Psychopharmacology

Psychiatric drug lists look arbitrary, and trying to memorise which drug causes which adverse effect is close to impossible.

Two principles convert the whole subject into reasoning.

A side effect is a therapeutic action occurring somewhere you did not intend. Antipsychotics block dopamine because dopamine excess in the mesolimbic pathway produces psychosis. But dopamine has three other major pathways, and blocking those produces the movement disorders, the hyperprolactinaemia and the worsening of negative symptoms. The drug is not doing something extra; it is doing the same thing in the wrong place.

A drug's receptor profile predicts its side effects better than any list. Antihistaminic action gives sedation and weight gain. Antimuscarinic action gives dry mouth, constipation, urinary retention and confusion. Alpha-1 blockade gives postural hypotension. Knowing which receptors a drug touches lets you derive the adverse effects instead of recalling them.

A third principle governs safety across the chapter. The dangerous reactions are recognisable syndromes, not isolated symptoms, and the ones that kill are neuroleptic malignant syndrome, serotonin syndrome and lithium toxicity.

1. The Four Dopamine Pathways

This single table explains most of what antipsychotics do, both wanted and unwanted.

The therapeutic effect and the main adverse effects come from the same action in different tracts, which is why a perfectly selective antipsychotic has never been achieved by dopamine blockade alone.

Roughly 65 to 80 per cent striatal D2 occupancy gives antipsychotic effect; above about 80 per cent extrapyramidal effects appear. That narrow window is the pharmacological reason dose matters so much.

2. Extrapyramidal Side Effects

These are separated by timing, and timing is the most reliable diagnostic feature.

Two points carry disproportionate marks.

Akathisia is subjective and is frequently mistaken for agitation or worsening psychosis, which leads to a dose increase that makes it worse. It is associated with distress and with suicide, so it must be actively asked about rather than observed for.

Anticholinergics help dystonia and parkinsonism but worsen tardive dyskinesia. Giving the wrong drug for the wrong syndrome is a common error and is exactly what the timing table prevents.

3. Typical and Atypical Antipsychotics

Typical antipsychotics act principally by D2 blockade. High-potency agents such as haloperidol produce more extrapyramidal effects and less sedation; low-potency agents such as chlorpromazine produce more sedation, postural hypotension and antimuscarinic effects.

Atypical antipsychotics combine D2 with 5-HT2A antagonism, which reduces extrapyramidal effects but introduces a metabolic burden.

The trade is real and is the central clinical decision. Atypicals cause less movement disorder but more weight gain, dyslipidaemia and diabetes, and metabolic syndrome in this population contributes to a substantially shortened life expectancy. Baseline and periodic monitoring of weight, waist circumference, glucose and lipids is part of prescribing rather than an optional extra.

Clozapine

Clozapine is the only antipsychotic with established superiority in treatment-resistant schizophrenia, defined as failure of two adequate trials of other antipsychotics.

It also carries the most demanding safety profile, and its distinctive adverse effects are examined repeatedly.

Agranulocytosis requires mandatory regular blood count monitoring, frequent initially and less so later, and is the reason clozapine is dispensed through a registry.

Myocarditis occurs typically in the first weeks and is easily missed, presenting with tachycardia, fever and malaise.

Seizures are dose-related. Constipation is common and, unusually, is a genuine cause of death through ileus and bowel obstruction, so it is treated proactively.

Hypersalivation is the paradox worth knowing: an antimuscarinic-rich drug that causes drooling, and it is a frequent reason patients stop taking it.

Clozapine also reduces suicide risk in schizophrenia, which is a specific indication in its own right.

4. Antidepressants

Three points govern practice.

Tricyclics are dangerous in overdose, causing cardiac conduction block, arrhythmia and seizures, which is a decisive consideration in a population at risk of self-poisoning. Sodium bicarbonate is the treatment for the cardiac toxicity.

