Perphenazine

TRILAFON

What it isMid-potency first-generation D2 antagonist; schizophrenia and severe nausea.

Why this oneIn CATIE it matched several atypicals for effectiveness while causing less metabolic burden than olanzapine.

What limits itCYP2D6 variation changes exposure; extrapyramidal symptoms and tardive dyskinesia remain the major liabilities.

FDA-approved for

BOXED WARNING Increased mortality in elderly patients with dementia-related psychosis treated with antipsychotics.

FDA dosing	Population	Start	Target	Max
Schizophrenia (outpatient, moderately disturbed)	Adult	4-8 mg TID	min effective dose
Schizophrenia (hospitalized)	Adult	8-16 mg BID-QID		64 mg/day
Severe nausea/vomiting	Adult	8-16 mg/day divided		24 mg/day

Renal Undefined

Hepatic Contraindicated in liver damage

Use lowest effective dose; reduce dose or add antiparkinsonian agent for extrapyramidal symptoms
Doses >24 mg/day reserved for hospitalized or closely observed patients
Initiate lower doses in elderly (higher plasma levels per dose)

Comatose or greatly obtunded patients
Patients receiving large doses of CNS depressants (barbiturates, alcohol, narcotics, analgesics, antihistamines)
Existing blood dyscrasias or bone marrow depression
Liver damage
Suspected or established subcortical brain damage (risk of hyperthermic reaction >104°F)

Elderly dementia-related psychosis: increased mortality (boxed)
Extrapyramidal reactions and tardive dyskinesia (more common with piperazine group)
Neuroleptic malignant syndrome
Hyperthermic reaction in subcortical brain damage

Pregnancy Use only if benefit justifies risk; third-trimester exposure risks neonatal extrapyramidal/withdrawal symptoms.

Lactation Safe use during nursing not established.

⚠ BOXED WARNING

Cost, est. cash$5–$150/month

Generic entry1987

Therapeutic safety burden2 / 4

Overdose danger2 / 4

Weight-gain liability1 / 4

Sedation liability1 / 4

QT / Torsades2 / 4

Direct muscarinic antagonism1 / 4

Embryofetal risk2 / 4

Legacy pregnancy categoryC

Defining liabilityMetabolic effects, extrapyramidal symptoms/tardive dyskinesia and agent-specific QT or orthostatic risk.

CYP2D6 substrate