What it is:A chronic thought disorder with three symptom clusters that don't respond the same way to treatment: positive symptoms(hallucinations, delusions, disorganized speech/behavior, the stuff that's "added on"), negative symptoms(flat affect, avolition, alogia, social withdrawal, the stuff that's "taken away"), and cognitive dysfunction(working memory, executive function). About 1% of the population, onset typically 15-25, and it carries a roughly 10% excess mortality.
The core problem:Dopamine signaling is unevenly distributed. Too much dopamine in the mesolimbic pathway drives positive symptoms; too little in the mesocortical (prefrontal) pathway drives negative and cognitive symptoms. Every antipsychotic blocks dopamine somewhere, but the drug can't tell the difference between the mesolimbic pathway you want blocked and the nigrostriatal or tuberoinfundibular pathways you don't. That collateral blockade is where basically every antipsychotic side effect comes from.
What you do about it:Pick an antipsychotic based on side-effect fit, not efficacy, since efficacy across agents is roughly similar (clozapine is the one true exception). Start low, especially in first-episode patients. Move through defined algorithm stages instead of drifting. Reach for clozapine after two adequate trials fail, don't wait longer.
Antipsychotics are effective in roughly 70% of psychotic patientsand drop the 12-month relapse rate from ~90% untreated to ~40% treated. They don't cure schizophrenia and they barely touch negative or cognitive symptoms. Reframe the goal for yourself and the patient: this is chronic disease control, not a cure, the same way you'd think about insulin for diabetes.
Mnemonic from lecture: HD-BS(Hallucinations, Delusions, disorganized Behavior, disorganized Speech, Negative symptoms).
| Criterion | Requirement |
|---|---|
| A | ≥2 of: delusions, hallucinations, disorganized speech, grossly disorganized/catatonic behavior, negative symptoms - present for a significant portion of ≥1 month. At least one must bedelusions, hallucinations, or disorganized speech (you can't diagnose off negative symptoms plus disorganized behavior alone). |
| B | Significant impairment in functioning (work, relationships, self-care). |
| Duration | Continuous signs persist ≥6 months, including the ≥1 month of active symptoms above; the rest can be prodromal or residual symptoms. |
Positive ≠ good."Positive" means symptoms added on top of normal experience (hallucinations, delusions). "Negative" means normal function subtracted away (affect, motivation, speech). Don't let the words fool you on an exam question.
Underlying cause is still unknown. Leading theories: genetic predisposition (monozygotic twins are concordant far more often than fraternal, but not 100%, so environment matters too), obstetric complications with hypoxia, neurodevelopmental insults, glutamatergic/NMDA receptor abnormalities driving excess neuronal pruning, and a growing body of evidence for immune dysfunction and autoantibody involvement in a subset of patients. Structurally, some patients show enlarged cerebral ventricles and reduced cortical mass, especially reduced prefrontal processing ("hypofrontality").
| Pathway | Route | Normal job | What happens when you block D2 here |
|---|---|---|---|
| Mesolimbic | VTA → nucleus accumbens | Emotion, reward, salience | This is the target.Blocking excess dopamine here reduces positive symptoms. |
| Mesocortical | VTA → prefrontal cortex | Logic, judgment, affect | Already hypoactive in schizophrenia. Further blockade here worsens negative/cognitive symptoms, this is the pathway you don't want to touch. |
| Nigrostriatal | Substantia nigra → striatum | Movement initiation and control | Extrapyramidal side effects (EPS): dystonia, akathisia, parkinsonism, tardive dyskinesia. |
| Tuberoinfundibular | Hypothalamus → pituitary | Tonic inhibition of prolactin release | Hyperprolactinemia: galactorrhea, gynecomastia, amenorrhea, sexual dysfunction. |
Positive symptoms correlate with dopamine hyperactivityin the mesolimbic pathway. Negative and cognitive symptoms correlate with dopamine hypofunctionin the prefrontal cortex. That's the same neurotransmitter, same receptor family, opposite problem in two different places, and the drug can't aim. This is why antipsychotics are reliably good at positive symptoms and reliably weak on negative symptoms: the mechanism that fixes one pathway can worsen the other.