SSRIs cause hyponatraemia through syndrome of inappropriate antidiuretic hormone secretion, particularly in older adults, and this should be checked in any patient who becomes confused after starting one.

SSRI discontinuation syndrome produces dizziness, electric shock sensations, irritability and flu-like symptoms, and is commonest with short half-life agents such as paroxetine. It is not withdrawal in the addictive sense, and it is prevented by tapering.

Sexual dysfunction is the adverse effect most likely to cause silent non-adherence, because patients rarely raise it and clinicians rarely ask.

5. The Three Syndromes That Kill

These are separated on clinical grounds, and confusing them leads to opposite treatments.

Clonus and hyperreflexia are the decisive findings for serotonin syndrome. Rigidity occurs in both; hyperreflexia does not occur in neuroleptic malignant syndrome.

Both feature hyperthermia, autonomic instability and raised creatine kinase, and both risk rhabdomyolysis and renal failure.

Management of both begins with stopping the offending drug and supportive care with cooling and fluids. Dantrolene and bromocriptine are used in neuroleptic malignant syndrome; cyproheptadine is used in serotonin syndrome.

Serotonin syndrome is usually an interaction rather than a single drug. Combinations to remember include an SSRI with tramadol, with linezolid, with a triptan, with St John's wort, or with a monoamine oxidase inhibitor, and the last is the most dangerous.

Lithium toxicity is the third, with coarse tremor, ataxia, dysarthria, vomiting and confusion, precipitated by dehydration, sodium depletion, thiazides, non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors.

6. Mood Stabilisers and Antiepileptics in Psychiatry

Three agents dominate, and each is chosen for a different reason.

Lithium is the reference agent, effective against both poles and uniquely associated with reduced suicide risk. Its constraints are pharmacokinetic: a narrow therapeutic index, renal handling that mirrors sodium, and long-term effects on thyroid and kidney.

Valproate is effective in acute mania and is fast-acting, but its use in women of childbearing potential is restricted because it is teratogenic and additionally impairs neurodevelopment in exposed children.

Lamotrigine is the agent for the depressive pole of bipolar disorder rather than for mania. Its dose must be titrated slowly, because rapid escalation raises the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis, and the risk rises further when it is combined with valproate, which inhibits its metabolism.

Carbamazepine is an enzyme inducer, which matters more than its own side effects, because it reduces levels of oral contraceptives, warfarin and many antiretrovirals. It also causes hyponatraemia and, in patients of certain Asian ancestries carrying HLA-B*1502, a markedly increased risk of severe cutaneous reactions.

Drugs that cause psychiatric symptoms

The reverse direction is examined and is easy to overlook.

Corticosteroids cause mood elevation, depression and frank psychosis, typically dose-related and appearing within the first weeks. Isotretinoin, interferon and some antiretrovirals are associated with depression. Levodopa and dopamine agonists cause hallucinations and impulse control disorders including pathological gambling. Antimalarials, particularly mefloquine, cause vivid dreams and neuropsychiatric disturbance.

The clinical rule is that any new psychiatric presentation deserves a drug history before a psychiatric diagnosis, because withdrawal of the offending agent is both diagnostic and curative.

7. Anxiolytics, Hypnotics and Prescribing Judgement

Benzodiazepines act on the GABA-A receptor, increasing the frequency of chloride channel opening, while barbiturates increase the duration, which is why barbiturates are far more dangerous in overdose.

Their problem is behavioural rather than pharmacological. Rapid relief is strongly reinforcing, tolerance develops within weeks, and withdrawal produces rebound anxiety and insomnia that the patient interprets as their illness returning.

Withdrawal from benzodiazepines, like withdrawal from alcohol, can cause seizures and can be fatal, unlike opioid withdrawal, which is intensely unpleasant but not usually life-threatening. That asymmetry is examined frequently.

Flumazenil reverses benzodiazepine effect but is used cautiously, since it can precipitate seizures in dependent patients.

