| Agent | Initial oral dose range (mg/day) | Usual oral dose range (mg/day) | Adjustment of oral dose in older* or medically compromised patients¶ | Usual maximum oral dose (mg/day)Δ | Formulations | Half-life after oral administration (hours) | Primary metabolism◊ | Enzyme(s) inhibited (refer to Notes)§ | Notes |
| Second-generation antipsychotics (SGAs) | |||||||||
| Aripiprazole | 5 to 10 | 10 to 15 | None | 30 | Tab, ODT, LAI, oral solution Aripiprazole lauroxil LAI | 75 to 94 | CYPs 2D6 and 3A4 to active and inactive metabolites | None | For augmentation of antidepressant, a lower oral daily dose of 2 to 5 mg is useful. |
| Asenapine¥ | 10 | 10 to 20 | None Exception: Use contraindicated in severe hepatic impairment | 20 | SL tab | 24 | CYP1A2 and UGT-glucuronidation | None | Patient should not eat or drink within 10 minutes of SL administration. SL preparation should not be swallowed due to poor gastrointestinal absorption. |
| Brexpiprazole | 0.5 to 1 | 2 to 4 | Dose adjustments are needed in renal or hepatic impairment‡ | 4 | Tab | 91 | CYP2D6 and 3A4 | None | |
| Cariprazine | 1.5 | 1.5 to 6 | Not recommended in severe renal or hepatic impairment | 6 | Capsule | 48 to 96 (parent drug) 7 to 21 days (active metabolites)† | CYP3A4 to active† and inactive metabolites | None | |
| Clozapine¥ | 12.5 to 25 | 150 to 600 | Titrate gradually to reduced maintenance range of 100 to 150 mg/day; maximum 300 mg/day Lower doses advised in renal or hepatic impairment; specific dose adjustment recommendations are not available | 900 | Tab, ODT, oral suspension | 12 | CYP1A2, other CYPs, and UGT-glucuronidation | None | Hypotension is the most frequent dose-limiting factor during titration. Other side effects requiring monitoring include agranulocytosis, sedation, and sialorrhea. Once titrated to 300 to 450 mg daily, rate of titration may be increased to 100 mg once or twice weekly. |
| Iloperidone | 2 | 12 to 24 | Not recommended in severe hepatic impairment | 24 12 (CYP2D6 poor metabolizer or receiving 2D6 inhibitor cotreatment) | Tab | 18 to 26 | CYP2D6 and other CYPs to active and inactive metabolites | None | Orthostatic hypotension is usually the dose limiting factor in titration. |
| Lumateperone | 42 | 42 (dose is not titrated) | Not adequately evaluated in patients aged 65 years or more Not recommended in moderate to severe hepatic impairment | 42 (dose is not titrated) | Capsule | 18 after IV administration (IV form is not commercially available) | CYP3A4, other CYPs, and UGT-glucuronidation; activity of metabolites not reported | None | Needs to be taken with a meal to be adequately absorbed. Dose adjustments should be made for individuals treated with CYP 3A4 inhibitors. Avoid use in individuals taking CYP3A4 inducers. Refer to separately available list in UpToDate. |
| Lurasidone | 40 20 (renal or hepatic insufficiency) | 40 to 80 | Dose adjustments are needed in renal and hepatic impairment‡ | 160 80 (moderate or severe renal impairment, moderate hepatic impairment) 40 (severe hepatic insufficiency) | Tab | 29 to 37 (at steady state) | CYP3A4 to active and inactive metabolites | None | Needs to be taken with a meal to be adequately absorbed. |
| Olanzapine¥,** | 5 to 10 | 10 to 20 | Initially 1.25 to 2.5 mg/day; typical maintenance 5 mg/day; maximum 10 mg/day | 30 | Tab, ODT, IM, LAI | 30 to 38 | CYP1A2 and UGT-glucuronidation | None | |
| Paliperidone | 6 | 6 to 12 | Older adults or renal impairment: 3 mg/day‡ | 12 | ER tab, LAI | 23 | Paliperidone is excreted mainly unchanged in urine necessitating dose reduction in renal insufficiency‡ | None | Tablets need to be swallowed whole. |
