Psychiatric pharmacy is about matching the right drug to the right patient and staying ahead of adverse effects. Antipsychotics and antidepressants can transform lives, but they also carry risks that demand respect. Two emergencies—neuroleptic malignant syndrome (NMS) and serotonin syndrome—are rare but deadly if missed. This guide explains how these medicines work, how to choose and monitor them, and what to do when things go wrong. The goal: confident prescribing with fewer surprises.
Antipsychotics at a glance
Antipsychotics primarily block dopamine D2 receptors. This reduces psychotic symptoms because dopamine overactivity in certain brain circuits drives hallucinations and delusions. But dopamine also regulates movement, prolactin, and motivation, so blocking it causes side effects.
- First-generation (typical) antipsychotics: e.g., haloperidol, fluphenazine. Strong D2 blockade. More extrapyramidal symptoms (EPS) and prolactin elevation.
- Second-generation (atypical) antipsychotics: e.g., risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone. Add 5-HT2A antagonism, which eases EPS risk but increases metabolic effects in some agents.
- Clozapine: the most effective for treatment-resistant schizophrenia and reduces suicidality. It requires blood monitoring because of agranulocytosis risk.
Choosing an antipsychotic
Start with the patient’s risks and goals, not the drug’s marketing label. The same symptom can be treated by many agents; side effects often decide the winner.
- Metabolic risk: If the patient has obesity, prediabetes, or dyslipidemia, prefer aripiprazole, ziprasidone, lurasidone, or haloperidol. Avoid or closely monitor olanzapine and clozapine because they strongly increase appetite and insulin resistance.
- Prolactin concerns: If the patient has sexual dysfunction, amenorrhea, or osteoporosis risk, avoid risperidone/paliperidone. Consider aripiprazole, which can lower prolactin due to partial D2 agonism.
- Cardiac/QT risk: If the patient has long QT, electrolyte issues, or is on other QT-prolonging drugs, avoid ziprasidone and high-dose haloperidol. Correct K+ and Mg2+ because low electrolytes amplify QT prolongation.
- Adherence: If adherence is poor or relapse risk is high, consider a long-acting injectable (LAI). This improves continuity because missed oral doses often drive relapse.
- Past response: What worked before usually works again. Dopamine receptor sensitivity is patient-specific.
- Special roles: Clozapine for persistent psychosis or suicidality; quetiapine for prominent insomnia/anxiety; aripiprazole for negative symptoms or metabolic concerns.
The side-effect map for antipsychotics
- EPS (from D2 blockade in the nigrostriatal pathway):
- Acute dystonia (hours–days): painful spasms. Treat with IM diphenhydramine or benztropine because anticholinergics rebalance dopamine-acetylcholine tone.
- Akathisia (days–weeks): inner restlessness. Treat with propranolol first-line; benzodiazepines or switch agents if needed.
- Parkinsonism (weeks): tremor, rigidity, bradykinesia. Reduce dose, switch to lower EPS agent, or add benztropine short term.
- Tardive dyskinesia (months–years): choreiform movements from dopamine receptor supersensitivity. Prevent by using the lowest effective dose and regular AIMS exams; consider VMAT2 inhibitors if persistent.
- Metabolic syndrome (via histamine, serotonin, and hypothalamic effects): weight gain, dyslipidemia, insulin resistance. Baseline and periodic BMI, waist, fasting glucose, and lipids are essential because early weight gain predicts long-term gain.
- Hyperprolactinemia: galactorrhea, sexual dysfunction, bone loss. Switching to aripiprazole often normalizes levels because of partial agonism at D2.
- QT prolongation: risk of torsades. ECG if cardiac risk, high doses, or multiple QT-prolonging drugs. Correct electrolytes to stabilize cardiac repolarization.
- Anticholinergic effects: constipation, dry mouth, urinary retention. Clozapine and low-potency FGAs are worst; aggressive bowel regimens prevent ileus.
- Orthostasis and sedation: alpha-1 and H1 blockade. Slow titration and bedtime dosing improve tolerability.
- Agranulocytosis (clozapine): ANC monitoring because neutropenia removes the body’s defense against infection.
- Seizure risk: dose-related with clozapine; titrate slowly and monitor for myoclonus.
Neuroleptic Malignant Syndrome (NMS)
NMS is a dopamine-blockade emergency. It often follows rapid dose escalation, depot injections, dehydration, agitation, or combination with lithium. The brain loses dopaminergic control of muscle tone and temperature, causing rigidity and hyperthermia.
- Timing: usually 1–3 days after a change, but can occur anytime.
- Core signs: high fever, “lead-pipe” rigidity, mental status change, autonomic instability (labile BP/HR), diaphoresis.
