DrugTheGuide

Clinical pharmacology

Psychiatric medication guide

A clinical pharmacology reference for antidepressants, antipsychotics, and mood stabilisers — covering mechanisms of action, pharmacokinetics, therapeutic drug monitoring, drug interactions, and safety monitoring requirements.

Overview of psychiatric drug classes

Psychiatric medications span several mechanistically distinct classes. All act on monoamine neurotransmitter systems (serotonin, dopamine, norepinephrine) or on inhibitory/excitatory neurotransmission (GABA, glutamate). The table below summarises the major classes, primary targets, and representative agents.

Class Primary target Key agents Main indications
SSRIs SERT inhibition → ↑ synaptic 5-HT Fluoxetine, sertraline, escitalopram, paroxetine MDD, anxiety disorders, OCD, PTSD
SNRIs SERT + NET inhibition Venlafaxine, duloxetine, desvenlafaxine MDD, GAD, neuropathic pain, fibromyalgia
TCAs SERT/NET + muscarinic/H1 blockade Amitriptyline, nortriptyline, clomipramine MDD, neuropathic pain, migraine prophylaxis
MAOIs MAO-A/B inhibition → ↑ all monoamines Phenelzine, tranylcypromine, moclobemide Treatment-resistant MDD, atypical depression
FGA (typical antipsychotics) D2 blockade Haloperidol, chlorpromazine, fluphenazine Schizophrenia, acute psychosis, agitation
SGA (atypical antipsychotics) D2 + 5-HT2A blockade Olanzapine, quetiapine, risperidone, aripiprazole, clozapine Schizophrenia, bipolar disorder, treatment-resistant depression
Mood stabilisers Multiple: GSK-3β inhibition (lithium), GABA/Na+ channel (valproate), Na+/Ca²⁺ channel (lamotrigine) Lithium, sodium valproate, lamotrigine, carbamazepine Bipolar disorder (maintenance + acute), epilepsy
Benzodiazepines GABA-A positive allosteric modulation Diazepam, lorazepam, clonazepam, temazepam Anxiety, insomnia, seizures, alcohol withdrawal

Antidepressant pharmacokinetics

SSRIs and SNRIs are well-absorbed orally and extensively metabolised by hepatic CYP enzymes. Their half-lives and CYP inhibitory profiles differ substantially, which determines drug interaction risk, dose titration requirements, and discontinuation strategy. Fluoxetine is the only SSRI with a clinically significant active metabolite.

Drug Half-life Active metabolite Key CYP interactions Notes
Fluoxetine 1–4 days (norfluoxetine: 4–16 days) Norfluoxetine (active) Inhibits CYP2D6, CYP3A4, CYP2C9 5-week washout before MAOI; protects against missed doses
Sertraline ~26 hours Desmethylsertraline (weakly active) Weak CYP2D6 inhibitor Preferred in elderly, pregnancy; most evidence base
Escitalopram ~30 hours None significant CYP2C19 substrate; weak CYP2D6 inhibitor QTc dose-dependent; max 10 mg in elderly / CYP2C19 PM
Paroxetine ~20 hours (non-linear) None Potent CYP2D6 inhibitor (irreversible) Worst discontinuation syndrome; avoid in pregnancy
Fluvoxamine ~15 hours None significant Potent CYP1A2 + CYP3A4 inhibitor ↑ clozapine, theophylline, warfarin levels substantially
Venlafaxine ~5 hours (ODV: ~11 hours) O-desmethylvenlafaxine (active) Weak CYP2D6 inhibitor Dose-dependent BP increase; severe discontinuation syndrome
Duloxetine ~12 hours None significant Moderate CYP2D6 inhibitor; CYP1A2 substrate Avoid in hepatic impairment; useful for neuropathic pain
Serotonin syndrome risk: SSRIs and SNRIs combined with tramadol, triptans, linezolid, methylene blue, or other serotonergic agents can precipitate serotonin syndrome — fever, clonus, hyperreflexia, agitation. MAOIs must not be combined with any serotonergic drug. Full 5-week washout (fluoxetine) or 2-week washout (other SSRIs/SNRIs) required before starting an MAOI. See the drug interactions guide.

