Comparison of Atypical Antipsychotics (United States)

The chart below compares atypicals in regard to adult indications and dosing, metabolic side effects, sedation, CYP metabolism, and cost. Prescribers can bill for IM antipsychotic injections under their supervision using CPT code 96372 and add the medication code.

NOTE: *Usual or target daily ADULT dosage range may not include initial and maximum doses. Use lowest effective dose. Dosing in special populations (e.g., renal impairment, geriatrics) is not included. Maximum doses of oral aripiprazole, brexpiprazole, cariprazine, lurasidone, olanzapine, olanzapine/samidorphan, paliperidone, quetiapine XR, and risperidone are approved for once-daily administration. Total daily doses of asenapine, iloperidone, quetiapine IR (except for bipolar depression), and ziprasidone are divided twice daily. Clozapine doses above 12.5 mg should be divided.

Generic (Brand)/ Cost^b	*FDA-Approved Indication(s) for ADULTS and Usual or Target Adult Daily Dosage Range (mg/day)^,a**	Notable Adverse Effects^4,a,c				CYP450 Metabolism^a
Generic (Brand)/ Cost^b		Weight Gain	Diabetes Risk	Dys-lipidemia	Sedation	CYP450 Metabolism^a
Aripiprazole (Abilify, generics) 10 mg tablet ~$25 Oral solution, orally disintegrating tablet, and Abilify Mycite (tablet with embedded event marker to track adherence) also available.	Schizophrenia: 10-15 mg Bipolar I disorder (manic or mixed episodes [and maintenance (Abilify Mycite)]): 15 mg (monotherapy or with lithium or valproate) Major depression (adjunct to antidepressants): 5-10 mg	Low	Low	Low	Low (may cause insomnia²)	CYP3A4, CYP2D6 Reduce dose by 50% with strong CYP3A4 or strong CYP2D6 inhibitors, and in known CYP2D6 poor metabolizers. Reduce dose by 75% with strong CYP2D6 plus strong CYP3A4 inhibitors, or in CYP2D6 poor metabolizers taking a strong CYP3A4 inhibitor. Use twice the usual dose (increase over one to two weeks) with strong CYP3A4 inducers.
Aripiprazole (Abilify Asimtufii) 960 mg/ two months $5,438.46	Schizophrenia or Bipolar I maintenance: 960 mg every two months IM (gluteal). Establish tolerability with oral aripiprazole before use. Continue oral antipsychotic for 14 days after first dose, then stop. Missed dose: if >14 weeks have elapsed since the last injection, restart oral aripiprazole for 14 days with the injection.	Low	Low	Low	Low	CYP3A4, CYP2D6 CYP450 modulators added for >14 days may require dosage changes. Dose is 720 mg every two months with strong CYP3A4 or strong CYP2D6 inhibitors, and in CYP2D6 poor metabolizers. Avoid with CYP3A4 inducers, concomitant use of a strong CYP2D6 inhibitor plus a strong CYP3A4 inhibitor, and in CYP2D6 poor metabolizers taking a CYP3A4 inhibitor.
Aripiprazole (Abilify Maintena long-acting injection) 400 mg $2,719.23	Schizophrenia: 400 mg IM (gluteal or deltoid) once monthly. Continue oral agent for 14 days after first dose, then stop. Missed dose: If >6 weeks elapse since last dose (>5 weeks if 2^nd or 3^rd dose is missed), restart oral aripiprazole x 14 days with the next dose.	Low	Low	Low	Low	CYP3A4, CYP2D6 CYP450 modulators added for >14 days may require dosage changes.Reduce dose with strong CYP2D6 and/or CYP3A4 inhibitors. Reduce dose in CYP2D6 poor metabolizers taking a CYP3A4 inhibitor. Avoid with CYP3A4 inducers.