- Labs: very high CK, leukocytosis, elevated creatinine from rhabdomyolysis.
- Differentiate from serotonin syndrome: NMS has severe rigidity and hyporeflexia; serotonin syndrome has hyperreflexia and clonus. NMS evolves over days; serotonin syndrome over hours.
Immediate actions:
- Stop all antipsychotics and any dopamine-depleting drugs.
- Transfer for urgent medical care. Aggressive IV fluids, cooling, and electrolyte correction prevent renal failure and arrhythmias.
- Consider bromocriptine (restores dopamine tone) and dantrolene (reduces muscle heat generation) in severe cases. Benzodiazepines calm agitation and reduce sympathetic surge.
Restarting after NMS:
- Wait at least two weeks after full recovery because dopamine systems need time to reset.
- Choose a lower-risk SGA (e.g., quetiapine, clozapine) at low dose; avoid depot early on.
- Titrate slowly with close monitoring for rigidity, fever, and CK.
Antidepressants in practice
Antidepressants adjust neurotransmission to improve mood, anxiety, and function. Choice depends on symptoms, comorbidities, and drug interactions.
- SSRIs (sertraline, escitalopram, fluoxetine, paroxetine, citalopram): first-line for depression and anxiety because they’re effective and well tolerated.
- SNRIs (venlafaxine, desvenlafaxine, duloxetine): help when pain, fatigue, or partial SSRI response is present because norepinephrine adds energy and analgesia.
- Bupropion: activating; useful for low energy and SSRI sexual dysfunction because it lacks serotonergic sexual side effects. Avoid in seizure or eating disorders.
- Mirtazapine: sedating and appetite-stimulating; helpful in insomnia or weight loss because H1 antagonism promotes sleep and hunger.
- TCAs/MAOIs: effective but used when others fail due to side effects, cardiac risk (TCAs), and interactions (MAOIs).
Dosing strategy:
- Start low and go slow over 1–2 weeks to reduce early side effects.
- Assess response at 4–6 weeks at a therapeutic dose because neuroadaptation takes time.
- Continue for at least 6–12 months after remission to prevent relapse; longer for recurrent depression.
Antidepressant side effects to anticipate
- GI upset and headaches: common early; take with food or dose at night because tolerance develops in 1–2 weeks.
- Activation/insomnia: especially with SSRIs and bupropion. Morning dosing or adding sleep hygiene helps.
- Sexual dysfunction: SSRIs often cause delayed orgasm or low libido because serotonin inhibits sexual reflexes. Consider dose reduction, drug holidays (short half-life agents only), add bupropion, or switch to bupropion/mirtazapine.
- Weight changes: mirtazapine and paroxetine increase weight; bupropion is weight-neutral or lowers weight.
- Discontinuation syndrome: dizziness, “brain zaps,” flu-like symptoms when stopped abruptly, especially with paroxetine and venlafaxine. Taper slowly because synaptic receptors need time to readjust.
- Hyponatremia (SIADH): more common in older adults. Check sodium if confusion, falls, or seizures occur.
- Bleeding risk: SSRIs inhibit platelet serotonin, increasing bleeding with NSAIDs/anticoagulants. Use gastroprotection if needed.
- QT prolongation: citalopram at higher doses; consider ECG in cardiac risk.
- Hypertension: SNRIs can raise BP via norepinephrine; monitor especially at higher doses.
- Mania switch: screen for bipolar disorder because antidepressant monotherapy can trigger mania or mixed states.
- Suicidality warning in youth: monitor closely early in treatment due to activation and energy changes preceding mood lift.
Serotonin Syndrome
Serotonin syndrome comes from too much serotonergic activity, often after combining agents or rapid dose increases. It is dangerous because excessive serotonin overstimulates the brainstem and spinal cord, driving autonomic instability and neuromuscular hyperactivity.
- Common triggers: SSRI/SNRI with MAOI, linezolid, methylene blue, tramadol, meperidine, fentanyl, dextromethorphan, triptans, St. John’s wort, lithium with serotonergic agents, and overdose of SSRIs/SNRIs.
- Timing: usually within hours of a change because serotonin signalling is rapid.
- Symptoms (Hunter criteria focus): spontaneous or inducible clonus, hyperreflexia (more in legs), agitation, diaphoresis, tremor, hyperthermia, diarrhea.
- Differentiate from NMS: serotonin syndrome has clonus/hyperreflexia and rapid onset; NMS has lead-pipe rigidity and slower onset.
Immediate actions:
- Stop all serotonergic agents.
- Supportive care: IV fluids, cooling, benzodiazepines for agitation and to reduce muscle activity.
