CNS Pharmacology: Antidepressants, Antipsychotics, and Antiepileptics

Clinical Pharmacology, Lecture 5. This lecture covers the pharmacology of drugs acting on the central nervous system — focusing on antidepressant agents, antipsychotic drugs, and antiepileptic medications. CNS pharmacology is clinically challenging because CNS drugs are pleiotropic, have complex receptor profiles, and require particular caution regarding drug interactions and special populations.

ANTIDEPRESSANTS

Depression is a heterogeneous disorder; all antidepressants have delayed onset (~2-4 weeks), suggesting neuroplastic mechanisms (increased BDNF, hippocampal neurogenesis) rather than simple monoamine correction underlie therapeutic effect. The monoamine hypothesis (depression = deficiency in serotonin and/or noradrenaline) provides a mechanistic framework for drug development but is an oversimplification.

Selective serotonin reuptake inhibitors (SSRIs): fluoxetine, sertraline, escitalopram, paroxetine, citalopram. Mechanism: block SERT (serotonin transporter), increasing synaptic serotonin concentration. First-line for depression, anxiety disorders, OCD, PTSD, panic disorder. Adverse effects: GI (nausea, diarrhoea — most common early, usually resolves); sexual dysfunction (reduced libido, anorgasmia — underreported, affects up to 30-40%); insomnia or sedation; QTc prolongation (citalopram and escitalopram — avoid high doses and avoid co-prescribing with other QT-prolonging drugs); hyponatraemia — SIADH, especially in elderly; discontinuation syndrome (particularly paroxetine — short half-life; taper when stopping). Serotonin syndrome: excess serotonergic activity from drug combinations (SSRI + MAOI, SSRI + tramadol/fentanyl, SSRI + linezolid); triad: altered mental status, autonomic instability (hyperthermia, tachycardia, diaphoresis), neuromuscular changes (hyperreflexia, clonus, tremor, myoclonus); severe cases: rhabdomyolysis, DIC, death; management: stop serotonergic drugs, supportive care, cyproheptadine (serotonin antagonist) in moderate cases, benzodiazepines for agitation. MAOI interaction: at least 2 weeks washout after SSRI before starting MAOI (5 weeks for fluoxetine — long half-life); 2 weeks washout after MAOI before SSRI.

Serotonin-noradrenaline reuptake inhibitors (SNRIs): venlafaxine, duloxetine, desvenlafaxine. Block both SERT and NET. Duloxetine is first-line for diabetic peripheral neuropathic pain and stress urinary incontinence in addition to depression. Venlafaxine at high dose causes hypertension (noradrenergic effect — monitor BP). Discontinuation syndrome similar to SSRIs. Useful in depression with anxiety comorbidity.

Tricyclic antidepressants (TCAs): amitriptyline, nortriptyline, imipramine, clomipramine. Block SERT and NET but also block muscarinic, histamine H1, and alpha-1 receptors — hence their broad side effect profile. Anticholinergic effects: dry mouth, urinary retention, constipation, confusion (especially in elderly); cardiac: prolonged QRS and QTc — dangerous in overdose; sedation (H1 block); orthostatic hypotension (α1 block). Amitriptyline at low dose (10-50 mg) is used for neuropathic pain and migraine prophylaxis — different mechanism from antidepressant doses. Overdose is a medical emergency: QRS widening, hypotension, seizures, coma; treat with sodium bicarbonate (alkalinisation narrows QRS).

Mirtazapine: noradrenergic and specific serotonergic antidepressant (NaSSA). Blocks presynaptic α2 autoreceptors (increasing NA and 5-HT release) and 5-HT2, 5-HT3, H1 receptors. Sedating (useful in depression with insomnia), anxiolytic, antiemetic, appetite-stimulating (useful in low appetite/underweight depression). Good choice for elderly, depression with anxiety or nausea.

Monoamine oxidase inhibitors (MAOIs): phenelzine, tranylcypromine, moclobemide (reversible MAOI-A). Block MAO-A (5-HT/NA) and/or MAO-B (dopamine). Irreversible MAOIs (phenelzine): tyramine interaction — cheese reaction; tyramine in food normally broken down by intestinal MAO-A; MAOI inhibition → dietary tyramine absorbed intact → noradrenaline surge → hypertensive crisis (severe headache, hypertension, intracerebral haemorrhage). Extensive dietary restrictions required. Reserved for treatment-resistant depression. Moclobemide is selective and reversible MAO-A inhibitor — much safer, fewer interactions.

ANTIPSYCHOTIC DRUGS

Dopamine D2 receptor block in the mesolimbic pathway is the presumed mechanism of antipsychotic effect (positive symptom relief). However, D2 block in other pathways causes adverse effects: nigrostriatal (extrapyramidal symptoms), tuberoinfundibular (hyperprolactinaemia), mesocortical (cognitive worsening, negative symptom exacerbation with typical antipsychotics).

Typical (first-generation) antipsychotics: haloperidol, chlorpromazine. Predominantly D2 block. Effective for positive symptoms (hallucinations, delusions), but high rates of extrapyramidal side effects (EPS): acute dystonia (sustained muscle contraction, torticollis, oculogyric crisis — within hours to days; treat with procyclidine or benztropine), akathisia (subjective restlessness — most distressing, may worsen apparent agitation), parkinsonian features (bradykinesia, rigidity, tremor), tardive dyskinesia (abnormal involuntary movements, especially perioral — late complication, may be irreversible; strongest predictor is prolonged typical antipsychotic use).