Antipsychotic monitoring: metabolic risk and clozapine

First-generation antipsychotics carry high risk for extrapyramidal symptoms (EPS) — acute dystonia, parkinsonism, akathisia, and tardive dyskinesia — due to high D2 receptor occupancy in nigrostriatal pathways. Second-generation antipsychotics reduced EPS risk but introduced significant metabolic adverse effects. Clozapine, the most effective antipsychotic for treatment-resistant schizophrenia, requires mandatory haematological monitoring due to agranulocytosis risk.

Metabolic monitoring (all SGAs)

Baseline and at 4–6 weeks, 3 months, then annually: weight + BMI, waist circumference, fasting glucose + HbA1c, fasting lipid panel, blood pressure, and eGFR. Clozapine/olanzapine: monthly FBG recommended for first year. Screen for T2DM risk factors before initiating.

Clozapine ANC monitoring

Mandatory absolute neutrophil count (ANC): weekly for first 18 weeks, fortnightly for weeks 18–52, then monthly indefinitely. Stop clozapine if ANC <1.5×10⁹/L. Do not rechallenge if ANC <0.5×10⁹/L (agranulocytosis). All prescribers and dispensers must be registered with a monitoring programme.

EPS monitoring (FGAs)

Assess at each visit using AIMS (Abnormal Involuntary Movement Scale) for tardive dyskinesia. Acute dystonia: benztropine or procyclidine. Akathisia: propranolol or benzodiazepine. Tardive dyskinesia: consider switching to SGA or valbenazine/deutetrabenazine (VMAT2 inhibitors). Risk increases with cumulative dose and duration.

QTc prolongation

Many antipsychotics (particularly haloperidol, ziprasidone, thioridazine) prolong QTc. Baseline ECG before initiating; repeat at therapeutic dose. Avoid combining with other QTc-prolonging drugs (ondansetron, fluoroquinolones, azithromycin). Do not use in congenital long QT syndrome. Stop if QTc >500 ms or increases >60 ms from baseline.

Mood stabiliser pharmacokinetics and therapeutic drug monitoring

Lithium, valproate, and carbamazepine all require therapeutic drug monitoring (TDM) due to narrow therapeutic windows and clinically significant PK variability. Lamotrigine does not have a firmly established therapeutic range but levels can guide dose adjustments in pregnancy and when adding or removing interacting drugs.

Drug Therapeutic range Sampling time Key monitoring Major interactions
Lithium 0.6–1.0 mmol/L (maintenance); 0.8–1.0 (acute) 12-hour post-dose trough eGFR, TSH, ECG (baseline); levels 3-monthly when stable NSAIDs, thiazides, ACE inhibitors → ↑ Li+ levels
Sodium valproate 50–100 mg/L (epilepsy); 50–125 mg/L (bipolar) Trough (before morning dose) LFTs, FBC (thrombocytopaenia), weight; free fraction in hypoalbuminaemia Inhibits UGT → ↑ lamotrigine; enzyme inducers ↓ levels
Lamotrigine 3–14 mg/L (indicative, not firmly validated) Trough Clinical response; monitor in pregnancy (levels ↓ with ↑ clearance) Valproate doubles levels; carbamazepine/enzyme inducers halve levels
Carbamazepine 4–12 mg/L Trough (before dose) FBC (aplastic anaemia — rare), LFTs, sodium (SIADH), HLA-B*1502 in Asian patients (SJS risk) Potent CYP3A4/1A2/2C9 inducer — reduces levels of many drugs including OCP
Valproate in pregnancy: Sodium valproate is teratogenic — associated with neural tube defects (1–2%), hypospadias, and neurodevelopmental impairment (IQ reduction ~8–10 points on average; autism spectrum disorder risk ~3×). The UK MHRA Pregnancy Prevention Programme restricts prescribing to women of childbearing potential to specialist-initiated use with annual review, mandatory contraception, and patient acknowledgment form. In Australia, TGA has equivalent risk minimisation materials. The WHO Pregnancy Category is D. Lamotrigine and lithium (with caution) are preferred alternatives for bipolar disorder in women planning pregnancy.