Aripiprazole lauroxil Aristada long-acting injection 662 mg $2,251.21 Aristada Initio (for loading) 675 mg x 1 $2,295.42	Schizophrenia: 441 mg IM (gluteal or deltoid), 662 mg (gluteal), or 882 mg (gluteal) once monthly; 882 mg (gluteal) once every 6 weeks; or 1,064 mg every 2 months (gluteal). Continue corresponding oral aripiprazole dose for 21 days after first dose, then stop. Alternatively, load with Aristada Initio 675 mg IM plus oral aripiprazole 30 mg x 1. Can start Aristada on same day or up to 10 days later. Missed dose: If >6 to ≤7 weeks (441 mg), >8 to ≤12 weeks (662 mg and 882 mg), or >10 to ≤12 weeks (1,064 mg) since last dose, restart oral aripiprazole x 7 days with next dose, or give with Aristada Initiox 1. If >7 weeks (441 mg) or >12 weeks (662 mg, 882 mg, and 1,064 mg) since last dose, restart oral aripiprazole x 21 days with next dose, or give with Aristada Initio 675 mg x 1 plus oral aripiprazole 30 mg x 1.	Low	Low	Low	Low	CYP3A4, CYP2D6 Aristada: CYP450 modulators added for >14 days may require dosage changes. Reduce dose with strong CYP3A4 or CYP2D6 inhibitors. Avoid doses >441 mg with concomitant use of a strong CYP2D6 inhibitor AND a strong CYP3A4 inhibitor. Dosage increase may be needed with strong CYP3A4 inducers. Dose reduction may be needed in CYP2D6 poor metabolizers. Aristada Initio: Avoid with strong CYP2D6 inhibitors; with strong CYP3A4 inhibitors; with strong CYP3A4 inducers; and in CYP2D6 poor metabolizers.
Asenapine (Saphris, generics) 10 mg twice daily ~$310	Schizophrenia: 10 mg (acute), 10-20 mg (after one week) Bipolar I disorder (manic or mixed episodes and maintenance): 10-20 mg (monotherapy, or with lithium or valproate [acute treatment]) For sublingual use. Avoid food/drink for 10 min afterward.	Moderate	Moderate	Moderate	Moderate	CYP1A2, CYP3A4 (minor), CYP2D6 (minor) Weak CYP2D6 inhibitor. Consider dose reduction with strong CYP1A2 inhibitors.
Asenapine (Secuado) All patch strengths $1,335.60	Schizophrenia: 3.8 to 5.7 mg (Doses of 7.6 mg can be used, but are unlikely to provide additional benefit, and may increase adverse effects.) Patch applied once daily.	Moderate	Moderate	Moderate	Moderate	CYP1A2, CYP3A4 (minor), CYP2D6 (minor) Weak CYP2D6 inhibitor. Consider dose reduction with strong CYP1A2 inhibitors.
Brexpiprazole (Rexulti) All tablet strengths $1,419.04	Schizophrenia: 2-4 mg Major depressive disorder (adjunct to antidepressants): 2 mg Agitation associated with Alzheimer’s dementia: 2 mg	Low	Low	Moderate	Moderate	CYP3A4, CYP2D6 Reduce dose by 50% with strong CYP2D6 inhibitors (schizophrenia indication) or strong CYP3A4 inhibitors, and in CYP2D6 poor metabolizers. Reduce dose by 75% for patients taking a strong or moderate CYP2D6 inhibitor plus a strong or moderate CYP3A4 inhibitor. Reduce dose by 75% for CYP2D6 poor metabolizers taking a strong or moderate CYP3A4 inhibitor. Double the dose over one to two weeks with strong CYP3A4 inducers.
Cariprazine (Vraylar) All capsule strengths $1,377.67	Schizophrenia: 1.5-6 mg Bipolar I disorder (manic or mixed episodes): 3-6 mg Bipolar I disorder (depression): 1.5 to 3 mg Major depressive disorder (adjunct to antidepressants): 1.5 to 3 mg	Moderate	Low	Low	Moderate	CYP3A4, CYP2D6 (minor) Reduce dose by 50% with strong CYP3A4 inhibitors. Avoid with CYP3A4 inducers.