Atypical (second-generation) antipsychotics: clozapine, olanzapine, risperidone, quetiapine, aripiprazole, amisulpride. Multi-receptor profiles with lower D2 occupancy relative to 5-HT2A block — lower EPS risk but new metabolic and other concerns. Clozapine: reserved for treatment-resistant schizophrenia (at least 2 failed antipsychotic trials); most effective antipsychotic for positive AND negative symptoms; reduces suicidality in schizophrenia. Critical adverse effect: agranulocytosis (1-2% — potentially fatal; mandatory neutrophil count monitoring: weekly for 18 weeks, then monthly lifelong — in New Zealand via CPMS). Other clozapine adverse effects: hypersalivation, sedation, constipation (can cause fatal bowel obstruction), weight gain, myocarditis (rare but serious — check troponin and CRP in first month), seizures at high doses. Olanzapine: significant weight gain and metabolic syndrome (dyslipidaemia, hyperglycaemia) — fasting glucose and lipids at baseline and 3-monthly. Risperidone/paliperidone: potent D2 block — higher EPS risk at higher doses; hyperprolactinaemia. Aripiprazole: partial D2 agonist (functional antagonist in high-dopamine states, partial agonist in low-dopamine states) — minimal metabolic effects and low EPS; useful in akathisia-sensitive patients. Quetiapine: strongly sedating; often used in bipolar disorder and as adjunct in depression and anxiety. QTc prolongation: multiple antipsychotics (haloperidol, ziprasidone, amisulpride) — risk of torsades de pointes; ECG monitoring.

Neuroleptic malignant syndrome (NMS): rare, life-threatening complication of antipsychotics (and other D2-blocking agents including metoclopramide). Tetrad: hyperthermia, muscle rigidity ("lead pipe"), autonomic instability, altered consciousness. Raised CK (can be extremely high → rhabdomyolysis, acute renal failure), leukocytosis. Onset days to weeks after starting or increasing antipsychotic. Management: stop antipsychotic immediately; supportive care (cooling, IV fluids, ITU); dantrolene (reduces muscle rigidity via RyR1 block), bromocriptine (dopamine agonist to restore dopaminergic tone).

ANTIEPILEPTIC DRUGS (AEDs)

AEDs target ion channels (Na+, Ca2+), enhance GABA inhibition, or block glutamate excitation. Mechanism determines spectrum and interactions.

Sodium channel blockers: carbamazepine, phenytoin, oxcarbazepine, lamotrigine, lacosamide. Stabilise the inactivated state of voltage-gated Na+ channels, reducing neuronal firing frequency. Carbamazepine: first-line for focal epilepsy and trigeminal neuralgia; potent CYP inducer (↑ metabolism of many drugs including OCPs, warfarin, other AEDs — monitor and adjust doses); adverse effects: ataxia, diplopia, hyponatraemia (SIADH), aplastic anaemia (rare), Stevens-Johnson syndrome (rare but serious — screen for HLA-B*1502 in Han Chinese/Thai patients — 10-fold higher risk of SJS). Phenytoin: narrow therapeutic index; zero-order kinetics at therapeutic concentrations (small dose increases cause disproportionate rises in plasma levels); non-linear TDM essential (therapeutic range 40-80 µmol/L or 10-20 µg/mL); IV formulation for status epilepticus; adverse effects: gingival hyperplasia, hirsutism, coarsening of facial features, peripheral neuropathy, osteomalacia (CYP induction → ↑vitamin D metabolism). Lamotrigine: broad-spectrum (focal + generalised); preferred in women of childbearing age; slow titration required to reduce risk of Stevens-Johnson syndrome; metabolised by glucuronidation (affected by valproate — ↑ lamotrigine levels → toxicity, reduce dose; and by enzyme inducers — carbamazepine ↓ lamotrigine levels, increase dose); safe in pregnancy (teratogenicity lower than valproate/carbamazepine).

GABA enhancers: valproate (sodium valproate/valproic acid): broad-spectrum (most effective for generalised epilepsies — juvenile myoclonic epilepsy, absence, tonic-clonic); mechanism: blocks Na+ channels, enhances GABA synthesis, reduces GABA reuptake; also inhibits T-type Ca2+ channels. Adverse effects: teratogenicity (major concern — neural tube defects 2-3%, cardiac malformations, fetal valproate syndrome, neurodevelopmental impairment; MHRA guidance — valproate must not be prescribed to women of childbearing potential without a Pregnancy Prevention Programme); weight gain, hair loss (reversible on stopping), tremor, hyperammonaemia (liver toxicity — LFTs at baseline and periodically); CYP inhibitor (↑ lamotrigine, ↑ carbamazepine-epoxide). Benzodiazepines (diazepam, lorazepam, clonazepam): enhance GABA-A receptor activity (allosteric modulation, ↑ Cl− channel opening frequency); IV lorazepam or diazepam rectal are first-line for status epilepticus; clonazepam for myoclonic and absence seizures; tolerance develops to antiepileptic effect; dependence and withdrawal risk. Gabapentin, pregabalin: bind α2δ subunit of voltage-gated Ca2+ channels → reduce presynaptic neurotransmitter release; NOT structural analogues of GABA despite the name; used for neuropathic pain and partial seizures; pregabalin also for generalised anxiety disorder; dependence and abuse potential (pregabalin is a Class C controlled drug in the UK).

Levetiracetam: binds SV2A (synaptic vesicle protein 2A) — unique mechanism; broad-spectrum; excellent tolerability; no significant CYP interactions; excreted renally (dose adjust in CKD); may cause irritability, depression, psychosis (monitor mental health); now first-line for many seizure types.