Caplyta (lumateperone): mechanism and indications

Caplyta (lumateperone) is a second-generation antipsychotic with a unique multi-receptor pharmacology that distinguishes it from other SGAs. Lumateperone simultaneously modulates serotonin 5-HT2A receptors (potent antagonist), dopamine D2 receptors (presynaptic partial agonist and postsynaptic antagonist), and the serotonin transporter (SERT inhibitor) — combining antipsychotic, antidepressant, and mood-stabilising properties in a single molecule.

Caplyta indications: Lumateperone is FDA-approved for: (1) schizophrenia in adults (42 mg once daily); and (2) depressive episodes associated with bipolar I or bipolar II disorder in adults, as monotherapy or as adjunctive therapy with lithium or valproate. The bipolar depression indication is notable because few antipsychotics have been approved for bipolar II depression specifically. In clinical trials (Study 401, Study 402), Caplyta demonstrated significant improvement in MADRS total scores vs placebo in bipolar depression.

Pharmacokinetics: Lumateperone is a CYP3A4 substrate — concomitant use with strong CYP3A4 inhibitors (ketoconazole, clarithromycin) is not recommended, and strong CYP3A4 inducers (rifampicin, carbamazepine) should be avoided. It is also a UGT1A4 substrate. Lumateperone has a lower metabolic side-effect burden than olanzapine or quetiapine — weight gain was not significantly different from placebo in clinical trials. Common adverse effects include somnolence and dry mouth. See the DailyMed Caplyta (lumateperone) prescribing information ↗ and NCBI lumateperone review ↗.

Discontinuation syndromes

Abrupt withdrawal of antidepressants, antipsychotics, and benzodiazepines can cause significant discontinuation syndromes. These are not the same as addiction (dependence without craving or drug-seeking), but can be severe and require gradual tapering.

  • Antidepressants (FINISH mnemonic): Flu-like symptoms, Insomnia, Nausea, Imbalance (dizziness), Sensory disturbances (electric shocks), Hyperarousal. Worst with paroxetine (short t½, no active metabolite); minimal with fluoxetine (self-tapering via long t½). Taper over 4–8 weeks minimum; slower for longer courses.
  • Antipsychotics: Cholinergic rebound (nausea, vomiting, diarrhoea, excessive sweating), insomnia, anxiety. Risk of psychotic relapse if stopped abruptly. Taper over months for long-term use.
  • Benzodiazepines: Most severe discontinuation syndrome — anxiety, insomnia, tremor, sweating, and (for high-dose or long-term use) seizures and delirium. Taper by 10% per 2 weeks; switch to diazepam (long t½) before tapering if on shorter-acting agents (lorazepam, temazepam). Refer to specialist services for complex cases.