Clozapine^d (Clozaril, etc, generics) 100 mg tablet three times daily ~$150 Oral suspension and generic orally disintegrating tablet also available.	Schizophrenia (treatment-resistant): 300-450 mg Reducing suicidal behavior in schizophrenia & schizoaffective disorder: 300-450 mg NOTE: initial dose is 12.5 mg once or twice daily (for both indications).	High	High	High	High	CYP1A2, CYP3A4, CYP2D6 Reduce dose by one-third with strong CYP1A2 inhibitors. Not recommended with strong CYP3A4 inducers. Consider dose reduction with weak or moderate CYP1A2 inhibitors, CYP2D6 or CYP3A4 inhibitors, and in CYP2D6 poor metabolizers.
Iloperidone (Fanapt) 6 mg tablet twice daily $2,157.74	Schizophrenia: 12-24 mg	Moderate	Moderate	Low	Moderate	CYP3A4, CYP2D6 Reduce dose with strong CYP2D6 or strong CYP3A4 inhibitors.
Lumateperone (Caplyta) All capsule strengths $1,569.17	Schizophrenia: 42 mg Bipolar I or II depression: 42 mg	Low	Low to moderate	Low	Moderate	CYP1A2, CYP2C8, CYP3A4 Avoid with CYP3A4 inducers. Reduce dose with strong or moderate CYP3A4 inhibitors.
Lurasidone (Latuda, generics) 40 mg tablet ~$35	Schizophrenia: 40-160 mg Bipolar I depression (monotherapy or with lithium or valproate): 20-120 mg Take with food (at least 350 kcal).	Low	Low⁶	Low⁶	Moderate	CYP3A4 Contraindicated with strong CYP3A4 inhibitors or inducers. Reduce dose by 50% with moderate CYP3A4 inhibitors. Increase dose with moderate CYP3A4 inducers.
Olanzapine (Zyprexa, generics) 10 mg tablet ~$15 Injection: ~$35/10 mg Generic orally disintegrating tablet available.	Schizophrenia: 10 mg Bipolar I disorder (manic or mixed episodes and maintenance): 5-20 mg (monotherapy, or with lithium or valproate [acute treatment]) Bipolar I depression, with fluoxetine: 5-12.5 mg Depression (treatment-resistant), with fluoxetine: 5-20 mg Zyprexa IntraMuscular, agitation associated with psychosis or bipolar I mania: 10 mg (lower dose [5 mg, 7.5 mg] may be given). May repeat dose in 2 hours. A third dose may be given no sooner than 4 hours after the second dose.	High	High	High	High	CYP1A2, CYP2D6
Olanzapine pamoate (Zyprexa Relprevv long-acting injection) 300 mg $842.40	Schizophrenia: Establish tolerability and target dose with oral olanzapine first. Patients can switch to Zyprexa Relprevv with or without tapering.¹Zyprexa Relprevvis initiated with an 8-week loading regimen and is dosed every 2 or 4 weeks IM (gluteal). Available only through a restricted distribution program requiring prescriber, facility, patient, and pharmacy enrollment. Missed dose: see footnote e.	High	High	High	High Rare risk of post-injection sedation (including coma) and/or delirium. Monitor for at least 3 hours post-dose.	CYP1A2, CYP2D6
Olanzapine/ samidorphan (Lybalvi) 15 mg/10 mg tablet $1,510.44	Schizophrenia: 10 mg/10 mg to 20 mg/10 mg Bipolar I (manic or mixed episodes [acute treatment or maintenance]): 5 mg/10 mg to 20 mg/10 mg Bipolar I (adjunct to lithium or valproate for manic or mixed episodes [acute treatment]): 10 mg/10 mg to 20 mg/10 mg	High	High	High	High	CYP1A2, CYP2D6, CYP3A4 Avoid strong CYP3A4 inducers. It may be necessary to: reduce the dose of the olanzapine component with strong CYP1A2 inhibitors. increase the dose of the olanzapine component with CYP1A2 inducers.