- Cyproheptadine (serotonin antagonist) for moderate–severe toxicity.
- Avoid antipyretics (fever is not prostaglandin-driven) and avoid bromocriptine/dantrolene, which are not useful here.
Re-challenge rules:
- Identify the culprit combination. Do not restart the same combo.
- Allow a washout: 2 weeks for most SSRIs/SNRIs; 5 weeks for fluoxetine due to its long half-life.
- Reintroduce a single serotonergic agent at low dose with close monitoring.
Interactions that matter
- CYP450 effects: fluoxetine and paroxetine strongly inhibit CYP2D6, raising levels of drugs like some antipsychotics, TCAs, and beta-blockers. Fluvoxamine inhibits 1A2 and 3A4, increasing clozapine and olanzapine levels.
- Smoking: induces CYP1A2, lowering clozapine/olanzapine levels. Stopping smoking can double clozapine exposure; reduce dose and monitor because nicotine replacement does not induce 1A2.
- QT stacking: combining multiple QT-prolonging drugs (e.g., ziprasidone + methadone) multiplies torsades risk.
- MAOI rules: 14-day washout before starting or stopping most serotonergic antidepressants; 5 weeks for fluoxetine. This prevents serotonin syndrome.
- Lithium with antipsychotics: increases neurotoxicity risk and can complicate NMS detection; monitor for confusion, tremor, and rigidity.
Monitoring checklist
Before and during antipsychotics:
- Weight/BMI, waist circumference, BP.
- Fasting glucose/A1c and lipid panel at baseline, 3 months, then at least annually because early metabolic changes predict long-term risk.
- EPS screening (AIMS) every 3–6 months to catch tardive dyskinesia early.
- ECG when using QT-prolonging agents or in cardiac risk.
- For clozapine: ANC per program schedule; also monitor for constipation, myocarditis signs (tachycardia, chest pain), and seizures.
Before and during antidepressants:
- Screen for bipolar disorder and suicidality to prevent mania switch and to monitor activation risk.
- Blood pressure for SNRIs; sodium in older adults or if confusion/falls occur.
- ECG if high citalopram doses or cardiac disease.
- Bleeding risk if combined with NSAIDs/anticoagulants.
Practical prescribing moves
- Start low, go slow: Reduces early side effects, which improves adherence because most discontinuations happen in the first weeks.
- One change at a time: Avoids diagnostic confusion when side effects or benefits appear.
- Cross-taper thoughtfully: Cross-taper SSRIs/SNRIs to minimize discontinuation, but avoid overlap with MAOIs to prevent serotonin syndrome. For antipsychotics, cross-taper if relapse risk is high; otherwise consider a brief overlap with clear stop dates.
- Treat side effects proactively: Akathisia with propranolol; SSRI sexual dysfunction with bupropion add-on or switch; constipation with scheduled osmotic laxatives on clozapine.
- Use LAIs when relapse costs are high: Hospitalizations and functional losses drop when missed doses are removed from the equation.
- Elderly caution: Minimize anticholinergic burden and orthostasis because falls and delirium carry high morbidity.
Case snapshots
- Case 1: NMS: A man on high-dose haloperidol with dehydration develops 39.5°C fever, severe rigidity, confusion, tachycardia, and CK of 9,000. NMS is likely because onset followed rapid escalation and rigidity is profound. Stop antipsychotic, transfer to ICU, give IV fluids, cooling, and consider bromocriptine/dantrolene. When recovered, restart with quetiapine at low dose and titrate slowly.
- Case 2: Serotonin syndrome: A woman on sertraline starts linezolid for pneumonia. Within hours she has agitation, diaphoresis, hyperreflexia, and ankle clonus. Stop sertraline and linezolid, give benzodiazepines and supportive care, and administer cyproheptadine. Reintroduce antidepressant only after full resolution and safe washout.
Bottom line
Mastering antipsychotics and antidepressants is less about memorizing lists and more about thinking in systems: dopamine and serotonin pathways, patient-specific risks, and time courses of toxicity. Anticipate common side effects, screen for the dangerous ones, and act fast when patterns point to NMS or serotonin syndrome. The payoff is safer care and steadier recovery.
I am a Registered Pharmacist under the Pharmacy Act, 1948, and the founder of PharmacyFreak.com. I hold a Bachelor of Pharmacy degree from Rungta College of Pharmaceutical Science and Research. With a strong academic foundation and practical knowledge, I am committed to providing accurate, easy-to-understand content to support pharmacy students and professionals. My aim is to make complex pharmaceutical concepts accessible and useful for real-world application.
Mail- Sachin@pharmacyfreak.com