First-generation antipsychotics (FGAs) are high-affinity D2 antagonists with low serotonin-2A (5-HT2A) affinity. Second-generation antipsychotics (SGAs) are moderate-to-high D2 antagonists plushigh 5-HT2A antagonism (clozapine is the outlier: low D2, high 5-HT2A). Serotonin normally suppresses dopamine release in the striatum, so blocking 5-HT2A there disinhibits some dopamine release, which partially counteracts the D2 blockade in the nigrostriatal pathway. That's mechanistically why SGAs cause less EPS than FGAs, not just an empirical observation.
Beyond D2 and 5-HT2A, antipsychotics are a grab-bag of antagonism at histamine H1 (sedation, weight gain), muscarinic M1 (dry mouth, constipation, urinary retention, blurred vision, cognitive fog), and alpha-1 adrenergic receptors (orthostatic hypotension, reflex tachycardia). "Dirty" drugs like chlorpromazine and clozapine hit all of these hard, which is why they have the most side effects but, interestingly, also the leastEPS, since strong muscarinic antagonism independently suppresses movement side effects (muscarinic antagonist affinity is inversely correlated with EPS risk).
| Category | Findings |
|---|---|
| Positive symptoms | Hallucinations (especially auditory), delusions (fixed false beliefs), ideas of influence, loose associations, illogical conversation, ambivalence |
| Negative symptoms | Alogia (poverty of speech), avolition (lack of goal-directed behavior), flat affect, anhedonia, social isolation |
| Cognitive dysfunction | Impaired attention, working memory, executive function |
| Associated features | Uncooperativeness, hostility, verbal/physical aggression, impaired self-care, disturbed sleep and appetite |
| Residual (post-episode) | Anxiety, suspiciousness, poor insight, impaired judgment, social withdrawal, poor self-care |
Comorbidity is the rule, not the exception: depression, anxiety, substance use, and medical conditions (respiratory, cardiovascular, metabolic) all cluster with schizophrenia. Medication nonadherence is extremely commonand should be assumed and screened for at every visit, not treated as a surprise.
An initial dysphoric responseto a new antipsychotic (patient says they hate it, feels worse, develops anxiety or akathisia early) predicts poor eventual response, more adverse effects, and nonadherence down the line. Take it seriously the first time a patient says a drug feels wrong, it's not just a side effect complaint, it's prognostic.
Diagnosis is clinical, built on the DSM-5 criteria above, but every new patient needs a baseline workup before you commit to a drug, both to rule out organic causes and to have a pre-treatment baseline for monitoring adverse effects later.
Nearly every one of these baseline labs becomes a monitoring parameter once the patient starts an antipsychotic (weight/BMI, glucose, lipids, ECG for QTc, ANC if clozapine). If you don't get a true baseline before starting the drug, you can't tell later whether an abnormal value is drug-induced or was always there.
Goals:alleviate target symptoms, avoid adverse effects, improve psychosocial functioning, achieve adherence, and prevent relapse, ideally with the patient involved in treatment planning from the start (shared decision-making, not a prescription handed down).
Nonpharmacologic therapyis not an afterthought: psychosocial rehabilitation, supported employment and housing, and family-involved programs are "best practices" that reduce rehospitalization and improve community functioning. Pair it with medication, don't treat it as optional.
Aripiprazole, risperidone, or ziprasidone preferred. SGAs show better treatment retention and relapse prevention than FGAs in first episode.
Any antipsychotic except clozapine. Never re-use an agent that previously failed or was intolerable.
Any monotherapy not yet tried, except clozapine. Consider clozapine early if the patient is severely suicidal, clozapine has unique anti-suicidal efficacy.
This is treatment-resistant schizophrenia (TRS) by definition.