Paliperidone (Invega, generics) 6 mg extended-release tablet ~$320	Schizophrenia: 3-12 mg Schizoaffective disorder: 3-12 mg (monotherapy or adjunct to mood stabilizers or antidepressants)	Moderate	Low	Moderate	Low	CYP2D6 (minor), CYP3A4 (minor) It may be necessary to increase the dose if used with a strong inducer of both CYP3A4 and P-glycoprotein.
Paliperidone palmitate (Invega Sustenna long-acting injection) 117 mg $1,674.04	Schizophrenia or schizoaffective disorder: IM monthly after 2 doses one week apart. Establish tolerability with oral paliperidone or risperidone before use. Taper oral agent with first dose. When switching from a long-acting injectable, start in place of the next scheduled dose. Missed maintenance dose: resume regular monthly dosing if up to 2 weeks late. Details on handling other missed dosing scenarios are provided in the product labeling.	Moderate	Low	Moderate	Low	CYP2D6 (minor), CYP3A4 (minor) Avoid CYP3A4 and/or P-glycoprotein inducers, if possible.
Paliperidone palmitate (Invega Trinza long-acting injection) 410 mg $1,674.04	Schizophrenia, after adequate treatment with Invega Sustenna for at least 4 months: IM every 3 months. Dose depends on previous Invega Sustenna dose. Missed maintenance dose: can give up to two weeks early or up to 1 month late. Details on handling missed doses are provided in the product labeling.	Moderate	Low	Moderate	Low	CYP2D6 (minor), CYP3A4 (minor) Avoid CYP3A4 and/or P-glycoprotein inducers, if possible.
Paliperidone palmitate (Invega Hafyera long-acting injection 1,092 mg $2,212.98	Schizophrenia, after adequate treatment with Invega Sustenna for at least 4 months or Invega Trinza for at least one 3-month cycle: IM every 6 months. Dose depends on previous Invega Sustenna or Invega Trinza dose. Missed maintenance dose: Can give up to two weeks early or 3 weeks late. Details on handling missed doses are provided in the product labeling.	Moderate	Low	Moderate	Low	CYP2D6 (minor), CYP3A4 (minor) Avoid CYP3A4 and/or P-glycoprotein inducers, if possible.
Quetiapine (Seroquel, generics) 200 mg tablet twice daily ~$15	Schizophrenia: 150-750 mg Bipolar depression (bipolar I and II): 300 mg Bipolar mania or bipolar I maintenance (monotherapy [acute] or as an adjunct to lithium or valproate [acute, maintenance]): 400-800 mg	Moderate	Moderate	High	High	CYP3A4 Reduce dose to one-sixth with strong CYP3A4 inhibitors. Increase dose up to five-fold with a strong CYP3A4 inducer taken for >7 to 14 days.
Quetiapine (Seroquel XR, generics) 400 mg extended-release tablet $~25	Schizophrenia: 400-800 mg Bipolar depression (acute): 300 mg Bipolar I manic or mixed episode (monotherapy [acute] or as an adjunct to lithium or valproate [acute, maintenance]): 400-800 mg Major depressive disorder (adjunct to antidepressants): 150-300 mg Take without food or with a light meal (about 300 kcal).	Moderate	Moderate	High	High	CYP3A4 Reduce dose to one-sixth with strong CYP3A4 inhibitors. Increase dose up to five-fold with a strong CYP3A4 inducer taken for >7 to 14 days.
Risperidone (Risperdal, generics) 4 mg tablet ~$35 Generic oral solution and orally disintegrating tablet available.	Schizophrenia: 4-8 mg Bipolar I disorder (acute manic or mixed episodes; monotherapy or as an adjunct to lithium or valproate): 1-6 mg	Moderate	Moderate	Low	Moderate	CYP2D6, CYP3A4 (minor)² Reduce initial dose and do not exceed 8 mg max with strong CYP2D6 inhibitors. Dose can be doubled for use with CYP3A4 or P-glycoprotein inducers.
