First-generation antipsychotic medications for maintenance treatment of schizophrenia in adult patients: Oral dosing, pharmacokinetics, and selected characteristics

Agent	Initial dose (mg/day)	Usual dose range (mg/day)	Maximum dose (mg/day)	Half-life (hours)	Metabolism and clearance	Selected characteristics
Chlorpromazine^*	25 to 200	400 to 600	800	Approximately 30	CYP2D6, other CYPs, and glucuronidation to active and inactive metabolites	Doses greater than 800 mg/day approved by some regulatory authorities are not recommended Avoid use in older adults Other formulation: Short-acting IM
Fluphenazine	2 to 10	6 to 20	12 (maintenance) 20 (acute)	14 to 16	CYP2D6	Routinely given in 1 to 2 divided doses Oral absorption is highly variable; dose must be individualized based on response Dose adjustment may be needed with CYP2D6 inhibitors^¶ Avoid use in hepatic impairment (per manufacturer) Other formulations: Oral solution, short-acting IM, LAI
Haloperidol	2 to 10	2 to 20	30	14 to 37	CYP2D6, 3A4, and glucuronidation; some metabolites active and potentially neurotoxic	Daily dose administered in 1 to 3 divided doses Oral bioavailability approximately 60%; adjust accordingly when switching between oral and short-acting parenteral formulations Oral doses greater than 30 mg/day approved by some regulatory authorities are not recommended Variable dose requirements due to CYP2D6 metabolizer phenotype QTc prolongation risk increased with IV doses greater than 2 mg (off-label route); for IV use assess baseline and on-treatment ECG Other formulations: Oral solution, short-acting IM/IV, LAI
Loxapine	20	20 to 80	100 (maintenance) 250 (acute)	6 to 8 (parent) 12 (active metabolites)	CYP1A2, 2D6, 3A4 and glucuronidation to active and inactive metabolites	Routinely given in 1 to 2 divided doses Other formulations: Inhalation for acute treatment in health care setting; oral solution and short-acting IM available in some areas (not United States)
Molindone	50 to 75	15 to 100	225	1.5	CYP2D6
Perphenazine	8 to 16	12 to 24	24 (refer to selected characteristics)	9 to 12 (parent) 10 to 19 (active metabolites	CYP2D6, 3A4, and other CYPs to active and inactive metabolites	Routinely given in 2 to 3 divided doses daily 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 for severe symptoms Variable dose requirements due to CYP2D6 metabolizer phenotype Avoid use in hepatic impairment (per manufacturer)
Pimozide	1 to 2	2 to 4	10	55 150 (CYP2D6 poor metabolizers)	CYP1A2, 2D6, 3A4 and others	Oral bioavailability is variable due to extensive hepatic first-pass metabolism QTc prolongation risk; assess baseline and on-treatment ECG Maximum dose 4 mg/day in CYP2D6 poor metabolizers Avoid use with CYP2D6 inhibitors^¶
Thioridazine^*	150 to 300	200 to 600	800	4 to 10 (parent) 21 to 25 (active metabolites	CYP2D6 and other CYPs to active (mesoridazine) and inactive metabolites	Given in 1 to 2 divided doses QTc prolongation risk; assess baseline and on-treatment ECG Avoid use with CYP2D6 inhibitors^¶
Thiothixene	6 to 10	10 to 20	60	34	CYP1A2 and others	Given in 1 to 3 divided doses Oral bioavailability is variable; dose must be individualized based on patient response Tobacco smoking may decrease levels
Trifluoperazine	4 to 10	15 to 20	40	3 to 12 (parent drug) 22 (active metabolites)	CYP1A2 and other CYPs to active and inactive metabolites	Oral bioavailability is variable; dose must be individualized based on patient response Tobacco smoking may decrease levels

This table is intended for use in conjunction with UpToDate content on treatment of schizophrenia. Doses shown are total daily dose, oral administration, for maintenance treatment of schizophrenia in adult patients with normal kidney and liver function. Refer to UpToDate drug monographs for dose adjustments.
Antipsychotic medications are to be used with caution and at significantly reduced doses (eg, by 50% or more) in older adults, those who are medically ill or with a first episode of psychosis.
The dosing and other information provided in this table differs from dosing used in management of behavioral symptoms of dementia in older adults; in general, these medications are not recommended for that use. For additional information, refer to the relevant UpToDate clinical topics.
Although several first-generation antipsychotic medications are subject to drug interactions via CYP metabolism as listed above, they are not themselves important inhibitors or inducers of metabolism of other drugs (exception: thioridazine moderately inhibits CYP2D6).

CYP: cytochrome P450; ECG: electrocardiogram; IM: intramuscular (short-acting); IV: intravenous; LAI: long-acting injectable (eg, depot).

* More prominent adverse effects relative to other antipsychotics including orthostatic hypotension, sedation, QTc prolongation, anticholinergic effects, and pigmentary retinopathy (thioridazine). Refer to UpToDate topic on pharmacology of first-generation antipsychotic medications.

¶ Dose adjustment may be necessary if coadministered with medication(s) that alter drug metabolism (eg, CYP2D6 or 3A4). Lists of CYP2D6 and 3A4 inhibitors and inducers are available as separate tables in UpToDate; refer to the drug interactions program for specific interactions.

Data from: American Psychiatric Association. Practice Guideline for the Treatment of Patients with Schizophrenia, 3rd ed, American Psychiatric Association, 2021 and UpToDate Lexidrugs. Copyright © 1978-2024 Lexicomp, Inc. All Rights Reserved.

Reference:

Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209.

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First-generation antipsychotic medications for maintenance treatment of schizophrenia in adult patients: Oral dosing, pharmacokinetics, and selected characteristics