Learn — Psychopharmacology & ECT

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Extrapyramidal symptoms (EPS)

Extrapyramidal symptoms are drug-induced movement disorders caused by blockade of dopamine D2 receptors in the nigrostriatal pathway, most often by antipsychotics and also by metoclopramide and prochlorperazine. They comprise four classic syndromes that differ mainly in how soon they appear after the drug is started or the dose is raised: acute dystonia within hours to days, akathisia within days to weeks, drug-induced parkinsonism within weeks to months and tardive dyskinesia after months to years.

Acute dystonia appears within hours to a few days, most often in young men early in treatment, as sustained painful muscle spasm: torticollis, trismus, opisthotonus, tongue protrusion and oculogyric crisis with the eyes rolled upward; treatment is intramuscular promethazine or diphenhydramine, or benztropine or trihexyphenidyl, with relief usually within 15 to 30 minutes.
Laryngeal and pharyngeal dystonia is the emergency within the emergency: stridor, an inability to swallow saliva and respiratory distress require immediate parenteral anticholinergic or antihistamine, oxygen and airway support.
Akathisia is a subjective inner restlessness with an inability to sit still, pacing and constant leg movement; it is commonly mistaken for agitation or worsening psychosis, and raising the antipsychotic dose makes it worse. Management is to reduce the dose or switch drug, and to add propranolol, with a short course of a benzodiazepine as an alternative.
Drug-induced parkinsonism develops over weeks to a few months with bradykinesia, cogwheel rigidity, a coarse resting tremor, a mask-like face and a shuffling gait; it is more common in older people and in women, and is managed by dose reduction or a switch to a lower-potency drug, with an anticholinergic added if needed.
Tardive dyskinesia appears after months to years of exposure as involuntary choreoathetoid movements, classically bucco-linguo-masticatory chewing and lip-smacking with tongue protrusion; risk rises with age, female sex, duration of exposure and typical antipsychotics, and it may be irreversible.
Tardive dyskinesia is managed by stopping any anticholinergic, which worsens it, and by switching to an antipsychotic with a lower risk such as clozapine or quetiapine; the vesicular monoamine transporter 2 inhibitors valbenazine and deutetrabenazine are the specific treatments where available. Anticholinergics help the first three syndromes and harm this one.
Neuroleptic malignant syndrome is the life-threatening reaction and is not a simple extrapyramidal symptom: lead-pipe rigidity, hyperthermia, altered consciousness and autonomic instability, with a raised creatine kinase and leucocytosis; the drug is stopped immediately and treatment is supportive cooling and fluids, with dantrolene or bromocriptine.
Risk is highest with high-potency typical drugs such as haloperidol and fluphenazine, intermediate with risperidone at higher doses, and lowest with clozapine and quetiapine; the Abnormal Involuntary Movement Scale is the standard tool for periodic screening, and prophylactic anticholinergics are not given routinely because they add anticholinergic burden and worsen tardive dyskinesia.

Chlorpromazine (Thorazine) side effects

Chlorpromazine is the first antipsychotic drug, introduced in 1952, and is an aliphatic phenothiazine and a low-potency first-generation agent, given orally in a usual adult range of about 300 to 600 mg a day in divided doses for schizophrenia, with smaller doses used for severe nausea and hiccups. Because it blocks muscarinic, histamine and alpha-1 receptors as well as dopamine D2 receptors, its adverse effects are dominated by sedation, postural hypotension and anticholinergic symptoms, with fewer extrapyramidal symptoms than high-potency drugs such as haloperidol.

Sedation, postural hypotension and dizziness are the effects that limit the dose early; the blood pressure is checked lying and standing, the dose is increased slowly, and the patient is taught to get up in stages and to avoid driving until settled.
Anticholinergic effects are dry mouth, blurred vision, constipation and urinary retention, so it is avoided in narrow-angle glaucoma and in prostatic enlargement, and older patients are watched for confusion.
Photosensitivity is characteristic: severe sunburn on brief exposure, and after long high-dose use a slate-grey or bluish discolouration of sun-exposed skin; the patient uses sunscreen, long sleeves and a hat, and avoids the midday sun.
Cholestatic jaundice is the classic hypersensitivity reaction, usually in the first month, presenting with itching, dark urine, pale stools and yellow sclerae; the drug is stopped and liver function tested.
Other named effects: extrapyramidal symptoms including acute dystonia with oculogyric crisis, which is treated with a parenteral anticholinergic; hyperprolactinaemia with amenorrhoea and galactorrhoea; weight gain; lowering of the seizure threshold; QT prolongation; blood dyscrasias including rare agranulocytosis; and, after years of use, fine granular deposits in the cornea and lens, for which periodic eye examination is advised.
Neuroleptic malignant syndrome can occur with chlorpromazine as with any antipsychotic: fever, lead-pipe rigidity, altered consciousness and autonomic instability with a raised creatine kinase; the drug is stopped immediately and the patient is cooled and supported.
Chlorpromazine 100 mg is the reference unit against which the potency of other antipsychotics is expressed, which is why it is called the chlorpromazine equivalent; intramuscular injection is given deep into a large muscle with the patient lying down, and the blood pressure is measured before and after because the fall can be sharp.
Practical nursing points: the liquid preparation causes contact dermatitis, so gloves are worn when handling it; the drug is not given with antacids, which reduce absorption; and it is stored away from light.