Stage 4(inadequate response even to clozapine): minimal evidence for anything. Alternate monotherapies may work as well as augmentation or combination strategies, and antipsychotic polypharmacy remains controversial (commonly done, weakly supported).
No improvement within 2 weeksat a therapeutic dose means move to the next stage, don't just wait longer. In partial responders who are tolerating the drug well, titrating above the usual range for 2-4 weeks with close monitoring is reasonable before declaring failure. Improvement in formal thought disorder specifically can take an additional 6-8 weeksbeyond initial response, so don't judge that domain too early.
Base the choice on three things: (1) avoiding adverse effects that matter most to this patient, (2) concurrent medical/psychiatric conditions, (3) prior personal or family response. Efficacy is not usually the deciding factor, head-to-head trial data (AHRQ/McDonagh 2017 meta-analysis, CATIE, EUFEST) consistently shows no strong preference between FGAs and SGAs as a class, with the sole exception of clozapine's superior efficacy in treatment-resistant disease. Olanzapine and risperidone showed slightly better response rates than quetiapine in some network meta-analyses, and olanzapine beat haloperidol, but the differences are modest.
Long-acting injectables are drastically underutilized. They are not a last resort for "problem" or nonadherent patients, and shouldn't be framed to patients as punitive. LAIs can and should be considered at anystage, including first episode, because they consistently reduce hospitalization and relapse versus oral therapy. A Finnish national cohort found rehospitalization risk about one-third that of oral therapy(adjusted HR 0.36) for depot vs. equivalent oral formulations.
| Phase | Timeline | Goal |
|---|---|---|
| Initial/acute | First 7 days | Decrease agitation, hostility, anxiety, aggression; normalize sleep and eating. Titrate to the middle of the dosing range shown in the table below over the first few days; rapid titration is not recommended. |
| Stabilization | Weeks 2-3 | Improve socialization, self-care, mood. Continue titrating every 1-2 weeks if tolerated and not yet responding; once response starts, hold the dose steady. |
| Maintenance | Ongoing | Relapse prevention. Continue for at least 12 monthsafter a first psychotic episode remits; many experts recommend 5+ years, and most patients ultimately need lifelong therapy at the lowest effective dose. |
Full antipsychotic effect on positive symptoms evolves over 2-8 weeks, though calming/tranquilizing effects show up within minutes to hours and psychotic symptoms start improving within 24-48 hours. Improvement can keep accruing for up to 6 months. Set that expectation early: the sedative effect they'll feel on day one is not the same as the antipsychotic effect, which takes weeks.
When switching agents, taper and discontinue the first drug over 1-2 weekswhile cross-titrating the second upward, especially slow with FGAs and clozapine to avoid cholinergic rebound (nausea, diarrhea, diaphoresis, insomnia from abrupt muscarinic un-blockade).
IM formulations (aripiprazole 5.25-9.75 mg, ziprasidone 10-20 mg, olanzapine 2.5-10 mg, or haloperidol 2-5 mg) treat acute agitation but don't shorten time to remission or length of hospitalization, they just calm the moment. IM lorazepam 2 mg PRN added to the maintenance antipsychotic is a reasonable alternative to another antipsychotic injection.
IM lorazepam plus olanzapine or clozapine is not recommended, risk of hypotension, CNS depression, and respiratory depression stacks dangerously. Inhaled loxapine (Adasuve) is REMS-restricted to healthcare facilities only, limited to one 10 mg dose per 24 hours, and contraindicated in any bronchospastic lung disease (asthma, COPD).
