Thioridazine

Has been shown to prolong the QTc interval in a dose-related manner; this may potentially cause Torsades de Pointes and sudden death. Therefore, thioridazine should be reserved for patients with schizophrenia who have failed to respond to adequate levels of other antipsychotic drugs. Risk of torsades de pointes and/or sudden death may be higher with in patients with bradycardia, hypokalemia, the presence of congenital prolongation of the QTc interval, reduced activity of cytochrome P450 (CYP-450) 2D6, or concomitant use of other drugs that prolong the QTc interval, inhibit CYP2D6, or interfere with the clearance of thioridazine. Consider a cardiac evaluation (including Holter monitoring) in patients who experience symptoms that may be associated with Torsades de Pointes (dizziness, palpitations, syncope). Discontinue therapy in patients with a QTc >500 msec.

May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. Relative to other neuroleptics, thioridazine has a high potency of cholinergic blockade (Richelson 1999).

Leukopenia, neutropenia, and/or agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count 3.

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of pneumonia (ie, Alzheimer disease) (Maddalena, 2004).

May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia. Risk of dystonia (and possibly other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Lehman 2004]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.

Use associated with increased prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.

May be associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability. Following recovery from NMS, reintroduction of drug therapy should be carefully considered; if an antipsychotic agent is resumed, monitor closely for NMS.

May cause pigmentary retinopathy, characterized by diminution of visual acuity, brownish coloring of vision, and impairment of night vision, in patients exceeding recommended doses. Periodic eye examinations are recommended in patients receiving 600 mg/day or more (Oshika, 1995).

May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).

Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects (Kwok, 2005; Martinez, 2002). Disease-related concerns:

Use with caution in patients with severe cardiovascular disease. Do not initiate therapy in patients with a QTc interval >450 msec.

Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death. The APA recommends giving preference to second generation antipsychotics over first generation antipsychotics in elderly patients with dementia-related psychosis due to a potentially greater risk of harm relative to second generation antipsychotics (APA [Reus 2016]). Thioridazine is not approved for the treatment of dementia-related psychosis.

Use with caution in patients with narrow-angle glaucoma; condition may be exacerbated by cholinergic blockade (APA [Lehman, 2004]).

Use with caution in patients with hepatic impairment.

Use with caution in patients with Parkinson disease; antipsychotics may aggravate motor disturbances (APA [Lehman 2004]; APA [Reus 2016]).

Use with caution in patients at risk of seizures; first-generation antipsychotics may lower the seizure threshold (APA [Lehman, 2004]). Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Avoid use; potent anticholinergic agent with potential to cause QT-interval prolongation. Other warnings/precautions:

When discontinuing antipsychotic therapy, the American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid physical withdrawal symptoms, including anorexia, anxiety, diaphoresis, diarrhea, dizziness, dyskinesia, headache, myalgia, nausea, paresthesia, restlessness, tremulousness, and vomiting (APA [Lehman 2004]; CPA [Addington 2005]; Lambert 2007; WFSBP [Hasan 2012]). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013). Additional factors such as duration of antipsychotic exposure, the indication for use, medication half-life, and risk for relapse should be considered. In schizophrenia, there is no reliable indicator to differentiate the minority who will not from the majority who will relapse with drug discontinuation. However, studies in which the medication of well-stabilized patients were discontinued indicate that 75% of patients relapse within 6 to 24 months. Indefinite maintenance antipsychotic medication is generally recommended, and especially for patients who have had multiple prior episodes or 2 episodes within 5 years (APA [Lehman 2004]).