Risperidone (Perseris long-acting injection) 90 mg $2,070.59	Schizophrenia: 90-120 mg once monthly (subcutaneous in the abdomen or upper arm). Establish tolerability with oral risperidone before starting. Perseris 90 mg monthly equals ~3 mg oral risperidone once daily; Perseris 120 mg equals ~4 mg oral risperidone once daily. Missed dose: restart as soon as possible.	Moderate	Moderate	Low	Moderate	CYP2D6, CYP3A4 (minor)² Consider dose reduction to 90 mg beginning two to four weeks before starting a strong CYP2D6 inhibitor. Consider increasing the dose to 120 mg with CYP3A4 inducers. Additional oral risperidone may be needed.
Risperidone (Risperdal Consta long-acting injection) 25 mg $1,172.82	Schizophrenia: 25 mg IM every 2 weeks Bipolar I maintenance (monotherapy or as an adjunct to lithium or valproate): 25 mg IM every 2 weeks Continue oral agent for 3 weeks after first dose, then discontinue. Missed dose, and <4 consecutive doses received: Give injection, plus oral agent for 3 weeks.³ Missed dose, and 4 or more consecutive doses received: If only 3-6 weeks have passed since last injection, give injection alone. If >6 weeks have passed since last injection, give injection, plus oral agent for 3 weeks.³	Moderate	Moderate	Low	Moderate	CYP2D6, CYP3A4 (minor)² Consider dose reduction to 25 mg beginning two to four weeks before starting a strong CYP2D6 inhibitor. Consider initiating with 12.5 mg in patients already taking a strong CYP2D6 inhibitor. A dosage increase or additional oral risperidone may be needed with a strong CYP3A4 inducer.
Risperidone (Rykindo extended-release injectable suspension) 25 mg $1,172.82	Schizophrenia or Bipolar I maintenance (monotherapy or as an adjunct to lithium or valproate): 25 mg every 2 weeks IM (gluteal) Establish tolerability with oral risperidone before starting. Continue oral risperidone for 7 days after first dose, then stop.	Moderate	Moderate	Low	Moderate	CYP2D6, CYP3A4 (minor)² Consider dose reduction to 25 mg two to four weeks before starting a strong CYP2D6 inhibitor. A dosage increase or the addition of oral risperidone may be needed with a strong CYP3A4 inducer.
Risperidone (Uzedy) Extended-release injectable suspension 100 mg $2,464	Schizophrenia: 50 mg once monthly to 250 mg every two months. Dose is based on prior oral risperidone dose. 2 mg/day = 50 mg once monthly or 100 mg every 2 months.	Moderate	Moderate	Low	Moderate	CYP2D6, CYP3A4 (minor)² Consider dose reduction to 50 mg once monthly or 100 mg every 2 months before starting a strong CYP2D6 inhibitor. A dosage increase or the addition of oral risperidone may be needed with a strong CYP3A4 inducer.
Ziprasidone (Geodon, generics) 40 mg capsule twice daily $~55 Injection ~$30/20 mg	Schizophrenia: 40-160 mg Bipolar I disorder (acute manic or mixed episodes, maintenance [adjunct to lithium or valproate]): 80-160 mg Take with food. Injection: agitation associated with schizophrenia: 10 mg IM q 2 hrs or 20 mg q 4 hrs. Max 40 mg/day.	Low	Low	Low	Moderate	CYP3A4, CYP1A2 (minor)

Per U.S. product information: Abilify (November 2022), Abilify Asimtufii (August 2023), Abilify Maintena (June 2020), Abilify Mycite (February 2023), Aristada (March 2021), Aristada Initio (March 2021), Saphris (October 2021), Secuado (November 2022), Rexulti (May 2023), Vraylar (December 2022), Clozaril (May 2023), Fanapt (February 2017), Caplyta (June 2023), Latuda (May 2022), Zyprexa and Zyprexa IntraMuscular (February 2021), Zyprexa Relprevv (November 2021), Lybalvi (May 2021), Invega (February 2021), Invega Sustenna (July 2022), Invega Trinza (August 2021), Invega Hafyera (August 2021), Seroquel (January 2022), Seroquel XR (January 2022), Risperdal (August 2022), Perseris (December 2022), Risperdal Consta (February 2021), Rykindo (May 2023), Uzedy (May 2023), Geodon (February 2022).