Frequently asked questions

What are the main classes of psychiatric medications and how do they work?
Psychiatric drug classes: Antidepressants — SSRIs (fluoxetine, sertraline, escitalopram): block SERT → ↑ synaptic 5-HT; SNRIs (venlafaxine, duloxetine): block SERT + NET → ↑ 5-HT + NE; TCAs (amitriptyline, nortriptyline): non-selective SERT/NET inhibition + muscarinic/histamine blockade → more side effects; MAOIs (phenelzine, tranylcypromine): inhibit MAO-A/B → ↑ all monoamines — dangerous tyramine interactions. Antipsychotics — FGA (haloperidol, chlorpromazine): D2 blockade — high EPS risk; SGA (olanzapine, quetiapine, risperidone, aripiprazole): D2 + 5-HT2A blockade → lower EPS, higher metabolic risk. Mood stabilisers: lithium, valproate, lamotrigine, carbamazepine. Anxiolytics: benzodiazepines (GABA-A PAM), buspirone (5-HT1A partial agonist). Reference: NIH psychiatric pharmacology review ↗.
What monitoring is required for lithium therapy?
Lithium TI is narrow: target 0.6–1.0 mmol/L (maintenance); 0.8–1.0 mmol/L (acute mania). Toxicity >1.5 mmol/L: coarse tremor, ataxia, confusion, polyuria; >2.0 mmol/L: seizures, cardiac arrhythmia. Required monitoring: (1) Serum Li+ (12-h trough) — weekly until stable, then 3-monthly; (2) eGFR + urine osmolality every 6 months — nephrogenic DI (30–40%), chronic tubulointerstitial nephropathy with long-term use; (3) TSH every 6 months — hypothyroidism in up to 40%; (4) Baseline ECG (≥50 years or cardiac risk). Drug interactions: NSAIDs ↑ Li+ (↓ renal prostaglandin → ↓ clearance); thiazides ↑ Li+ (~50%); ACE inhibitors ↑ Li+ — all require dose reduction. Hydration is critical — dehydration (hot weather, diarrhoea) precipitates toxicity. RCPsych lithium monitoring guidance ↗. See also our TDM glossary.
What are the metabolic risks of second-generation antipsychotics?
SGA metabolic risk ranking (highest to lowest): clozapine ≈ olanzapine > quetiapine ≈ risperidone > aripiprazole ≈ ziprasidone. Mechanisms: H1 antagonism → appetite stimulation/weight gain; M3 antagonism in pancreatic β-cells → impaired insulin secretion. Monitoring (recommended at baseline, 4–6 weeks, 3 months, then annually): weight + BMI, waist circumference, fasting glucose + HbA1c, fasting lipid panel, blood pressure. Clozapine-specific: mandatory ANC monitoring (weekly ×18 weeks, fortnightly ×1 year, then monthly) — clozapine must be stopped if ANC <1.5×10⁹/L; also causes sialorrhoea, sedation, seizures (dose-dependent). Intervention: lifestyle modification first; metformin effective for antipsychotic-induced weight gain and new-onset T2DM. American Diabetes Association antipsychotic metabolic monitoring consensus ↗.
What are the pharmacokinetic properties of SSRIs and how do they differ?
SSRI PK comparison: Fluoxetine — t½ 1–4 days (norfluoxetine 4–16 days); CYP2D6 + CYP3A4 inhibitor; 5-week washout before MAOI. Sertraline — t½ ~26 h; weak CYP2D6 inhibitor; preferred in elderly + pregnancy (most data); linear PK. Escitalopram — t½ ~30 h; CYP2C19 substrate (CYP2C19 poor metabolisers → ↑ AUC, QTc risk); QTc prolongation dose-dependent — max 20 mg/day (10 mg in elderly, CYP2C19 PM, hepatic impairment). Paroxetine — t½ ~20 h; potent CYP2D6 inhibitor; non-linear PK; worst discontinuation syndrome (no active metabolite + short t½). Fluvoxamine — CYP1A2 + CYP3A4 inhibitor (↑ clozapine, warfarin, theophylline). Serotonin syndrome risk with tramadol, triptans, linezolid, methylene blue — see drug interactions guide. SSRI pharmacology review (PubMed) ↗.
What is the pharmacokinetics of valproate and lamotrigine in mood disorders?
Valproate PK: 90% protein-bound (albumin); free fraction ↑ in hypoalbuminaemia, pregnancy, elderly → toxicity despite normal total levels. t½ 9–16 h (ER formulation extends this). Teratogen category X: neural tube defects (1–2%), neurodevelopmental impairment — AVOID in pregnancy; UK MHRA restricts use in women of childbearing potential without specialist oversight. Inhibits UGT → ↑ lamotrigine levels 2–3×. Lamotrigine PK: primarily glucuronidated (UGT1A4); t½ ~25 h alone. Interactions: with valproate → t½ doubles to ~50 h — start at 25 mg every other day; with carbamazepine/phenytoin/rifampicin (CYP/UGT inducers) → t½ ~15 h — use higher doses. Pregnancy: oestrogen induces UGT1A4 → lamotrigine clearance ↑ 40–60% by third trimester; dose increase required + rapid post-partum reduction (seizure/toxicity risk). Monitor levels. Epilepsy Action valproate in pregnancy ↗. Related: volume of distribution, half-life.
What is Caplyta (lumateperone) and what are its indications?
Caplyta (lumateperone) is an SGA with unique pharmacology: 5-HT2A antagonist + D2 presynaptic partial agonist/postsynaptic antagonist + SERT inhibitor. Caplyta indications: (1) schizophrenia in adults (42 mg QD); (2) bipolar I/II depressive episodes — monotherapy or adjunctive with lithium/valproate. Lower metabolic burden than olanzapine/quetiapine. CYP3A4 substrate — avoid strong inhibitors/inducers. See DailyMed Caplyta label ↗ and NCBI lumateperone review ↗.

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