Clozapine — monitoring (WBC)

Clozapine is a second-generation antipsychotic reserved for treatment-resistant schizophrenia, defined as failure to respond to adequate trials of at least two other antipsychotics, and for persistent suicidal behaviour in schizophrenia, where it is the only antipsychotic shown to reduce suicide. It is the most effective drug in this illness and causes almost no extrapyramidal symptoms, but it can suppress the bone marrow and cause severe neutropenia, so it can only be given within a monitoring scheme in which the blood count is checked before every stage of treatment continues.

Before the first dose: a full blood count with a normal absolute neutrophil count, a baseline pulse, blood pressure, weight, temperature, blood glucose, lipids and an electrocardiogram, and registration on the monitoring register used by the hospital.
The blood count is repeated weekly for the first 18 weeks of treatment, then fortnightly until the end of the first year, then monthly for as long as the drug is taken and for four weeks after it is stopped; some national schemes require weekly counts for the first six months, so follow the protocol in use locally.
Action on the count: a normal absolute neutrophil count is at least 1500 per cubic millimetre; a fall into the moderate range of about 1000 to 1499 requires the drug to be interrupted and the count repeated more often, and a count below 1000 is severe neutropenia and the drug is stopped and not restarted, with haematology involved and the patient watched for infection.
Dosing is deliberately slow: 12.5 mg on the first day, increasing by about 25 to 50 mg a day as tolerated to a usual range of 200 to 450 mg a day, with the larger part of the dose at night; the maximum is about 900 mg a day, and if two or more days of doses are missed the whole titration must start again from 12.5 mg because tolerance to hypotension is lost.
Myocarditis and cardiomyopathy occur mainly in the first eight weeks and present with chest pain, breathlessness, palpitations, fever or flu-like symptoms; a rising resting pulse in the first weeks is common but should never simply be ignored.
Seizures are dose-related and become likely above about 600 mg a day, so the dose is raised slowly and an anticonvulsant may be added; sedation, hypersalivation that is worst at night, postural hypotension and tachycardia, weight gain, diabetes and dyslipidaemia are the other frequent effects.
Severe constipation is the most under-recognised danger and can progress to paralytic ileus and death; bowel habit is asked about at every visit, fluid, fibre and activity are encouraged, and a laxative is started early.
Smoking induces the enzyme that clears clozapine, so stopping smoking abruptly, including on admission to a smoke-free ward, can raise the blood level sharply and cause toxicity; caffeine and some antibiotics raise it too, and the level should be checked when the picture changes.

MAO inhibitors — tyramine interactions

Monoamine oxidase inhibitors treat depression by blocking the enzyme that breaks down serotonin, noradrenaline and dopamine, so more transmitter is available at the synapse. The older drugs bind the enzyme irreversibly and block both its A and B forms, which means the gut and liver can no longer destroy dietary tyramine; the absorbed tyramine displaces stored noradrenaline and can cause a hypertensive crisis, so these drugs are given with a strict diet and are now reserved for atypical or treatment-resistant depression.