Wholesale acquisition cost (US) per month (unless otherwise specified), for generic if available, of dose specified. Medication pricing by Elsevier, accessed September 2023.
Extrapyramidal side effects are low with aripiprazole, brexpiprazole, cariprazine, iloperidone, quetiapine, ziprasidone, and high with lurasidone, paliperidone, and risperidone.⁴ Hyperprolactinemia (associated with sexual dysfunction, gynecomastia, and irregular periods) seems most common with risperidone and paliperidone, and lowest with aripiprazole, brexpiprazole, cariprazine, clozapine, lurasidone, and quetiapine.⁴ QT prolongation risk varies among agents. Aripiprazole and lurasidone may pose relatively lower risk vs other agents, while iloperidone and ziprasidone may pose the highest risk.⁴ See our chart, Drug-Induced QT Prolongation: A Stepwise Approach, for more information. Anticholinergic effects (e.g., dry mouth, constipation, difficult urination) may be most problematic with clozapine, cariprazine, olanzapine, and quetiapine,⁴ and least with brexpiprazole, asenapine, and lurasidone.⁷
Clozapine is associated with severe neutropenia, seizures, and myocarditis. Hematological monitoring (absolute neutrophil count [ANC]) is required. Clozapine is only available through the Clozapine REMS Program. Prescribers and pharmacies may obtain details at www.newclozapinerems.com or by calling the number in the manufacturer’s product information. Both pharmacies and prescribers need to register. This includes inpatient pharmacies and prescribers initiating clozapine.⁵ When a patient on clozapine is admitted to an inpatient facility, before dispensing, patient enrollment must be verified (“Eligibility Check”).⁵ In addition, the ANC should be verified as current (based on the patient’s monitoring frequency) and acceptable (or “Treatment Rationale” is on file in the case of moderate or severe neutropenia).⁵ ANC values should be submitted according to the patient’s monitoring frequency.⁵
Zyprexa Relprevv, missed dose: no specific dosing guidance is available; use clinical judgment. In some studies, up to 16 days (for every-2-week dosing) or 35 days (for every-4-week dosing) were allowed between doses. In practice, some patients can go >60 days between doses. The effective half-life of Zyprexa Relprevv is about 30 days.¹

References

Eli Lilly Medical Information. Zyprexa Relprevv (olanzapine) for extended-release injectable suspension: dosing of and switching to or from Zyprexa Relprevv. Last reviewed April 28, 2022. https://www.lillymedical.com/assets/vaultpdf/us/en/c648c5b04f299d0ff6bf8f25e3593a54a105acea4a94428da03d23c195e9a8b6/how-do-you-dose-and-switch-patients-to-or-from-zyprexa-relprevv-olanzapine-long-acting-injection. (Accessed September 22, 2023).
Clinical Pharmacology powered by Clinical Key. Tampa, FL: Elsevier; 2023. http://www.clinicalkey.com. (Accessed September 23, 2023).
Janssen Medical Information. Dosing of Risperdal Consta-dosage and administration. https://www.janssenscience.com/products/risperdal-consta/medical-content/dosing-of-risperdal-consta-dosage-and-administration. (Accessed September 23, 2023).
Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizopahrenia. Am J Psychiatry. 2020 Sep 1;177(9):868-872.
FDA. Clozapine REMS. Summary. Last update November 10, 2021. https://www.accessdata.fda.gov/Scripts/Cder/Rems/index.cfm?event=RemsDetails.page&REMS=351. (Accessed September 23, 2023).
Marder SR, Cannon TD. Schizophrenia. N Engl J Med. 2019 Oct 31;381(18):1753-1761.
Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019 Sep 14;394(10202):939-951. Erratum in: Lancet. 2019 Sep 14;394(10202):918.

Cite this document as follows: Clinical Resource, Comparison of Atypical Antipsychotics (United States). Pharmacist’s Letter/Pharmacy Technician’s Letter/Prescriber Insights. October 2023. [391004]