dopamine release — potentially improving negative symptoms). High doses (>400mg) block postsynaptic D2 receptors (antipsychotic effect).
Mood Stabilisers
Lithium: The most effective mood stabiliser for bipolar I disorder. Mechanism: inositol depletion and GSK-3β inhibition. Narrow therapeutic index (0.6–1.0 mmol/L maintenance). Side effects: polyuria/polydipsia (nephrogenic diabetes insipidus), tremor, weight gain, hypothyroidism, hypercalcaemia. Monitoring: U&Es, TFTs, calcium (6-monthly), eGFR, lithium levels (every 3–6 months).
Valproate: Broad-spectrum anticonvulsant and mood stabiliser. Contraindicated in women of childbearing potential without a pregnancy prevention programme due to high teratogenicity. Side effects: weight gain, tremor, thrombocytopenia, hepatotoxicity, PCOS. Monitoring: LFTs, FBC, valproate levels.
Lamotrigine: Best evidence for bipolar depression prophylaxis. Slow titration to avoid Stevens-Johnson syndrome. No therapeutic level monitoring required. Particularly useful when the depressive phase dominates the bipolar course.
Carbamazepine: CYP3A4 inducer. Used in bipolar II and rapid cycling. Side effects: hyponatraemia, leucopenia, rash, ataxia. Monitoring: FBC, LFTs, U&Es, carbamazepine levels.
Essential Trial Data for Paper A
- STAR*D (2006): Cumulative remission ~67% across 4 treatment steps for major depression. Level 1 (citalopram) remission = 36.8%. No difference between switch and augment strategies.
- CATIE (2005): Olanzapine had the lowest discontinuation rate but worst metabolic profile. Perphenazine (typical) was comparable to atypicals for efficacy. Olanzapine > risperidone > quetiapine > ziprasidone for time to discontinuation.
- CUtLASS (2006): No significant advantage of atypicals over typicals (sulpiride, haloperidol) for quality of life in schizophrenia. First-generation antipsychotics are not inferior in many patients.
- BALANCE (2010): Lithium + valproate combination was more effective than valproate alone for bipolar maintenance. Lithium alone was comparable to combination therapy.
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