Psychopharmacology
Psychopharmacology covers the mechanisms, clinical use, and side effects of medications used in psychiatric disorders including antidepressants, antipsychotics, mood stabilisers, and anxiolytics.
Key Facts
SSRIs are first-line for depression and anxiety — block serotonin reuptake transporter (SERT); sertraline, fluoxetine, citalopram, escitalopram, paroxetine Antipsychotics block D2 receptors — first-generation (typical, e.g., haloperidol) and second-generation (atypical, e.g., olanzapine, risperidone, quetiapine) Lithium is the gold standard mood stabiliser — narrow therapeutic index (0.4-0.8 mmol/L maintenance); toxicity >1.5 mmol/L Benzodiazepines enhance GABA-A receptor function — effective anxiolytics but significant dependence risk (max 2-4 weeks) Clozapine is the most effective antipsychotic — reserved for treatment-resistant schizophrenia; requires blood monitoring (agranulocytosis risk ~1%) Discontinuation syndromes occur with SSRIs (flu-like symptoms, electric shock sensations), benzodiazepines (seizures), and antipsychotics — always taper gradually QTc prolongation risk: Citalopram (max 40mg; 20mg if >65), haloperidol, droperidol, pimozide — ECG monitoring required CYP450 interactions are important: Fluoxetine and paroxetine are potent CYP2D6 inhibitors; fluvoxamine inhibits CYP1A2 (affects clozapine and theophylline levels)
Overview
Key Facts
Psychopharmacology is essential knowledge for all doctors. Understanding mechanisms of action, side effect profiles, drug interactions, and monitoring requirements enables safe and effective prescribing.
Epidemiology
Approximately 17% of the adult population in England were prescribed an antidepressant in 2022-23 (~8.3 million people). Antipsychotic prescribing affects approximately 1.5 million people. Benzodiazepine prescriptions are decreasing but remain significant.
Aetiology
Psychopharmacological treatment targets neurotransmitter systems involved in psychiatric disorders:
- Serotonergic: Depression, anxiety, OCD
- Dopaminergic: Psychosis, mania
- Noradrenergic: Depression, ADHD
- GABAergic: Anxiety, insomnia, epilepsy
- Glutamatergic: Emerging target — ketamine/esketamine for depression
Pathophysiology
Mechanism of action by class:
- SSRIs: Block SERT → increase synaptic 5-HT → downstream receptor changes (takes 2-4 weeks for clinical effect)
- SNRIs: Block SERT + NET → increase 5-HT and NA
- TCAs: Block SERT + NET + multiple receptors (muscarinic, histamine, alpha-1) → effective but side effects
- Typical antipsychotics: D2 receptor blockade → reduce positive symptoms; EPS risk proportional to D2 occupancy
- Atypical antipsychotics: D2 + 5-HT2A blockade → less EPS, but metabolic side effects
- Lithium: Inhibits inositol monophosphatase and GSK-3β → modulates intracellular signalling
- Benzodiazepines: Positive allosteric modulator of GABA-A receptor → enhanced Cl⁻ conductance → neuronal inhibition
Clinical Presentation
Drug Classes and Indications
- SSRIs: Depression, GAD, panic disorder, OCD, PTSD, social anxiety
- SNRIs: Depression (especially with pain), GAD, fibromyalgia
- TCAs: Depression, neuropathic pain, migraine prophylaxis, nocturnal enuresis
- MAOIs: Treatment-resistant depression (rarely used — dietary restrictions)
- Typical antipsychotics: Schizophrenia, acute psychosis, rapid tranquillisation
- Atypical antipsychotics: Schizophrenia, bipolar, augmentation in depression
- Lithium: Bipolar prophylaxis, augmentation in depression, reduces suicide risk
- Valproate: Bipolar mania (NOT in women of childbearing potential)
- Lamotrigine: Bipolar depression prophylaxis
- Benzodiazepines: Short-term anxiety, alcohol withdrawal, seizures, rapid tranquillisation
Red Flags
- Serotonin syndrome: Hyperthermia, clonus, agitation, diaphoresis — medical emergency
- NMS: Rigidity, hyperthermia, autonomic instability, raised CK — medical emergency
- Lithium toxicity: Coarse tremor, vomiting, ataxia, confusion — level >1.5 mmol/L
- QTc >500ms: Risk of torsades de pointes — stop offending drug