| Pimavanserin | 34 | 34 | Not recommended in hepatic impairment or severe renal impairment (not studied) | 34 | Tab | 57 parent drug (200 for active metabolite) | CYP3A4 and 3A5 to active metabolite | None | Approved for reducing Parkinson disease-related psychosis. Dose adjustment needed if used with strong inhibitors of CYP3A. Efficacy may be reduced if used with strong inducers of CYP3A. Refer to separately available list in UpToDate. |
| Quetiapine | 50 (immediate release) 300 (extended release) | 400 to 800 (According to the label, the usual range for acute therapy using immediate release tab is 150 to 750 mg/day) | Initially 25 to 50 mg/day; use substantially lower maintenance dose Dose adjustment needed in hepatic impairment‡ | 800 | Tab, ER tab | 6 to 12 | CYP3A4 | None | Titration often limited by excessive sedation or orthostatic hypotension; monitor clinical effect. |
| Risperidone | 1 to 2 | 2 to 6 | Initially 0.25 to 0.5 mg/day; typical maintenance 1 mg/day; maximum 2 mg/day Dose adjustments are needed in renal and hepatic impairment‡ | 8 | Tab, ODT, LAI, oral solution | 20 | CYP2D6 to active (paliperidone) and inactive metabolites; P-gp substrate | None | |
| Ziprasidone | 40 to 80 | 40 to 160 | Lower doses advised in hepatic impairment; specific adjustment recommendations are not available | 160 | Capsule, IM | 7 oral 2 to 5 IM | CYP3A4 | None | Needs to be taken with food to be adequately absorbed. Capsules should be swallowed whole. Oral preparation is not dependent on renal function for clearance, but a component of the IM injection is cleared by the kidney. |
| First-generation antipsychotics (FGAs) | |||||||||
| Chlorpromazine | 25 to 200 | 400 to 600 | Use low initial dose and increase more gradually | 800 | Tab, IM | 30 | CYP2D6, other CYPs, and UGT-glucuronidation to active and inactive metabolites | None | Oral absorption is variable and may require dose adjustment based on patient response. Older adults and medically ill patients are unlikely to tolerate cardiovascular, sedating, and anticholinergic side effects. |
| Fluphenazine | 2 to 10 | 2 to 15 | 1 to 2.5 mg daily initially, adjust dose gradually based on response | 12 | Tab, IM, LAI, oral solution | 33 | CYP2D6 | None | Oral absorption is highly variable and dose must be individualized based on patient response. |
| Haloperidol | 2 to 10 | 2 to 20 | 1 to 5 mg daily; adjust dose gradually based on response | 30 | Tab, IM, LAI, oral solution | 20 | CYPs 2D6, 3A4, and UGT-glucuronidation; some metabolites potentially active or toxic | None | The United States labeled maximum recommended dose of 100 mg/day (oral) is considerably higher than more recent practice supports. Bioavailability with oral dosing is approximately 60%; dose adjustments between oral and parenteral administration should be made accordingly. IV use has not been approved by the US Food and Drug Administration and is associated with increased risk of QT prolongation; refer to accompanying text. |
| Loxapine | 20 | 20 to 80 | Generally follows standard adult dosing, although a dose reduction may be indicated in some cases | 100 | Capsule; oral inhalation for use in health care settings as alternative to IM injection Oral solution and IM injection available in countries other than the United States | 6 to 8 (parent drug) 12 (active metabolites) | CYPs 1A2, 2D6, 3A4, and UGT-glucuronidation to active and inactive metabolites | None | Onset of oral (swallowed capsule) and IM within 30 minutes. |
| Perphenazine | 8 to 16 | 12 to 24 | Initiate dose at 8 mg/day and titrate more gradually to the usual adult range | 24 (a higher daily dose may be acceptable, refer to notes) | Tab | 9 to 12 (parent drug) 10 to 19 (active metabolite) | CYPs 2D6, 3A4, and other CYPs to active and inactive metabolites | None | Bioavailability is variable (60 to 80%). Higher daily doses (eg, up to 32 mg per day) were shown to be similar in tolerability and efficacy to some SGAs[1] and in practice up to 64 mg per day total may be acceptable in some circumstances. |