Irreversible non-selective inhibitors are phenelzine, tranylcypromine and isocarboxazid; moclobemide is a reversible inhibitor of monoamine oxidase A that is displaced by tyramine and therefore needs far less dietary restriction; selegiline is selective for monoamine oxidase B at low dose but loses that selectivity as the dose rises.
Tyramine-rich foods to avoid include aged and mature cheeses, fermented and cured or smoked meats and fish, yeast extracts, fermented soya products such as soy sauce and tofu, broad bean pods, overripe or spoiled fruit, sauerkraut, tap and home-brewed beer and red wine; fresh meat, fresh fish, milk, paneer, cottage cheese and cream cheese are safe.
Hypertensive crisis presents with a sudden severe occipital or throbbing headache, a sharply raised blood pressure, palpitations, neck stiffness, sweating, nausea and vomiting, photophobia and chest pain, and can lead to intracranial haemorrhage; it is treated by stopping the drug, monitoring closely and giving an intravenous agent such as phentolamine or sodium nitroprusside under medical supervision.
Drug interactions are as dangerous as the diet: indirectly acting sympathomimetics in cough and cold remedies (pseudoephedrine, phenylephrine, ephedrine) precipitate hypertensive crisis, and serotonergic drugs precipitate serotonin syndrome.
Serotonin syndrome from combining a monoamine oxidase inhibitor with a selective serotonin reuptake inhibitor, a tricyclic, tramadol, pethidine, dextromethorphan, linezolid, triptans or St John's wort presents with the triad of altered mental state, autonomic instability with fever and sweating, and neuromuscular excitation with clonus, hyperreflexia and rigidity; the drugs are stopped, the patient is cooled and supported, and a benzodiazepine is given, with cyproheptadine as the specific agent.
Washout periods are examinable: at least two weeks between stopping a monoamine oxidase inhibitor and starting another antidepressant, at least two weeks the other way for most drugs, and five weeks after fluoxetine because of its long-acting metabolite.
Pethidine is absolutely contraindicated, and the anaesthetist must be told before any surgery; other adverse effects of the class are postural hypotension, which is actually the commonest problem, insomnia and agitation with tranylcypromine, weight gain and oedema with phenelzine, sexual dysfunction, and peripheral neuropathy from vitamin B6 depletion with phenelzine.
The nurse's central task is teaching: a written food list the patient and family can keep, an instruction never to take any over-the-counter cold or cough medicine without asking, a card or note saying which drug is being taken, and clear directions on what a severe headache means and where to go with it.

Lithium — serum levels and toxicity

Lithium carbonate is the standard mood stabiliser for bipolar disorder, effective in acute mania, in prophylaxis of both manic and depressive relapse, and as an augmenting agent in resistant depression, and it is the only psychotropic drug shown to reduce suicide in bipolar illness. It has a narrow therapeutic index, is excreted unchanged by the kidney and is handled by the body like sodium, so the serum level must be measured regularly and anything that dehydrates the patient or lowers sodium pushes the level into the toxic range.

The therapeutic serum range is 0.6 to 1.2 mEq/L, with about 0.8 to 1.2 mEq/L aimed at in acute mania and about 0.6 to 1.0 mEq/L for maintenance; older people are kept at the lower end.
The sample is a trough taken 12 hours after the last dose, checked about five to seven days after starting or after any dose change, then repeated until two consecutive levels are stable, and thereafter about every three months and whenever the clinical picture or the physical state changes.
Toxicity begins above 1.5 mEq/L, is serious above 2.0 mEq/L and is life-threatening above about 2.5 mEq/L, but the level and the symptoms do not always match, and a patient with signs of toxicity is treated on the signs while the level is awaited.
Early toxicity produces coarse tremor replacing the usual fine tremor, nausea, vomiting, diarrhoea, drowsiness and slurred speech; moderate toxicity adds ataxia, gross incoordination, muscle twitching, blurred vision and confusion; severe toxicity produces nystagmus, myoclonus, hyperreflexia, seizures, cardiac arrhythmia, oliguria, coma and death.
Toxicity is precipitated by anything that reduces renal lithium clearance: dehydration from vomiting, diarrhoea, fever, heat or heavy sweating, a low-salt diet, and the drugs that must be memorised as unsafe alongside lithium, which are thiazide diuretics, ACE inhibitors and angiotensin receptor blockers, non-steroidal anti-inflammatory drugs including ibuprofen and diclofenac, metronidazole and tetracyclines.
Management of toxicity is to stop lithium immediately, check the level, electrolytes and renal function, correct dehydration with intravenous normal saline, monitor the electrocardiogram, cardiac rhythm and urine output, and use haemodialysis for a very high level or for serious neurological or cardiac features; there is no antidote, and gastric lavage and activated charcoal do not bind lithium.
Ordinary adverse effects at therapeutic levels are a fine tremor, polyuria and thirst from nephrogenic diabetes insipidus, weight gain, acne and psoriasis flares, a benign leucocytosis, hypothyroidism, hyperparathyroidism with hypercalcaemia and, over years, reduced renal concentrating capacity, so thyroid function, renal function, calcium and weight are checked before treatment and about every six months thereafter, with an electrocardiogram at baseline in anyone with cardiac risk.
In pregnancy lithium in the first trimester is associated with Ebstein's anomaly of the tricuspid valve, so it is used only when the alternative is worse and after counselling; the dose needs review around delivery because of the fluid shifts, and lithium passes into breast milk.

