Medications for schizophrenia
What antipsychotics are used for schizophrenia, where clozapine and LAIs fit, and how metabolic monitoring changes the picture.
First-line options
Second-generation antipsychotics
For a first episode of schizophrenia, current guidelines steer toward second-generation (atypical) antipsychotics as first line. Within the class the choice is mostly about side effect fit.
Risperidone at 2 to 6 mg works, is cheap, and has decades of data. It raises prolactin more than most of the class, which matters for women (menstrual changes, galactorrhea) and for men over long courses (sexual dysfunction, bone density).
Olanzapine at 10 to 20 mg is one of the more effective atypicals in trials. It's also the worst offender for weight gain and metabolic effects. It's still used when other options haven't worked and the patient can accept the tradeoff.
Aripiprazole at 10 to 30 mg has a partial agonist mechanism at dopamine receptors that gives it a distinct profile: less prolactin, less metabolic burden, sometimes more akathisia. Available as a long-acting injection.
Paliperidone at 3 to 12 mg is the active metabolite of risperidone. Similar profile with slightly less hepatic metabolism (mostly renal). Available as monthly, 3-monthly, and 6-monthly LAIs.
Quetiapine at 400 to 800 mg (usually XR) works. It's sedating, which suits some presentations and doesn't others. It has less EPS than most of the class and more metabolic burden.
Ziprasidone at 40 to 80 mg twice daily (with food, or absorption drops sharply) is metabolically kinder than most. Has to be taken with 500 kcal for adequate absorption, which trips people up.
Lurasidone at 40 to 160 mg with food (350 kcal) has a favorable metabolic profile and is FDA-approved for schizophrenia and bipolar depression. The food requirement is real.
Cariprazine at 1.5 to 6 mg is a partial dopamine agonist like aripiprazole with a longer half-life. May have some benefit for negative symptoms.
Brexpiprazole at 2 to 4 mg is similar in spirit to aripiprazole with less akathisia in trials.
Asenapine at 5 to 10 mg twice daily is available sublingually and as a transdermal patch (Secuado). Bitter taste, which patients often mention.
Iloperidone at 12 to 24 mg has a lower risk of akathisia and metabolic effects than some but is limited by the need for slow titration to avoid orthostatic hypotension.
Lumateperone at 42 mg once daily is a newer agent with a distinct receptor profile. Metabolic profile in trials is favorable.
Xanomeline-trospium (Cobenfy) was approved in 2024 as the first antipsychotic without primary D2 blockade. It acts at muscarinic M1 and M4 receptors. Early in real-world use, so tolerability and durability data are still accumulating.
See the antipsychotic class page for the fuller picture.
First-generation antipsychotics
The typicals still work. Haloperidol, fluphenazine, and perphenazine are effective, cheap, and available as LAI depots (for haloperidol and fluphenazine). The tradeoff is EPS: acute dystonia, parkinsonism, akathisia, and tardive dyskinesia risk over years. In the CATIE trial, perphenazine performed roughly comparably to several second-generation options.
They're not usually first pick anymore, but they remain reasonable when cost is an issue, when LAI is needed and the older depots fit the plan, or when a patient has done well on one historically.
Chlorpromazine, thioridazine, and thiothixene are older options with more anticholinergic, sedating, and cardiac (QT for thioridazine) burdens. Used less often. Loxapine is available in an oral form and as an inhaled formulation for acute agitation.
Second-line and augmentation
Clozapine
Clozapine has unique efficacy in treatment-resistant schizophrenia. In the trials where clozapine is the comparator, no other antipsychotic matches it for treatment-resistant symptoms. It also reduces suicide risk in schizophrenia, which is a mortality benefit no other antipsychotic replicates.
The reasons clozapine is not first line: agranulocytosis (roughly 0.8% cumulative incidence, requires REMS monitoring with weekly then biweekly then monthly ANC checks), myocarditis (highest risk in the first 4 to 8 weeks), seizures (dose-related), constipation (can be severe and fatal), sedation, sialorrhea, weight gain, and metabolic burden.
For a patient who has failed two adequate trials of other antipsychotics, clozapine is the standard next step, and there's decent evidence that earlier use (rather than after many failed trials) leads to better outcomes.
Long-acting injectables
LAIs matter in schizophrenia for one main reason: adherence. Missed oral doses are the most common reason for relapse, and LAIs remove that variable.
Options include:
- Aripiprazole as Abilify Maintena (monthly), Aristada (monthly, 6-weekly, or 2-monthly), and Abilify Asimtufii (every 2 months).
