Similar to other first-generation, or typical, antipsychotics, thioridazine is a medication FDA approved to treat schizophrenia and schizophrenia spectrum disorders. Other off-label uses include depression with psychotic features, pediatric behavioral disorders, and geriatric psychoneurotic manifestations. [1][2][3][4]

Typical antipsychotics, including thioridazine, work to treat psychosis by blocking dopamine (DA) receptors. These medications are effective in treating the positive symptoms of schizophrenia, such as hallucinations, delusions, and disorganization. Positive symptoms are believed to manifest as a result of increased levels of dopamine in the mesolimbic pathway. More specifically, thioridazine blocks DA-2 receptors in the mesolimbic pathway, diminishing positive symptoms. Thioridazine is classified as a low potency first-generation antipsychotic, and as such is relatively sedating. Thioridazine is a substrate of the hepatic enzyme CYP450 2D6 and is also an inhibitor of the same enzyme. 

Thioridazine is an oral medication taken in tablet form. The tablets come in either 10 mg, 15 mg, 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg. For schizophrenia, recommendations are to initiate thioridazine at 50 mg to 100 mg three times per day and gradually increase the dose as indicated, to a maximum of 800 mg per day. Of import is the risk of inducing dose-dependent QTc prolongation, and so it is suggested to start low and dose slow. Thioridazine also comes in liquid form at 30 mg/mL and 100 mg/mL. 

Extrapyramidal Side Effects (EPS)

Similar to other typical antipsychotics, thioridazine is associated with a risk of developing EPS. Because it is a low potency antipsychotic, however, the development of EPS occurs less frequently than with high potency antipsychotics. Extrapyramidal side effects include symptoms of dystonia, parkinsonism, and tardive dyskinesia. Dystonic reactions are muscle spasms that may occur early on and involve the eyes, tongue, or neck. Dystonic reactions precipitate in response to the decreased ratio of dopamine to acetylcholine, and thus are treatable by normalizing the ratio with anticholinergic medications, such as benztropine or diphenhydramine. It is essential to monitor patients for dystonia to avoid problems breathing, such as laryngospasm, which may require intubation. Parkinsonism results from DA antagonism and can manifest as resting tremor, cogwheel rigidity, postural instability, and shuffling gait. Parkinsonism is also treatable with benztropine or diphenhydramine, as well as the NMDA antagonist amantadine. And lastly, typical antipsychotics are associated with an even higher risk of tardive dyskinesia (TD) than atypical antipsychotics. TD is the result of the chronic administration of antipsychotics. The abnormal choreoathetoid movements seen in patients with tardive dyskinesia can affect the head, tongue, or face. Tardive dyskinesia is a serious adverse effect as it is not only embarrassing and uncomfortable for the patient, but it is mostly irreversible in nature. If a patient begins to develop tardive dyskinesia, the best treatment is to stop the antipsychotic medication and substitute thioridazine for an atypical antipsychotic with less risk.[5][6][7]

Neuroleptic Malignant Syndrome (NMS) 

NMS is another serious side effect of all antipsychotics and occurs more frequently with typical antipsychotics. This adverse effect may occur suddenly. The provider should monitor for unstable vital signs, such as tachycardia, fever, muscle rigidity, elevated white blood cell count, and creatinine phosphokinase. If the patient develops NMS, the clinician should immediately initiate hydration and supportive therapy. The antipsychotic should be discontinued as well. If necessary, further management is possible with dantrolene and bromocriptine.

ECG Changes

Thioridazine is associated with prolonged QTc intervals, which may have serious or even fatal consequences, such as Torsades de pointes. The recommendation is that patients with known prolonged QTc or arrhythmias avoid thioridazine. Before starting this medication, it would be wise to order an ECG and monitor for QTc prolongation or other ECG changes during treatment.

Other Side Effects

The development of pigmentary retinopathy is a unique adverse manifestation associated with thioridazine, and not with other antipsychotics. Patients may have nonspecific symptoms while taking thioridazine, such as dry mouth, dry eyes, sedation, weight gain, dizziness, erectile dysfunction, pruritus, photosensitivity, and constipation. Other rare and more unique side effects of thioridazine include irreversible retinal pigmentation, poikilothermia, and agranulocytosis.

There is a black-box warning for dementia-related psychosis because it may increase the risk of death secondary to cerebrovascular events in the elderly. Thioridazine is associated with a prolonged QT interval. Thus patients with long QT syndrome, QT intervals prolonged to more than 450, or taking concomitant medications known to prolong the QT interval should avoid thioridazine. Also, patients with known heart arrhythmias or hypotensive or hypertensive heart disease should avoid this medication, as well.

Because of drug-drug interactions, the clinician should be aware of the patient's medication profile. Thioridazine is metabolized by the hepatic enzyme CYP450 2D6. Medications that inhibit CYP450 2D6 should be used with caution when prescribing thioridazine. Medications that may affect thioridazine levels include but are not limited to fluoxetine, paroxetine, duloxetine, fluvoxamine, propranolol, citalopram, and pindolol.

Another rare, but serious, side effect of thioridazine is agranulocytosis. Each patient should be evaluated for abnormal white blood cell counts pre and post administration of thioridazine. [8]