Codeine

Codeine is a weak opioid used for mild to moderate pain and, at lower doses, as a cough suppressant acting on the medullary cough centre. It is a prodrug: only about a tenth of a dose is converted by the liver enzyme CYP2D6 into morphine, and that conversion is what produces the analgesia, so the response depends on which version of the enzyme the patient inherited.

The usual analgesic dose is 30 to 60 mg every four to six hours to a maximum of about 240 mg a day, most often combined with paracetamol, and the antitussive dose is lower than the analgesic dose.
Poor CYP2D6 metabolisers convert almost no codeine to morphine and get no pain relief, so a patient who says codeine does nothing for them is often describing their genotype rather than seeking a stronger drug.
Ultra-rapid metabolisers, who carry extra copies of the gene, convert too much too quickly and can reach morphine levels that stop breathing; deaths have been reported in children and in breastfed infants of mothers taking codeine.
For that reason codeine is contraindicated in children under 12 years for any indication, in anyone under 18 years after tonsillectomy or adenoidectomy for obstructive sleep apnoea, and in breastfeeding mothers.
Adverse effects are the opioid class effects of sedation, nausea, dizziness, respiratory depression and dependence, plus constipation, which does not wear off with continued use, so a stimulant laxative is prescribed alongside from the first dose.
Naloxone reverses codeine toxicity, and CYP2D6 inhibitors such as fluoxetine, paroxetine and bupropion blunt codeine's effect by blocking its conversion to morphine.
Codeine-containing cough syrup is a common drug of misuse in India; it is a prescription-only preparation whose sale and stock are regulated, and repeated requests for it deserve a substance-use assessment rather than a refill.
Tramadol is the other weak opioid that also depends on CYP2D6, and because it is serotonergic as well, combining it with an SSRI or SNRI risks serotonin syndrome.

Electroconvulsive therapy (ECT)

Electroconvulsive therapy is the deliberate induction of a generalised seizure by passing a brief controlled electrical stimulus across the scalp, carried out under general anaesthesia with a muscle relaxant and oxygenation so that the brain seizes while the body does not convulse. A course is usually six to twelve treatments given two or three times a week, and it is the fastest-acting treatment in psychiatry, which is why it is chosen when a patient cannot safely wait weeks for a drug to work.

The strongest indications are severe depression with active suicidal intent, with refusal of food and fluid, or with stupor or psychotic features; catatonia of any cause, which often responds dramatically; severe or treatment-resistant mania; neuroleptic malignant syndrome; and schizophrenia with catatonia or persistent risk of harm.
Modified electroconvulsive therapy means anaesthesia plus a muscle relaxant, and Section 95 of the Mental Healthcare Act 2017 prohibits unmodified electroconvulsive therapy outright in India and prohibits it for a minor except with the informed consent of the guardian and the prior permission of the Mental Health Review Board.
Informed consent is taken in writing from a patient with capacity, or through the advance directive and nominated representative route when capacity is absent, and consent may be withdrawn at any point during the course.
Preparation: nil by mouth for six to eight hours, written consent checked, baseline pulse, blood pressure, temperature and weight recorded, a baseline cognitive assessment such as the Mini-Mental State Examination, removal of dentures, jewellery, hairpins, spectacles and nail varnish, bladder emptied, and benzodiazepines and anticonvulsants withheld where the doctor has ordered it because they raise the seizure threshold.
The anaesthetic sequence is an anticholinergic such as atropine or glycopyrrolate to dry secretions and blunt vagal bradycardia, an induction agent such as thiopentone or propofol, succinylcholine for muscle relaxation, a bite block, and ventilation with 100% oxygen; an adequate seizure is usually about 25 to 60 seconds of motor activity.
Bitemporal placement is the most effective and the most amnestic, right unilateral placement at a high stimulus dose causes less memory disturbance, and bifrontal placement sits between the two.
Adverse effects are post-ictal confusion, headache, muscle aches and nausea in the short term, and anterograde and retrograde memory impairment that usually recovers over weeks, though gaps in memory for the period around the course may persist; a transient bradycardia followed by tachycardia and a rise in blood pressure occurs with every treatment.
There is no absolute contraindication other than raised intracranial pressure from a space-occupying lesion; recent myocardial infarction or stroke, unstable angina, an aneurysm, retinal detachment and phaeochromocytoma are relative contraindications weighed against the risk of leaving the illness untreated.
Electroconvulsive therapy does not prevent relapse by itself, so continuation treatment with an antidepressant, with lithium, or with maintenance electroconvulsive therapy is planned before the course finishes.
After treatment the patient is nursed on the side in the recovery position with suction and oxygen ready, observed continuously until fully awake, reoriented gently at every waking because they wake confused and frightened, kept nil by mouth until the gag reflex has returned, and helped to sit and stand only with assistance.

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