- TCA overdose: QRS prolongation, seizures, arrhythmias — sodium bicarbonate
- Clozapine: Agranulocytosis, myocarditis, constipation (can be fatal)
Differential Diagnosis
| Side Effect | Likely Drug Class | Management |
|---|---|---|
| Weight gain, metabolic syndrome | Olanzapine, clozapine, mirtazapine | Monitoring, lifestyle, consider switch |
| QTc prolongation | Citalopram, haloperidol, pimozide | ECG, dose reduction, switch |
| Sexual dysfunction | SSRIs (especially paroxetine) | Switch to mirtazapine or bupropion |
| Hyponatraemia | SSRIs (especially in elderly) | U&Es, consider switch |
| Extrapyramidal symptoms | Typical antipsychotics (haloperidol) | Reduce dose, procyclidine, switch |
| Agranulocytosis | Clozapine, carbamazepine | FBC monitoring, stop if WCC/ANC falls |
Diagnosis / Investigation
Baseline Monitoring (Before Starting Psychotropics)
- FBC: Baseline for clozapine, carbamazepine, valproate
- U&Es, eGFR: Lithium, all medications in renal impairment
- LFTs: Valproate, carbamazepine, antipsychotics
- TFTs: Lithium (causes hypothyroidism), baseline for depression
- Fasting glucose, HbA1c, lipids: Antipsychotic metabolic monitoring
- ECG: QTc baseline — citalopram, antipsychotics, TCAs
- Weight, BMI, waist circumference: All antipsychotics
- BP: All antipsychotics, SNRIs (venlafaxine), clonidine
- Pregnancy test: Before valproate (contraindicated), carbamazepine, lithium
Ongoing Monitoring
- Lithium: Levels 3-monthly (stable), U&Es/TFTs 6-monthly, calcium annually
- Clozapine: FBC weekly × 18 weeks → fortnightly × 1 year → monthly thereafter
- Antipsychotics: Metabolic monitoring at 6 weeks, 3 months, 6 months, then annually
- Valproate: LFTs, FBC at 6 months then annually
Management
Prescribing Principles
- Start low, go slow — especially in elderly and CYP
- Adequate trial duration: SSRIs 4-6 weeks, antipsychotics 4-6 weeks, lithium 6-8 weeks
- Document informed consent — risks, benefits, alternatives
- Monitor for side effects proactively
- Review regularly — medication should not continue indefinitely without clear indication
Key Drug Interactions
- SSRIs + MAOIs: Serotonin syndrome — must be 2-week washout (5 weeks for fluoxetine)
- Lithium + NSAIDs/diuretics/ACEi: Increased lithium levels → toxicity
- Carbamazepine: Potent CYP3A4 inducer — reduces efficacy of many drugs
- Clozapine + fluvoxamine/ciprofloxacin: CYP1A2 inhibition → raised clozapine levels
- Metoclopramide + antipsychotics: Additive D2 blockade → EPS risk
Referral Criteria
- Complex polypharmacy — pharmacy review
- Treatment-resistant conditions — specialist psychiatry
- Clozapine initiation — specialist service required
- Drug interactions or adverse effects — specialist advice
Prognosis
- Psychopharmacological treatment significantly improves outcomes across psychiatric conditions
- Adherence is a major challenge — ~50% of patients discontinue within 6 months
- Side effect burden is the most common reason for non-adherence
- Personalised prescribing (considering side effect profile, comorbidities, preferences) improves adherence
- Pharmacogenomics (CYP2D6, CYP2C19 testing) may guide prescribing in the future
Other Relevant Information
Antidepressant Comparison
| Drug | Key Advantages | Key Disadvantages |
|---|---|---|
| Sertraline | Best evidence base, safe in cardiac disease | GI side effects |
| Fluoxetine | Long half-life (less withdrawal), good in CYP | CYP2D6 inhibition, activating |
| Citalopram | Few drug interactions | QTc prolongation (max 40mg) |
| Mirtazapine | Sedating (good for insomnia), appetite stimulation | Weight gain |
| Venlafaxine | Dual action, effective at higher doses | Hypertension, withdrawal syndrome |
| Duloxetine | Effective for pain, anxiety | Nausea, limited dose range |
Antipsychotic Side Effect Profiles
| Drug | Weight | Sedation | EPS | Prolactin | QTc |
|---|---|---|---|---|---|
| Olanzapine | +++ | ++ | + | ++ | + |
| Risperidone | ++ | + | ++ | +++ | + |
| Quetiapine | ++ | +++ | + | + | + |
| Aripiprazole | + | + | + | ↓ | + |
| Haloperidol | + | + | +++ | +++ | ++ |
| Clozapine | +++ | +++ | − | + | + |