In first-episode patients, start and target doses are generally halfthe ranges shown here.
| Drug | Start (mg/day) | Usual range (mg/day) | Notable comment |
|---|---|---|---|
| First-generation antipsychotics | |||
| Chlorpromazine | 50-150 | 300-1000 | Most weight gain among FGAs |
| Fluphenazine | 5 | 5-20 | - |
| Haloperidol | 2-5 | 2-20 | Higher dropout rate in first episode |
| Loxapine (oral) | 20 | 50-150 | - |
| Loxapine (inhaled) | 10 | 10 max/24h | REMS program only, healthcare facility administration |
| Perphenazine | 4-24 | 16-64 | - |
| Thioridazine | 50-150 | 100-800 | Significant QTc prolongation, boxed warning |
| Thiothixene | 4-10 | 4-50 | - |
| Trifluoperazine | 2-5 | 5-40 | - |
| Second-generation antipsychotics | |||
| Aripiprazole | 5-15 | 15-30 | D2 partial agonist |
| Asenapine | 5 | 10-20 | Sublingual only; no food/drink for 10 min after dosing |
| Brexpiprazole | 1 | 2-4 | - |
| Cariprazine | 1.5 | 1.5-6 | Long half-life, steady state takes weeks |
| Clozapine | 25 | 100-800 | REMS program; check plasma level before exceeding 600 mg |
| Iloperidone | 1-2 | 6-24 | Dose carefully in CYP2D6 poor metabolizers |
| Lumateperone | 42 | 42 | Bioavailability up 9% with a high-fat meal |
| Lurasidone | 20-40 | 40-120 | Take with food, ≥350 calories |
| Olanzapine | 5-10 | 10-20 | Avoid in first episode, worst weight gain risk |
| Paliperidone | 3-6 | 3-12 | Bioavailability increased with food |
| Quetiapine (IR) | 50 | 300-800 | - |
| Quetiapine XR | 300 | 400-800 | - |
| Risperidone | 1-2 | 2-8 | EPS risk rises sharply above 6 mg/day |
| Ziprasidone | 40 | 80-160 | Take with food, ≥500 calories, or absorption drops badly |
All FGAs are D2 antagonists; the difference between them is D2 affinity ("potency") and how "dirty" (multi-receptor) they are. Low-potency FGAs(chlorpromazine, thioridazine) have weaker D2 affinity but hit histamine, muscarinic, and alpha-1 receptors hard, so they cause more sedation, anticholinergic effects, and orthostasis, but comparatively less EPS. High-potency FGAs(haloperidol, fluphenazine, trifluoperazine, thiothixene) are cleaner D2 antagonists, so they cause less sedation and fewer anticholinergic effects, but far more EPS.
Most are metabolized through CYP2D6, 1A2, or 3A4. Haloperidol specifically goes through CYP2D6, 1A2, and 3A4, meaning it's vulnerable to interactions from multiple directions.
Boxed warning for QTc prolongation and torsades de pointes; doses above 800 mg/day (already the recommended max) can cause irreversible retinitis pigmentosa. This drug is a distractor-heavy exam favorite for both reasons.
Clozapineis the first atypical, a serotonin/dopamine antagonist metabolized mainly via CYP1A2 (with CYP2D6 and 3A4 contributing). Its unique efficacy in ~25-30% of treatment-resistant patients comes with the field's most serious toxicity profile: agranulocytosis, myocarditis, seizures, severe constipation, and cardiovascular collapse if combined carelessly with sedatives. See the dedicated clozapine section below.
Olanzapineis structurally and pharmacologically similar to clozapine but without the blood dyscrasia risk. Comparable efficacy (second-most-effective agent behind clozapine in CATIE), but the worst weight gain and metabolic burden of any commonly used SGA, which is why it's typically avoided as first-line in first-episode patients. Lybalvi (olanzapine/samidorphan) pairs it with an opioid antagonist/partial agonist that blunts the weight gain without much effect on cholesterol or A1c; it will precipitate opioid withdrawal, so screen for concurrent opioid use before prescribing.
Quetiapinetargets D2/5-HT2A less potently than clozapine or olanzapine but is a strong H1 antagonist, which is why it's so sedating and gets used off-label (not well supported) for insomnia and anxiety at low doses well below its antipsychotic dose. Low EPS, low adrenergic blockade, moderate weight gain and metabolic risk.