- Paliperidone as Invega Sustenna (monthly), Invega Trinza (every 3 months), and Invega Hafyera (every 6 months).
- Risperidone as Risperdal Consta (every 2 weeks, requires 3-week oral overlap) and Perseris and Uzedy (monthly, no oral overlap needed for Uzedy).
- Olanzapine as Zyprexa Relprevv (monthly, requires 3-hour post-injection monitoring for post-injection delirium/sedation syndrome). The monitoring requirement limits use.
- Haloperidol decanoate (monthly).
- Fluphenazine decanoate (every 2 to 4 weeks).
Choosing an LAI usually starts with what the patient has already tolerated orally. Uzedy and Abilify Asimtufii are the newer options with less injection burden.
Augmentation
For partial response to an antipsychotic at an adequate dose and duration, options include switching to clozapine, adding a second antipsychotic (limited evidence, common in practice), adding lithium or valproate for mood or aggression, adding an antidepressant for depressive symptoms, or referring for CBT for psychosis. ECT has evidence in treatment-resistant schizophrenia, particularly with catatonia or affective features.
When to consider a different approach
Treatment-resistant schizophrenia
Two adequate trials of different antipsychotics (adequate dose, 6 to 8 weeks each) without adequate response meets the standard definition. At that point, clozapine is the answer. It's underused, mostly because of the monitoring burden, but the data are clear.
Comorbid substance use
Substance use is common in schizophrenia and worsens outcomes. Cannabis in particular is associated with more relapses. LAIs help maintain treatment in this population. Clozapine has some evidence for reducing substance use in schizophrenia, which is one more argument in its favor when substance use is prominent.
Negative and cognitive symptoms
Antipsychotics work primarily on positive symptoms (hallucinations, delusions, disorganization). Negative symptoms (blunted affect, avolition, alogia) and cognitive symptoms respond less well to any antipsychotic. Cariprazine has some data suggesting benefit for negative symptoms. Brexpiprazole may as well. Clozapine has some cognitive benefit compared to typicals.
Adjunctive treatments for negative and cognitive symptoms are an area of active research. Nothing is a clear win yet.
Catatonia
Catatonic features in schizophrenia respond to benzodiazepines (lorazepam is standard) and to ECT. Antipsychotics can worsen catatonia in some cases. This is a scenario where identifying catatonia and stopping the antipsychotic temporarily can matter.
Special considerations
Metabolic monitoring
Every second-generation antipsychotic can affect weight, glucose, and lipids. The recommended monitoring cadence:
- Weight and BMI at each visit for the first 6 months, then quarterly.
- Waist circumference at baseline and annually.
- Fasting glucose or HbA1c at baseline, 3 months, then annually.
- Fasting lipid panel at baseline, 3 months, then every 5 years (or more often with abnormalities).
- Blood pressure at baseline and periodically.
The Carolan et al. work in Schizophrenia Bulletin makes a strong case for co-commencing metformin when starting a metabolically burdensome antipsychotic in a patient with risk factors. In practice, this is underused.
For patients on olanzapine or clozapine, metabolic monitoring should be more frequent. Weight loss counseling, dietician referral, and metformin all have a role.
EPS and tardive dyskinesia
First-generation antipsychotics and higher doses of risperidone and paliperidone carry the most EPS. Anticholinergics (benztropine, trihexyphenidyl) or amantadine can treat parkinsonism and dystonia. Beta blockers (propranolol) can help akathisia.
Tardive dyskinesia can appear after months to years of D2 blockade. Options at that point include reducing the antipsychotic dose (if feasible), switching to clozapine or quetiapine (lower TD risk), and starting a VMAT2 inhibitor (valbenazine or deutetrabenazine).
QTc
Ziprasidone, iloperidone, and some others prolong QT. Baseline ECG in patients with cardiac history or on other QT-prolonging medications is reasonable. Thioridazine has a boxed warning for QT prolongation and is rarely used now.
Pregnancy
Data are limited but growing. First-generation antipsychotics have the longest track record. Among atypicals, olanzapine, quetiapine, and risperidone have the most reproductive data. Aripiprazole and haloperidol are also used. The general principle: untreated schizophrenia in pregnancy is a major risk for mother and infant, and continuing an effective antipsychotic is often the right call. See the pregnancy safety reference.
Older adults
The mortality boxed warning in dementia-related psychosis applies to all antipsychotics. In older adults with schizophrenia (as opposed to dementia), antipsychotics are still standard, but doses are usually lower and monitoring is closer. See Beers Criteria.
