Thioridazine (Mellaril)

Class

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

Mechanism

Primarily blocks dopamine D₂ receptors; also has significant anticholinergic, antihistaminic, and alpha-adrenergic blocking activity contributing to its sedative and cardiovascular effects

FDA-Approved Use

Schizophrenia

Off-Label Use

Limited due to safety concerns; rarely used off-label

Formulation

Oral tablet

Titration

Usually initiated at 50–100 mg/day in divided doses, titrated cautiously based on response and tolerability

Dose Range

50–800 mg/day in divided doses

Kinetics

Extensively metabolized hepatically (CYP2D6 substrate); active metabolites; long half-life (~6–39 hours); risk of accumulation in poor metabolizers

Common AEs

Sedation, dry mouth, constipation, blurred vision, extrapyramidal symptoms, weight gain

Serious/Rare AEs

QTc prolongation, torsades de pointes, sudden cardiac death, neuroleptic malignant syndrome (NMS), and retinal pigmentary deposits with long-term high-dose us

Monitoring

Baseline and periodic ECGs recommended due to risk of QTc prolongation. Monitor electrolytes, especially potassium and magnesium, in high-risk patients.

Black Box Warning

Contraindicated in patients with congenital long QT syndrome or a history of cardiac arrhythmias. Risk of torsades de pointes and sudden death; should only be used when other antipsychotics are ineffective or not tolerated. Increased mortality in elderly patients with dementia-related psychosis.

Considerations

Thioridazine is generally avoided in elderly patients, individuals with cardiovascular disease, or those with cognitive impairment due to its high risk of QT prolongation, arrhythmia, and anticholinergic burden. Safer alternatives are strongly preferred in these populations.