Clozapine and olanzapine are both CYP1A2 substrates, and smoking induces CYP1A2, so smokers need higher doses of both (up to double for clozapine) while nonsmokers on a smoker's dose risk toxicity. This flips fast: a hospitalized patient who can't smoke on the unit will see rising levels of a previously stable outpatient dose. Fluvoxamine (a potent CYP1A2 inhibitor) raises clozapine levels 2-3 fold, essentially the opposite interaction.
Risperidoneacts roughly equally at serotonin and dopamine receptors, has the highest prolactin-elevating potential of the SGAs (comparable to FGAs), and its EPS risk rises sharply above 6 mg/day, above that dose it behaves more like an FGA. Paliperidoneis risperidone's active hydroxy-metabolite, similar profile, renally eliminated (59% unchanged), avoid in significant renal impairment.
Ziprasidoneis more potent at serotonin than dopamine receptors, causes less weight gain and less EPS than most SGAs (akathisia is the exception), but must be taken with food (≥500 calories) for adequate absorption and carries QT prolongation risk plus a rare DRESS reaction warning.
Aripiprazole and brexpiprazoleare D2 partial agonists (aripiprazole ~10-30% intrinsic activity), meaning they stabilize dopamine tone rather than pure-blocking it: less EPS, essentially no prolactin elevation (can even lower it slightly), minimal weight gain, but can cause activating side effects (agitation, restlessness, insomnia) since they're not purely sedating like most other agents, and are linked to impulse-control disorders (pathological gambling, compulsive spending, binge eating, hypersexuality), which is an important, easy-to-miss counseling point.
Cariprazine and lumateperoneare D2 partial agonists plus 5-HT2A antagonists (cariprazine is also a D3 partial agonist with 5x higher D3 affinity than D2). Low weight gain, low EPS, possibly slightly lower efficacy ceiling. Cariprazine's long half-life means steady state doesn't arrive for several weeks, don't judge response too early or chase the dose up before it's had time to equilibrate.
Pimavanserinis a pure 5-HT2A inverse agonist with essentially no dopamine affinity, approved specifically for Parkinson's disease psychosis because it doesn't worsen motor symptoms the way a D2 antagonist would. Xanomeline/trospium (Cobenfy)is the newest mechanism: a CNS-penetrant muscarinic agonist (xanomeline) paired with a peripherally-restricted muscarinic antagonist (trospium) to block GI/GI side effects. First-in-class, no D2 or 5-HT2A activity at all, no reported EPS or weight gain; side effects are anticholinergic-flavored from the trospium component, and it should be avoided with urinary or gastric retention.
LAIs solve the single biggest driver of relapse in schizophrenia: nonadherence. They should be discussed with every patient as an option, not reserved for those who've already failed oral therapy multiple times.
| Agent | Dose range | PO overlap needed | Interval | Notes |
|---|---|---|---|---|
| Fluphenazine decanoate | 12.5-100 mg | None | Every 2-3 weeks | Start 12.5 mg if hepatic/renal impairment |
| Haloperidol decanoate | 20-450 mg | 4 wks (unless loading) | Every 4 weeks | Can load |
| Risperidone (Consta) | 12.5-50 mg | 3 wks after 1st inj. | Every 2 weeks | - |
| Risperidone (Perseris) | 90-120 mg | None | Monthly | Subcutaneous, abdomen only; 90 mg = 3 mg PO, 120 mg = 4 mg PO |
| Paliperidone palmitate 1-month (Sustenna) | 39-234 mg | None (initiation required) | Every 4 weeks | - |
| Paliperidone palmitate 3-month (Trinza) | 273-819 mg | None | Every 3 months | Requires 4+ months on Sustenna first; avoid if CrCl <50 |
| Paliperidone palmitate 6-month (Hafyera) | 1092-1560 mg | None | Every 6 months | Requires 4+ months of Sustenna or 1 cycle of Trinza first |
| Olanzapine pamoate (Relprevv) | 150-405 mg | None | Every 2-4 weeks | REMS program; monitor for post-injection delirium/sedation syndrome 3+ hrs after each dose |
| Aripiprazole monohydrate (Maintena) | 300-400 mg | 2 wks PO (10-20 mg/day) | Monthly | - |
| Aripiprazole lauroxil (Aristada) | 441-882 mg | 21 days PO overlap | Every 4-8 weeks | Aristada Initio loading regimen skips PO overlap |
Unique to olanzapine pamoate, from accidental intravascular injection or rapid release. Observe the patient at least 3 hoursafter every dose in a REMS-registered facility for sedation, delirium, confusion, or altered consciousness.