Prescribing principles worth stating

Start low and go slow in older adults, in whom reduced renal and hepatic clearance, increased fat distribution for lipophilic drugs and greater receptor sensitivity all raise exposure.

Antimuscarinic burden accumulates across drugs, so a patient on a tricyclic, an antipsychotic and an anticholinergic for parkinsonism can become delirious from the sum rather than from any single agent.

Adherence is the commonest reason treatment fails, and the two most fixable causes are unwarned side effects in the first fortnight and the absence of any explanation of how long onset takes.

8. Prescribing in Special Situations

Pregnancy and breastfeeding

The decision is never between risk and no risk, because untreated maternal mental illness carries its own harms including poor antenatal care, substance use, self-harm and impaired mother-infant attachment.

Sodium valproate is the clearest prohibition, given both structural teratogenicity and impaired neurodevelopment in exposed children.

Lithium is associated with cardiac malformation, classically Ebstein anomaly, though the absolute risk is lower than older teaching suggested. Where it is continued, levels need closer monitoring because renal clearance rises through pregnancy and falls abruptly after delivery, which can precipitate toxicity postpartum.

Selective serotonin reuptake inhibitors are the antidepressants with most reassurance data. Paroxetine is generally avoided, and late exposure can produce a self-limiting neonatal adaptation syndrome.

The principle is to use the fewest drugs at the lowest effective dose, avoid switching an effective drug for an unfamiliar one purely because of pregnancy, and involve the woman in a documented decision.

Renal and hepatic impairment

Lithium is renally cleared and is the drug most affected by renal impairment, so it is either avoided or used with intensive monitoring.

Most other psychotropics are hepatically metabolised, so hepatic impairment demands dose reduction and avoidance of the most sedating agents, since hepatic encephalopathy is easily precipitated and easily mistaken for the psychiatric illness itself.

Cardiac considerations

QT prolongation is a class concern shared by many antipsychotics and by some antidepressants, and the risk compounds when several are combined or when electrolytes are disturbed.

Correcting hypokalaemia and hypomagnesaemia matters as much as choosing the drug, and a baseline electrocardiogram is appropriate where risk factors exist.

9. Worked Examples

Example 1. A young man given haloperidol for agitation develops a sustained upward deviation of the eyes and neck spasm four hours later. What is this and how is it treated?

Acute dystonia, comprising an oculogyric crisis with torticollis. The timing of hours after a first dose is characteristic, and young men receiving high-potency typical antipsychotics are at highest risk.

Treatment is a parenteral anticholinergic, such as promethazine or an antimuscarinic antiparkinsonian agent, which usually produces relief within minutes. This is important to recognise because it is frightening and painful for the patient, because laryngeal involvement can compromise the airway, and because a single bad experience frequently destroys any future willingness to take antipsychotic medication.

Example 2. A patient on an antipsychotic complains of feeling unable to sit still and appears agitated. The team increases the dose. What has gone wrong?

The team has treated akathisia as worsening psychosis, and increasing the dose will worsen it.

Akathisia is a subjective sense of inner restlessness with an inability to remain still, occurring within days to weeks of starting or increasing an antipsychotic. It is regularly mistaken for agitation, anxiety or psychotic deterioration precisely because it looks like all three from the outside.

The distinction rests on asking the patient. Akathisia is experienced as an unpleasant compulsion to move, not as fear or as a response to hallucinations. It matters because it is strongly associated with distress, treatment refusal and suicide.

Management is to reduce the dose or switch, with propranolol or a benzodiazepine as symptomatic treatment. Anticholinergics are relatively ineffective here, unlike in dystonia and parkinsonism.

Example 3. A patient on an SSRI is given tramadol for back pain. Within hours he is agitated and febrile with dilated pupils, hyperreflexia and clonus in the legs. What is the diagnosis, and how is it distinguished from the other syndrome it resembles?

Serotonin syndrome, precipitated by adding tramadol, which has serotonergic activity, to an SSRI.

