Antidepressants and antipsychotics

Dopamine pathways explain antipsychotic effects

All antipsychotics, including phenothiazines such as chlorpromazine, owe their antipsychotic effect to blockade of D2 receptors in the mesolimbic pathway, which reduces positive symptoms (delusions, hallucinations). Blocking the same receptor elsewhere produces the adverse effects.

• Many antipsychotics also block muscarinic (dry mouth, constipation, retention, blurred vision), H1 (sedation, weight gain) and α1 receptors (postural hypotension). These "dirty" effects are greatest with low-potency drugs such as chlorpromazine and with clozapine and olanzapine.

Typical and atypical antipsychotics

• First-episode schizophrenia: an atypical antipsychotic is usually started first; check the ECG for QT and baseline weight, glucose and lipids.
• Clozapine is used after failure of two antipsychotics. Adverse effects: agranulocytosis (mandatory blood count monitoring), myocarditis, seizures, hypersalivation, weight gain and severe constipation from antimuscarinic slowing of gut motility, which can progress to ileus. Stopping smoking raises clozapine levels sharply (smoke induces CYP1A2). If stopped for more than 48 hours, it must be re-titrated from a low dose; relapse after stopping it can present with catatonia (stupor, refusal to eat), treated with lorazepam or ECT and reintroduction of clozapine.
• In elderly patients with dementia, antipsychotics increase stroke and death; severe sensitivity suggests Lewy body dementia.

Extrapyramidal side effects

Exam trap Do not treat tardive dyskinesia with procyclidine; it helps dystonia and parkinsonism but worsens tardive movements.

Neuroleptic malignant syndrome and serotonin syndrome

Antidepressants

• Onset: improvement usually takes 2–4 weeks; SSRIs can worsen anxiety in the first weeks, so start low. Continue at least 6 months after remission and taper to avoid discontinuation symptoms.
• SSRI and NSAID: platelets cannot make serotonin and depend on uptake from plasma through the serotonin transporter; SSRIs deplete platelet serotonin, impairing aggregation. Combined with an NSAID, upper GI bleeding risk rises sharply; add a PPI. The same applies with warfarin, DOACs and antiplatelets.
• SSRIs also cause hyponatraemia (SIADH) in the elderly.
• TCA overdose: anticholinergic toxidrome, seizures, hypotension and wide QRS from sodium channel block, leading to ventricular arrhythmias. Treat with sodium bicarbonate.
• MAOI and tyramine: dietary tyramine (aged cheese, red wine, cured meats, yeast extract) normally destroyed by gut and liver MAO reaches the circulation, enters nerve endings and releases stored noradrenaline: hypertensive crisis with severe headache.
• ECT acts fastest and is indicated for severe depression with stupor, refusal to eat or drink, psychotic features such as nihilistic (Cotard) delusions, or high suicide risk; also for catatonia.

QT prolongation

• Drugs that block the cardiac hERG potassium channel prolong repolarisation: haloperidol, citalopram, methadone, macrolides, quinolones, ondansetron, amiodarone, sotalol.
• The most dangerous combinations add a second QT drug or a CYP3A4 inhibitor that raises the level of the first: erythromycin with haloperidol is the classic example. Hypokalaemia and hypomagnesaemia add to the risk of torsades de pointes.

Lithium

• Bipolar disorder (acute mania and prophylaxis); reduces suicide. The antimanic effect takes about 1–2 weeks, so an antipsychotic or benzodiazepine is used meanwhile.
• Mechanism: inhibits inositol monophosphatase (depleting phosphoinositide signalling) and GSK-3.
• Therapeutic range about 0.4–1.0 mmol/L, measured 12 hours after the dose. Lithium is handled like sodium: filtered and about 80% reabsorbed in the proximal tubule.
• Thiazides cause sodium and volume loss; the kidney responds with increased proximal reabsorption of sodium and, with it, lithium, so lithium excretion falls and levels rise by about a quarter or more. NSAIDs, ACE inhibitors, ARBs, dehydration and a low-salt diet do the same.
• Adverse effects: fine tremor, polyuria (nephrogenic diabetes insipidus), hypothyroidism and goitre, hyperparathyroidism with hypercalcaemia, weight gain, T-wave flattening, CKD; Ebstein anomaly with first-trimester exposure.
• Toxicity (above 1.5 mmol/L): coarse tremor, vomiting, diarrhoea, ataxia, dysarthria, confusion, seizures. Stop lithium, give fluids, haemodialysis if severe; charcoal does not bind lithium.

Remember A thiazide makes the proximal tubule thirsty for sodium, and lithium rides along.

Exam trap Coarse tremor and confusion in a patient on lithium after a new diuretic or NSAID is toxicity until proved otherwise.

Benzodiazepine and alcohol issues tested here

• Abrupt cessation of long-term high-dose diazepam causes withdrawal: anxiety, tremor, insomnia and seizures within days. Future withdrawal must be a slow taper, often after switching to diazepam.
• Acamprosate (glutamate NMDA modulator, renally excreted) maintains abstinence in liver disease without a disulfiram-type reaction; methadone or buprenorphine are first line for opioid dependence.

How FCPS asks about this

• Lithium plus thiazide: more proximal lithium reabsorption, reduced excretion, toxicity.
• Most dangerous QT combination: erythromycin with haloperidol.
• Drug-induced parkinsonism or dystonia on haloperidol: procyclidine.
• Amenorrhoea on an antipsychotic: risperidone (prolactin); aripiprazole lowers prolactin.
• Clozapine monitoring and constipation: blood count for agranulocytosis; antimuscarinic ileus.
• Antidepressant linked to hypercalcaemia or Ebstein anomaly: lithium.
• TCA overdose in ICU: wide QRS and arrhythmia; sodium bicarbonate.