Notice which agents need PO overlap(risperidone Consta, aripiprazole Aristada, olanzapine pamoate loading) vs. which have a true loading regimenthat gets to steady state fast without pills (paliperidone Sustenna, Aristada Initio). Missing the overlap window on a drug that needs it is a real gap-in-coverage risk, this is exactly the kind of detail that trips people up when converting a patient.
All from nigrostriatal D2 blockade. They cluster by timing, which is the fastest way to identify which one you're looking at.
| Syndrome | Onset | Presentation | Management |
|---|---|---|---|
| Dystonia | 24-96 hours after start/increase | Prolonged tonic contractions: torticollis, oculogyric crisis, trismus, tongue protrusion. Pharyngeal/laryngeal dystonia can be life-threatening. | IM/IV benztropine 2 mg or diphenhydramine 50 mg, or diazepam 5-10 mg slow IV push, or lorazepam 1-2 mg IM. Relief in 5 min (IV) to 15-20 min (IM). Risk factors: young males, high-potency FGA, high dose. Prophylactic anticholinergics reasonable if using high-potency FGAs in young males. |
| Akathisia | Days to a few months | Subjective inner restlessness and/or objective pacing, shifting, foot-tapping. Occurs in 20-40% on high-potency FGAs. Unique to humans, and notoriously easy to mistake for worsening psychotic agitation. | Dose reduction first. Switching to an SGA helps but doesn't eliminate risk (iloperidone, quetiapine, clozapine lowest risk). Beta-blockers (propranolol up to 160 mg/day) work better than anticholinergics here, this is the one EPS syndrome anticholinergics don't reliably fix. Avoid benzodiazepines if substance use history. |
| Parkinsonism | 1-2 weeks after start/increase; classic picture ~6 months | Bradykinesia, resting tremor, cogwheel rigidity, shuffling/festinating gait, mask-like facies. Risk: FGA/high dose, older age, possibly female sex. | Anticholinergics (benztropine 1-2 mg BID, up to 8 mg/day) or amantadine 100-400 mg/day (as effective, less memory impairment). Taper off 6 weeks to 3 months after symptoms resolve. |
| Tardive dyskinesia (TD) | After months to years of exposure | Involuntary buccolingual-masticatory movements: lip smacking, tongue rolling, grimacing, blinking; choreoathetotic limb movements in later stages. Worsens with stress, improves with sedation, vanishes in sleep. | Prevention is the real treatment: use SGAs first-line, screen with AIMS or DISCUS at baseline, then every 6 months for FGAsand every 12 months for SGAs. Once present, switch to lower-risk agent early. VMAT2 inhibitors(valbenazine, deutetrabenazine) are FDA-approved treatments; watch for their own warnings (suicidality, depression, QT prolongation). |
Chronic D2 blockade causes striatal dopamine receptors to become supersensitive(upregulate) as a compensatory response. TD is thought to reflect a state of relative dopaminergic excesssignaling in a system that's been chronically suppressed, which is why VMAT2 inhibitors (which reduce dopamine release) help, and why simply raising the antipsychotic dose can transiently mask TD symptoms while making the underlying problem worse.
