5.1 Psychiatric Pharmacology

Antidepressants

Selective Serotonin Reuptake Inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) - sertraline, fluoxetine, escitalopram, citalopram, paroxetine, fluvoxamine - block the serotonin transporter and are first-line for major depression and most anxiety disorders because of their safety in overdose. The single most important counseling point is the delayed onset of 2-4 weeks (full effect up to 6-8 weeks); patients who stop at day 10 because "it isn't working" were never told this. Key adverse effects:

• Hyponatremia via SIADH (syndrome of inappropriate antidiuretic hormone secretion) - most common in elderly patients, usually within the first weeks; check sodium if confusion or lethargy develops.
• Sexual dysfunction (anorgasmia, reduced libido) - a leading cause of non-adherence; ask directly.
• Serotonin syndrome - a potentially fatal hyper-serotonergic state (agitation, diaphoresis, diarrhea, hyperreflexia, clonus, hyperthermia), classically triggered by combining serotonergic agents (SSRI + tramadol, SSRI + triptan, SSRI + MAOI). Management is stopping the offending agents, supportive care, and cyproheptadine in severe cases.
• Bleeding risk - SSRIs impair platelet serotonin uptake; risk rises sharply with concurrent NSAIDs or anticoagulants.

Fluoxetine has a very long half-life (active metabolite norfluoxetine, days), making it useful when adherence is erratic and lowering discontinuation symptoms; paroxetine is the most anticholinergic and the worst for discontinuation syndrome and weight gain. Never combine an SSRI with a monoamine oxidase inhibitor (MAOI) and observe washout intervals (2 weeks for most agents, 5 weeks after stopping fluoxetine).

SNRIs, Tricyclics, and Atypical Antidepressants

Serotonin-norepinephrine reuptake inhibitors (SNRIs) - venlafaxine and duloxetine - add noradrenergic effects. Venlafaxine can cause dose-related hypertension (monitor blood pressure) and a marked discontinuation syndrome; duloxetine is also licensed for diabetic peripheral neuropathic pain, fibromyalgia, and stress urinary incontinence.

Tricyclic antidepressants (TCAs) such as amitriptyline, nortriptyline, and imipramine are now used more for neuropathic pain, migraine prophylaxis, and nocturnal enuresis than depression, because of their anticholinergic burden (dry mouth, constipation, urinary retention, blurred vision, confusion in the elderly) and cardiotoxicity in overdose - sodium-channel blockade causing QRS widening, ventricular arrhythmias, and seizures. A widened QRS after TCA overdose is treated with intravenous sodium bicarbonate. TCAs are dangerous in patients with cardiac conduction disease, glaucoma, and prostatic hypertrophy.

Mirtazapine blocks presynaptic alpha-2 receptors and specific serotonin receptors; it is sedating and increases appetite/weight, which can be exploited in depressed elderly patients with insomnia and poor intake. Bupropion inhibits norepinephrine-dopamine reuptake, lacks sexual dysfunction, and aids smoking cessation, but it lowers the seizure threshold and is contraindicated in epilepsy and in eating disorders (bulimia/anorexia with electrolyte disturbance).

Benzodiazepines and Z-Drugs

Benzodiazepines (lorazepam, diazepam, alprazolam, clonazepam) enhance GABA-A receptor activity and are effective for acute anxiety, alcohol withdrawal, and status epilepticus, but tolerance and physical dependence develop within weeks. They should be prescribed short-term (2-4 weeks); long-term users need a slow taper, typically switching to diazepam (long half-life) and reducing by roughly 10-25% every 1-2 weeks. In the elderly, benzodiazepines cause falls, fractures, and cognitive impairment and appear on every potentially-inappropriate-medication list. Flumazenil is the competitive benzodiazepine antagonist, but its use is restricted to iatrogenic overdose (e.g., procedural sedation) because it can precipitate seizures in dependent patients or mixed TCA overdoses. Z-drugs (zolpidem, zopiclone, zaleplon) are hypnotics acting at the same GABA-A site; they carry dependence, next-day impairment, and complex sleep-behavior risks and should also be short-term.

Antipsychotics

Typical (first-generation) antipsychotics such as haloperidol and chlorpromazine primarily block dopamine D2 receptors. Their signature toxicities are extrapyramidal symptoms (EPS): acute dystonia (treat with procyclidine or benztropine), akathisia, drug-induced parkinsonism, and tardive dyskinesia (often irreversible). Haloperidol also prolongs the QT interval - check the ECG, especially with other QT-prolonging drugs.

Atypical (second-generation) antipsychotics have less EPS but characteristic metabolic and hematologic risks:

Clozapine is reserved for treatment-resistant schizophrenia (failure of two antipsychotics) and is the most effective antipsychotic available; dispensing is tied to blood-monitoring programs in most jurisdictions, including UAE hospital formularies.

NMS vs Serotonin Syndrome - the classic differentiation

Neuroleptic malignant syndrome (NMS) follows dopamine blockade (antipsychotics) and develops over days: "lead-pipe" rigidity, hyperthermia, autonomic instability, elevated creatine kinase, and reduced consciousness. Serotonin syndrome follows serotonergic excess, develops within hours, and features hyperreflexia and clonus, mydriasis, diarrhea, and agitation, with rigidity less prominent. Management of NMS: stop the dopamine blocker, supportive cooling and fluids; dantrolene and bromocriptine are used in severe cases.

Mood Stabilizers

Lithium has a narrow therapeutic index with a usual target of 0.6-1.0 mmol/L (up to 1.2 for acute mania); levels above 1.5 mmol/L indicate toxicity (coarse tremor, vomiting, diarrhea, confusion, seizures, arrhythmia). Sample levels 12 hours post-dose, 5-7 days after any dose change. Lithium is renally cleared with no hepatic metabolism, so anything reducing renal clearance raises levels: NSAIDs, ACE inhibitors, angiotensin receptor blockers, and thiazide diuretics are the classic interactions, along with dehydration and low-sodium states. Long-term effects include hypothyroidism (monitor TSH), diabetes insipidus with polyuria, and declining renal function (monitor eGFR). Lithium is relatively contraindicated in pregnancy (Ebstein anomaly with first-trimester exposure).

Valproate is effective in mania but is teratogenic - neural tube defects and reduced childhood IQ - and is essentially contraindicated in women of childbearing potential unless a pregnancy-prevention program is in place; it also causes hepatotoxicity, pancreatitis, thrombocytopenia, and hyperammonemic encephalopathy. Lamotrigine is first-line for bipolar depression prophylaxis; it must be titrated slowly because of Stevens-Johnson syndrome / toxic epidermal necrolysis risk, and valproate doubles lamotrigine levels, requiring halved doses. Any rash on lamotrigine warrants immediate review.