Fluphenazine (Prolixin)

Class

First-generation (typical) antipsychotic; high-potency phenothiazine

Mechanism

Potent dopamine D₂ receptor antagonist; also antagonizes histamine H₁, muscarinic, and alpha-1 adrenergic receptors, contributing to its sedating, anticholinergic, and hypotensive side effects.

FDA-Approved Use

Schizophrenia and other psychotic disorders

Off-Label Use

Bipolar disorder (particularly manic episodes), augmentation in treatment-resistant psychosis

Formulation

Oral tablets, oral solution, short-acting intramuscular (IM), and long-acting IM decanoate injection

Titration

For oral formulations, start at 2.5–5 mg/day in divided doses (BID–TID), titrated gradually based on clinical response and tolerability. For the decanoate IM form, the typical initial dose is 12.5–25 mg every 2–4 weeks, with oral overlap recommended for the first 1–2 weeks.

Dose Range

Oral: 2.5–20 mg/day; Decanoate IM: 12.5–50 mg every 2–4 weeks

Kinetics

Metabolized hepatically via CYP2D6. The decanoate formulation has a prolonged half-life (up to 7–10 days), reaching steady state over several weeks.

Common AEs

Extrapyramidal symptoms including parkinsonism, akathisia, and dystonia are common. Sedation, dry mouth, constipation, blurred vision, and orthostatic hypotension may also occur.

Serious/Rare AEs

Tardive dyskinesia, neuroleptic malignant syndrome (NMS), QTc prolongation, hyperprolactinemia, seizure threshold reduction, and hepatotoxicity have been reported

Monitoring

Extrapyramidal symptoms should be assessed at baseline and regularly (e.g., every 3–6 months) using the AIMS scale. Tardive dyskinesia screening is recommended every 6–12 months for low-risk individuals and every 3–6 months in high-risk populations such as the elderly or those on long-term therapy. Metabolic parameters including weight, BMI, blood pressure, fasting glucose, and lipid profile should be obtained at baseline and at least annually. ECG is recommended at baseline in patients with cardiac risk factors or electrolyte abnormalities and should be repeated periodically if clinically indicated.

Black Box Warning

Increased mortality in elderly patients with dementia-related psychosis.

Considerations

Use with caution in patients with Parkinson’s disease (PD), traumatic brain injury (TBI), or dementia due to heightened sensitivity to extrapyramidal symptoms, sedation, and cognitive dulling. Long-acting injectable formulations may improve adherence in individuals with chronic psychotic illness but require careful monitoring for delayed-onset motor and metabolic side effects.