| Drug class | Agent | Equivalent dose (mg) | Daily range (mg) |
|---|---|---|---|
| Antimuscarinics | |||
| Benztropine | 1 | 1-8 (up to 12 in refractory cases) | |
| Biperiden | 2 | 2-8 | |
| Trihexyphenidyl | 2 | 2-15 | |
| Antihistaminic | |||
| Diphenhydramine | 50 | 50-400 | |
| Dopamine agonist | |||
| Amantadine | NA | 100-400 | |
| Benzodiazepines | |||
| Lorazepam | NA | 1-8 | |
| Diazepam | NA | 2-20 | |
| Clonazepam | NA | 2-8 | |
| Beta-blocker | |||
| Propranolol | NA | 20-160 | |
Rare (<1%), highest risk with high-potency FGAs, but potentially fatal (up to 10% mortality). Develops over 24-72 hours: fever >38°C, altered consciousness, autonomic instability (tachycardia, labile BP, diaphoresis, tachypnea), and lead-pipe rigidity. Labs show myoglobinuria, leukocytosis, and rising CK/AST/ALT/LDH. Stop all antipsychotics immediatelyand give supportive care; dantrolene, bromocriptine, or amantadine may speed recovery in severe cases. Rechallenge (lowest effective dose of an SGA or low-potency FGA) can be considered after ≥2 weeks off antipsychotics, titrate slowly and watch closely.
These come from H1, 5-HT2C, and alpha-1 receptor effects layered on top of the intended D2/5-HT2A antagonism, and they're the reason antipsychotics carry major long-term mortality risk independent of psychiatric outcomes.
| Effect | Highest risk agents | Lower risk agents |
|---|---|---|
| Weight gain | Olanzapine, clozapine, risperidone, quetiapine, iloperidone | Ziprasidone, aripiprazole, lumateperone, lurasidone, brexpiprazole, cariprazine |
| New-onset diabetes | Olanzapine, clozapine (highest), then risperidone, quetiapine | Aripiprazole, ziprasidone; asenapine/iloperidone/lurasidone/brexpiprazole/cariprazine/lumateperone likely lower but less data |
| Dyslipidemia | Olanzapine, clozapine, quetiapine | - |
| Hyperprolactinemia | FGAs, risperidone, paliperidone (highest of the SGAs) | Aripiprazole, asenapine, iloperidone, lurasidone, brexpiprazole, lumateperone, cariprazine |
Metabolic syndromecriteria to recognize: triglycerides ≥150 mg/dL, HDL ≤40 (men) / ≤50 (women) mg/dL, fasting glucose ≥100 mg/dL, BP ≥130/85 mmHg, waist circumference >102 cm (men) / >89 cm (women). Weight gain typically shows up fast (within the first 16 weeks) then plateaus; treat proactively with metformin, GLP-1 agonists, exercise counseling, or a switch, don't wait for the labs to become abnormal before intervening.
| System | Key facts |
|---|---|
| Anticholinergic | Worst with low-potency FGAs, clozapine, olanzapine: dry mouth, constipation, blurred vision, urinary retention, tachycardia, impaired memory. Older adults are especially sensitive, think twice before layering an anticholinergic EPS agent on top. |
| Seizures | Highest risk with chlorpromazine or clozapine, especially at treatment initiation, high doses, or rapid increases. Reduce dose after an isolated seizure; antiseizure medication usually not needed. |
| Thermoregulation | Poikilothermia (body temp tracks ambient temp) risks both hyperpyrexia in heat and hypothermia in cold, especially with low-potency FGAs and anticholinergic SGAs. |
| Ophthalmologic | Chronic phenothiazine use (especially chlorpromazine) can deposit pigment in cornea/lens; periodic slit-lamp exams recommended. Quetiapine also gets baseline/periodic slit-lamp exams (cataract signal in animal studies). Thioridazine >800 mg/day risks irreversible retinitis pigmentosa. |
| Genitourinary | Urinary retention with low-potency FGAs and clozapine, worse with concurrent BPH. Risperidone/paliperidone cause as much sexual dysfunction as FGAs. Priapism (painful erection >1 hour) is a urologic emergency, increasingly reported with antipsychotics generally. |
| Dermatologic | Photosensitivity with both FGAs and SGAs (counsel on sunscreen/protective clothing). Ziprasidone carries a DRESS warning. Blue-gray skin discoloration with long-term high-dose chlorpromazine. |
| Pregnancy/lactation | Haloperidol is the best-studied FGA; in-utero FGA exposure carries increased neonatal EPS risk lasting 3-12 months. SGAs cross the placenta; aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone don't appear to raise malformation risk collectively, though data quality is limited. Relative infant dose is <10% (the usual safety threshold) for essentially all agents; olanzapine and quetiapine are lowest (<4%). Avoid clozapine while nursing, risk of infant neutropenia and seizures. |
Treatment-resistant schizophrenia (TRS)is formally defined as inadequate response to two adequate antipsychotic trials (adequate dose, adequate duration, confirmed adherence, ideally confirmed with a serum level). Clozapine is the only agent with proven superiority here, response occurs slowly, with about 60% of patients improvingif given up to 6 months. It also has uniquely superior efficacy against suicidal behavior, which is why it can be considered earlier (Stage 2) in a severely suicidal patient rather than waiting for two full failed trials.
Give a 12.5 mg test dose. If no significant hypotension, start 25 mg at bedtime. After 3 days, increase to 25 mg twice daily, then increase by 25-50 mg/day every 3 daysuntil reaching at least 300 mg/day. Titrate slowly specifically to minimize orthostatic hypotension, which is the main limiter of how fast you can go.
A 12-hour postdose (trough) level of at least 350 ng/mLis associated with efficacy. Check a level before exceeding 600 mg/day, in patients with unusual/severe adverse effects, on interacting drugs, with altered pharmacokinetics (age, organ dysfunction), or when nonadherence is suspected.
Neutropenia risk ~3%, agranulocytosis ~0.8%. Highest risk window is 1-6 monthsafter starting. Baseline ANC must be ≥1500/μL to start. Monitor weekly for 6 months → every 2 weeks for the next 6 months → then monthly indefinitely, as long as ANC stays >1500/μL throughout. If ANC drops to <500/μL, discontinue clozapineand check ANC daily until it recovers above 1500/μL.
| Parameter | Frequency | Watching for |
|---|---|---|
| Akathisia | Every visit | Ask about restlessness/anxiety, observe; Barnes Akathisia Scale if formal assessment needed |
| Anticholinergic effects | Every visit | Constipation, blurred vision, urinary retention, dry mouth |
| Glucose intolerance | Baseline, 3 months, then annually if normal | Fasting glucose or A1c |
| Lipids | Baseline, 3 months, then annually if normal | Full lipid panel |
| Weight/BMI/waist circumference | Baseline, monthly x6 months, then quarterly | Waist circumference is the single best predictor of cardiac morbidity here |
| Orthostatic hypotension | Every visit | Ask about dizziness on standing; check sitting/standing BP and HR if present (≥20 mmHg drop is significant) |
| Hyperprolactinemia | Every visit (symptom-triggered) | Galactorrhea/menstrual irregularity in women, gynecomastia/nipple discharge in men; only check serum prolactin if symptomatic |
| Sedation | Every visit | Unusual sleepiness |
| Sexual dysfunction | Every visit | Desire, arousal, orgasm changes; compare to medication-free baseline since baseline dysfunction is already elevated in schizophrenia |
| Tardive dyskinesia | Baseline, then every 6 mo (FGA) / 12 mo (SGA) | AIMS or DISCUS scale |
| ANC (clozapine only) | Baseline, weekly x6mo, q2wk x6mo, then monthly | Agranulocytosis, per REMS |
| Sialorrhea (clozapine only) | Every visit | Ask about drooling, wet pillow on waking |