Cardiovascular disease
Schizophrenia is associated with substantial excess cardiovascular mortality. Antipsychotics contribute (metabolic effects), smoking rates are high, and healthcare engagement is often lower. Aggressive cardiovascular prevention (statins, blood pressure control, smoking cessation with bupropion or varenicline) is part of psychiatric care in this population.
What tips the choice
The framework: pick an agent the patient will actually take, that fits their metabolic and side effect risk, and that has the delivery format they need.
- First-episode, no strong risk factors: aripiprazole, risperidone, or paliperidone are common starts. Metabolically kinder options (lurasidone, aripiprazole, cariprazine, brexpiprazole, ziprasidone) are increasingly favored.
- Weight or metabolic risk already high: avoid olanzapine and quetiapine when possible. Favor aripiprazole, cariprazine, brexpiprazole, lurasidone, ziprasidone, or lumateperone.
- History of nonadherence: LAI. Aripiprazole and paliperidone LAIs have the widest use.
- Comorbid mood symptoms (depression, mania): quetiapine, lurasidone, or cariprazine cover both.
- History of EPS or family history of Parkinson's: quetiapine or clozapine have the lowest EPS. Avoid high-potency typicals.
- Prolactin concern: aripiprazole, brexpiprazole, cariprazine, quetiapine are prolactin-sparing. Avoid risperidone and paliperidone.
- Prior good response to a specific agent: reasonable to go back to it.
- Severe agitation in the acute setting: olanzapine IM, haloperidol IM (with a benzodiazepine and often an anticholinergic), or ziprasidone IM.
- Two failed trials at adequate dose and duration: clozapine.
- Comorbid substance use: clozapine has the best evidence for reducing substance use in schizophrenia.
Common questions
How long do I need to take an antipsychotic? For a first episode, most guidelines recommend at least 1 to 2 years of maintenance treatment after remission. For recurrent episodes, indefinite maintenance is usually recommended. Relapse rates off medication are high, and each relapse tends to be harder to treat than the last. The decision to taper is best made with a prescriber and usually done very slowly.
Why is clozapine reserved for treatment-resistant cases? The monitoring requirement (blood counts, myocarditis surveillance in the first weeks, seizure risk) and the side effect burden (sedation, weight, sialorrhea, constipation) make it a heavier lift than other options. But its efficacy in treatment resistance is genuinely unique, and there's an argument that it's used later than it should be. If two other antipsychotics haven't worked, clozapine is the answer.
What are long-acting injections and who are they for? LAIs deliver a steady dose of an antipsychotic over weeks or months from a single injection. They remove the daily dosing decision, which is often where relapse starts. They're not just for people who "don't take their meds." They're a reasonable choice for anyone who wants to remove one variable from their treatment. Options range from every 2 weeks to every 6 months.
Will I gain weight on this medication? Probably some, more with some agents than others. Olanzapine and clozapine are the worst offenders. Aripiprazole, ziprasidone, lurasidone, and lumateperone are metabolically kinder. Weight gain is monitored and can be treated (metformin has evidence, GLP-1 agonists are increasingly used, lifestyle changes matter). It's not something you have to endure passively.
Can I stop the medication if I feel better? The strong recommendation is not to stop without prescriber guidance. Feeling better usually means the medication is working, not that it's no longer needed. Abrupt discontinuation is one of the most common causes of relapse, and each relapse tends to erode long-term function. If a taper is being considered, it should be very slow (over months) and coordinated with a prescriber.
Sources
This guide draws on current prescribing information, treatment guidelines, and public health references. It is reviewed for clinical accuracy and updated as guidance changes.
- American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia.
- Lieberman JA et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia (CATIE).
- Siskind D et al. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia.
- Carolan A et al. Improving physical health monitoring in patients on antipsychotic medications. Schizophrenia Bulletin.
- National Institute of Mental Health. Schizophrenia.
THE KNOWLEDGE PATH
Walk this topic outward.
- GUIDE Medications for schizophrenia (current)
- CLASS SSRIs
- MEDICATION Sertraline (Zoloft)
- CONDITION Major Depressive Disorder (on Shrinkopedia)
- CARE Consider depression evaluation at shrinkMD
The Knowledge Path is a curated walk. Every step is one decision away from the next.
Managing a medication needs a prescriber
Any psychiatric medication has to be started and adjusted by a clinician who can follow you over time. If you don't have a prescriber, our guides section explains the options, including in-person care and telepsychiatry, and how to choose between them.