It is distinguished from neuroleptic malignant syndrome principally by hyperreflexia and clonus, which are decisive and do not occur in neuroleptic malignant syndrome. The other separating features are onset within 24 hours rather than over days to weeks, dilated pupils, increased bowel sounds, and rigidity that is greatest in the lower limbs rather than the lead-pipe rigidity of neuroleptic malignant syndrome.

Management is to stop all serotonergic agents, provide supportive care with cooling, fluids and benzodiazepines for agitation, and give cyproheptadine in moderate to severe cases. Resolution is usually rapid once the drugs are withdrawn, which is itself a diagnostic feature.

Example 4. A patient started on clozapine three weeks ago develops fever, tachycardia and malaise. What are the two diagnoses that must be excluded urgently?

Agranulocytosis and myocarditis, both of which occur characteristically in the early weeks of clozapine treatment and both of which can be fatal.

An urgent full blood count is required to exclude agranulocytosis, which is the reason clozapine is dispensed under mandatory haematological monitoring through a registry.

Myocarditis is the diagnosis more often missed, because fever, tachycardia and malaise in the first weeks are easily attributed to infection or to the drug's ordinary effects. Troponin, C-reactive protein, electrocardiography and echocardiography are indicated.

Neither should be dismissed as a simple febrile illness, and clozapine is withheld while they are being investigated.

Example 5. An 80-year-old woman on amitriptyline for neuropathic pain, an antipsychotic for agitation, and trihexyphenidyl for tremor becomes confused with urinary retention and a dry mouth. Explain.

This is anticholinergic toxicity from cumulative antimuscarinic burden rather than from any single drug.

Amitriptyline is strongly antimuscarinic, many antipsychotics have antimuscarinic activity, particularly the low-potency typicals, and trihexyphenidyl is a pure anticholinergic. The effects add together, and the total burden is what matters.

Older adults are especially vulnerable because of reduced cholinergic reserve, greater blood-brain barrier permeability and reduced clearance, which is why central effects such as confusion appear at doses tolerated by younger patients.

Management is to review the whole prescription rather than to treat the confusion symptomatically: withdraw or substitute the anticholinergic agents where possible, choose alternatives with lower antimuscarinic activity, and reassess whether each drug is still needed. Adding another drug to treat the confusion would be the wrong direction entirely.

Summary

A side effect is a therapeutic action in the wrong place.

Receptor profile predicts adverse effects better than any list.

Mesolimbic blockade treats psychosis; nigrostriatal blockade causes movement disorder.

Tuberoinfundibular blockade causes hyperprolactinaemia; mesocortical blockade worsens negative symptoms.

Antipsychotic effect needs about 65 to 80 per cent D2 occupancy; above 80 gives extrapyramidal effects.

Extrapyramidal syndromes are separated by timing.

Dystonia occurs in hours, akathisia in days to weeks, parkinsonism in weeks to months, tardive dyskinesia in months to years.

Akathisia is subjective and is mistaken for agitation, leading to harmful dose increases.

Anticholinergics treat dystonia and parkinsonism but worsen tardive dyskinesia.

Atypicals trade movement disorder for metabolic burden, which requires monitoring.

Clozapine is uniquely effective in treatment resistance and uniquely demanding in safety.

Clozapine causes agranulocytosis, myocarditis, seizures, constipation and hypersalivation.

Tricyclics are lethal in overdose through cardiac conduction block.

SSRIs cause hyponatraemia, particularly in older adults.

Sexual dysfunction is the adverse effect most likely to cause silent non-adherence.

Clonus and hyperreflexia distinguish serotonin syndrome from neuroleptic malignant syndrome.

Serotonin syndrome is usually an interaction, with SSRI plus tramadol a classic pairing.

Benzodiazepines increase chloride channel opening frequency; barbiturates increase duration.

Benzodiazepine and alcohol withdrawal can be fatal; opioid withdrawal usually is not.

Anticholinergic burden accumulates across drugs and causes delirium in older adults.