| Pimozide¥ | 1 to 2 | 8 to 10 | 1 mg/day initially and titrate more gradually to the usual adult range | 10 4 (CYP2D6 poor metabolizer) | Tab | 55 150 (CYP2D6 poor metabolizers) | CYPs 1A2, 2D6, 3A4, and others | None | Bioavailability is variable due to extensive hepatic first-pass metabolism. |
| Thiothixene¥ (tiotixene) | 5 to 10 | 10 to 20 | Use low initial dose and titrate more gradually to the usual adult dose range | 30 | Capsule | 34 | CYP1A2 and other CYPs | None | Oral absorption is variable and dose must be individualized based on patient response. |
| Thioridazine | 150 | 200 to 600 | Use low initial dose and titrate more gradually to the usual adult dose range | 600 | Tab | 4 to 10 (parent drug) 21 to 25 (active metabolites) | CYP2D6 and other CYPs to active (mesoridazine) and inactive metabolites | CYP2D6 (moderate) | |
| Trifluoperazine¥ | 4 to 10 | 15 to 20 | Initiate dose at 4 mg/day and titrate more gradually to the usual adult range | 40 | Tab | 3 to 12 (parent drug) 22 (active metabolites) | CYP1A2 and other CYPs to active and inactive metabolites | None | Bioavailability is variable. |
Tab: tablet; ODT: orally dissolving tablet; LAI: long-acting injectable (eg, depot); CYP: cytochrome P-450; UGT-glucuronidation: uridine 5'diphosphate-glucuronyltransferases; SL: sublingual; IV: intravenous; IM: short-acting intramuscular injection; ER tab: extended-release tablet; P-gp: membrane P-glycoprotein transporters.
* FGAs and SGAs are included on the Beers list of medications to be used with caution in older adults and should in general be avoided except for schizophrenia and bipolar disorder.[2]
¶ FGAs undergo extensive hepatic metabolism; levels may be elevated in hepatic impairment necessitating dose reduction and more gradual dose titration to avoid toxicity. FGAs should be used with caution at significantly reduced doses or avoided in severe hepatic impairment.
Δ Usual maximum total oral daily dose for maintenance treatment of schizophrenia in adult patients without significant comorbidity. Doses shown may not be the maximum dose used in some clinical trials or in exceptional patients.
◊ Dose adjustments of several antipsychotic medications listed in this table are recommended in presence of strong or moderate inhibitors or inducers of CYP drug metabolism; for specific recommendations refer to the individual Lexicomp drug monographs.
§ The classification of antipsychotic effects on drug metabolism are based upon US Food and Drug Administration guidance.[3,4] Other sources may use a different classification system resulting in some agents being classified differently. Weak inhibitor effects are not listed. Clinically significant interactions can occasionally occur due to weak inhibitors, particularly if the target drug has a narrow therapeutic margin. Refer to the Lexicomp drug interactions program for a full list of potential interactions.
¥ Smoking may decrease blood concentrations of antipsychotics primarily metabolized by CYP1A2.
‡ For specific dose adjustments in setting of renal or hepatic impairment, refer to Lexicomp drug monograph.
† Active metabolites of cariprazine are equipotent to cariprazine. Due to the long half-life of cariprazine and active metabolites, changes in dose will not reach plasma steady-state for several weeks or months.
** A combination formulation of olanzapine with an opioid antagonist, samidorphan, is also available. Refer to UpToDate content.Additional data from:
