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PH3.5 | PH3.5 | Antidepressants and Antipsychotics — SDL Guide — SDL Guide (Part 2)

Antidepressants — PK, PD, Uses, and ADRs

SSRIs are the first-line pharmacological treatment for major depressive disorder, generalised anxiety disorder, panic disorder, OCD, PTSD, and social anxiety disorder. Their selectivity for SERT reduces the non-serotonin-related adverse effects of older antidepressants. ADRs: GI effects (nausea, diarrhoea — usually transient), sexual dysfunction (reduced libido, anorgasmia — common and often not spontaneously reported), insomnia or somnolence, serotonin discontinuation syndrome (dizziness, 'brain zaps', irritability on abrupt cessation — taper doses on stopping). Fluoxetine has the longest t½ (and active metabolite norfluoxetine) — least discontinuation syndrome. SSRIs combined with MAOIs or pethidine/tramadol can produce serotonin syndrome (see below).

SNRIs share SSRI-class effects plus noradrenergic effects: effective for depression and neuropathic pain (duloxetine is approved for diabetic neuropathic pain). ADR additions over SSRIs: hypertension (NA-mediated), urinary hesitancy.

TCAs (amitriptyline, imipramine, clomipramine): more effective for severe depression and neuropathic pain than SSRIs in some patients, but multiple receptor actions produce: anticholinergic effects (dry mouth, constipation, urinary retention, tachycardia, glaucoma precipitation), antihistamine effects (sedation, weight gain), α₁-block (postural hypotension), Na⁺-channel block (QRS widening, ventricular arrhythmias — FATAL IN OVERDOSE). TCA overdose is a medical emergency: sodium bicarbonate IV (alkalinisation reverses Na⁺-channel block) + supportive care. TCAs are absolutely contraindicated in patients at risk for suicide due to their lethal overdose profile.

MAOIs: phenelzine and tranylcypromine irreversibly inhibit both MAO-A and MAO-B — dangerous tyramine interaction ('cheese reaction'): tyramine in food (aged cheese, red wine, yeast extract, fermented meats) is normally metabolised by intestinal/hepatic MAO-A; with MAO inhibited, dietary tyramine is absorbed → stimulates sympathetic nerve endings → massive noradrenaline release → hypertensive crisis (severe occipital headache, diaphoresis, hypertension, risk of stroke/haemorrhage). Moclobemide (RIMA) is reversible and selective for MAO-A — tyramine can competitively displace it from MAO-A, making the tyramine interaction much less severe. MAOIs require a washout period of at least 14 days before starting SSRIs/TCAs (and vice versa); fluoxetine requires 5 weeks washout before starting an MAOI (due to long t½ of norfluoxetine).

Mirtazapine: blocks presynaptic α₂ autoreceptors (increases NA and 5-HT release) + 5-HT₂ and 5-HT₃ antagonism (reduces GI side-effects). Sedating (H₁ block) and promotes appetite/weight gain — useful in depressed patients with insomnia and weight loss. Lower serotonin syndrome risk than SSRIs.

Class	Example	Mechanism	Key ADRs
SSRI	Fluoxetine, Sertraline	SERT block	Sexual dysfunction, GI, discontinuation syndrome
SNRI	Venlafaxine, Duloxetine	SERT + NET block	Hypertension, urinary hesitancy
TCA	Amitriptyline	5HT+NA + anticholinergic + Na-block	Fatal overdose (arrhythmia), anticholinergic effects
MAOI (irreversible)	Phenelzine	MAO-A+B inhibition	Tyramine hypertensive crisis, multiple drug interactions
RIMA	Moclobemide	Reversible MAO-A inhibition	Safer tyramine interaction
NaSSA	Mirtazapine	α₂-block + 5HT2/3 block	Sedation, weight gain

Antipsychotics — PK, PD, Uses, and ADRs

Typical antipsychotics (chlorpromazine, haloperidol, fluphenazine) act primarily by blocking D2 receptors across all four dopamine pathways: mesolimbic (therapeutic — reduces positive symptoms), mesocortical (worsens negative symptoms), nigrostriatal (EPS), and tuberoinfundibular (hyperprolactinaemia → galactorrhoea, menstrual irregularities). High-potency typicals (haloperidol) have high EPS risk; low-potency typicals (chlorpromazine) have more sedation and anticholinergic effects.

Extrapyramidal side-effects (EPS) of typical antipsychotics:
- Acute dystonia (hours-days): painful muscle spasm (torticollis, oculogyric crisis) — treat with IM/IV anticholinergic (benztropine or trihexyphenidyl)
- Akathisia (days-weeks): subjective restlessness — treat with propranolol or BZD
- Drug-induced parkinsonism (weeks-months): tremor, rigidity, bradykinesia — treat with anticholinergics (NOT levodopa, which does not help drug-induced parkinsonism and is not used for this indication)
- Tardive dyskinesia (TD) (months-years): repetitive involuntary orofacial movements — largely irreversible; treat with VMAT2 inhibitors (valbenazine, deutetrabenazine); prevent by using lowest effective dose for shortest time

Neuroleptic malignant syndrome (NMS): rare but life-threatening reaction to antipsychotics — tetrad: hyperthermia + muscle rigidity + autonomic instability + altered consciousness. Mechanism: dopamine receptor blockade in the hypothalamus and basal ganglia. Distinguish from serotonin syndrome (which features clonus and hyperreflexia rather than rigidity). Treatment: stop antipsychotic, supportive care, dantrolene (muscle relaxant, as in MH), bromocriptine (D2 agonist).

Atypical antipsychotics (clozapine, olanzapine, risperidone, quetiapine, aripiprazole) block D2 + 5HT2A receptors (and various others). Lower EPS (less nigrostriatal D2 blockade relative to mesolimbic), more metabolic side-effects:
- Clozapine: most effective antipsychotic overall; reserved for treatment-resistant schizophrenia (failed ≥2 antipsychotic trials). Risk of agranulocytosis (~1-2%) — mandatory WBC monitoring (weekly for 18 weeks, then fortnightly while on treatment; stop if WBC <3,000 or ANC <1,500). Also: sedation, weight gain, metabolic syndrome, salivation (paradoxical — muscarinic agonism), seizures at high doses, myocarditis.
- Olanzapine: effective, high metabolic risk (weight gain, diabetes, dyslipidaemia). IM formulation for acute agitation.
- Risperidone: moderate EPS risk (higher than other atypicals at high doses), raised prolactin.
- Quetiapine: sedating (useful at night), low EPS and low prolactin — frequently used in elderly with dementia-related psychosis.

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Management Plans for Depression and Psychotic Disorders

Depression management plan:

First-line pharmacological treatment: SSRI (e.g., sertraline or escitalopram). Counsel the patient that clinical response takes 2-4 weeks — early discontinuation is the most common cause of treatment failure. Assess response at 4-6 weeks: if partial response, increase dose; if no response, switch to another SSRI or to an SNRI.

If two adequate SSRI trials fail: escalate to augmentation (add lithium, atypical antipsychotic, or buspirone) or switch to SNRI → mirtazapine → TCA (with adequate patient safety assessment — avoid in suicidal patients). MAOIs are reserved for TCA-refractory cases with appropriate washout.

Duration: continue for ≥6 months after remission for a first depressive episode; 2 years after a second episode; indefinite for recurrent (3+) episodes.

Crucial safety rule: do not co-prescribe two serotonergic agents without careful assessment — specifically, never combine an SSRI (or SNRI or TCA) with an MAOI. Washout periods must be observed.

Psychosis/schizophrenia management plan:

Acute phase: IM haloperidol (or IM olanzapine) for rapid control of agitation and psychosis. Oral lorazepam as an adjunct to reduce agitation.

Stabilisation and maintenance: oral atypical antipsychotic (olanzapine, risperidone, quetiapine, amisulpride) — selected based on metabolic risk, EPS risk, and patient preference. Continue maintenance for ≥2 years after first episode; longer for recurrent psychosis.

Treatment-resistant schizophrenia (failed ≥2 adequate antipsychotic trials): clozapine — mandatory WBC monitoring protocol must be in place before initiating.

Poor adherence: depot (long-acting injectable) antipsychotics (fluphenazine decanoate, risperidone microspheres, paliperidone palmitate) given every 2-4 weeks — bypass the need for daily oral medication.

• Depression: SSRI first-line → 4-6 week assessment → switch/augment → TCA/MAOI last resort
• Psychosis acute: IM haloperidol/olanzapine; maintenance: oral atypical; resistant: clozapine
• Never SSRI + MAOI concurrently; 14-day washout between them (5 weeks for fluoxetine)