Continuing Education Activity

Similar to other first-generation or typical antipsychotics, thioridazine is a medication used to treat schizophrenia. Other indications for use include other psychotic disorders, depressive disorders, pediatric behavioral disorders, and geriatric psychoneurotic manifestations. This activity outlines the indications, mechanism of action, administration methods, significant adverse effects, contraindications, toxicity, and monitoring, of thioridazine, so providers can direct patient therapy where they are indicated as part of the interprofessional team.

Objectives:

• Identify the mechanism of action of thioridazine.
• Review the approved and off-label indications for thioridazine.
• Summarize the contraindications and adverse event profile of thioridazine.
• Explain the importance of improving care coordination among the interprofessional team to enhance care delivery for patients who can benefit from therapy with thioridazine.

Indications

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

It is not a first-line therapeutic choice for schizophrenia due to its adverse event profile. The brand-name version of this medication was withdrawn by its manufacturer from the market worldwide in 2005 because of adverse effects, notably cardiac arrhythmias., although generic versions remain available.[5]

Thioridazine combined with other antibiotics has been shown to be effective against drug-resistant tuberculosis, although there is no trial data to support its use for this indication.[6]

Mechanism of Action

Typical antipsychotics, including thioridazine, work to treat psychosis by blocking dopamine (DA) receptors. These medications effectively treat 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. 

The drug also exhibits activity at muscarinic receptors (most notably the M1 receptor), which is most likely the source of its anticholinergic effects (e.g., dry mouth, constipation, etc.), the alpha 1A adrenergic receptor (which may explain its association with orthostatic hypotension), the H1 histamine receptor (probably accounting for much of its sedating effect), and the hERG gene, which is likely responsible for its cardiotoxicity.[7]

Administration

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 refractory schizophrenia, dosing 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.

Prescribers must be aware of the risk of inducing dose-dependent QTc prolongation, hence the suggestion to start with a lower dose and increase slowly. Thioridazine also comes in liquid form at 30 mg/mL and 100 mg/mL. 

Adverse Effects

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.[8]

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.[9][10]

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 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.

Contraindications

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 also avoid this medication.

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.[11]

Caution is advised in pregnant patients during the third trimester, although teratogenicity is not expected. For breastfeeding, it is recommended to use an alternative agent as there is no data in humans to assess the risk in breast milk.

Monitoring

Patients require monitoring for medication side effects during treatment, and it is often necessary to screen patients before treatment to obtain baseline results. Since thioridazine can cause significant ECG (electrocardiogram) changes and arrhythmias, it is important to get a baseline ECG and potassium level. Furthermore, an additional ECG is recommended for any change in dose and periodically after that. Another possible side effect of thioridazine is leucopenia, and thus routine complete blood counts are recommended over the course of the initial weeks.[12]

Opthomalogic exams should be implemented as well, as thioridazine can also cause irreversible retinal pigmentation over time. Studies are equivocal regarding the use of thioridazine in pregnancy, so it may be advisable to get a pregnancy test before administering the drug. Thioridazine must be cautioned for use in the third trimester of pregnancy, as it may be associated with a risk of neonatal withdrawal symptoms and extrapyramidal side effects. Furthermore, thioridazine has a narrow therapeutic index, which means it is necessary to carefully monitor each patient for adverse side effects.[13]

In patients with pre-existing or a history of leukopenia or neutropenia, frequent CBC with differential is recommended during the initial phase of treatment.[14]

Toxicity

Thioridazine is a low potency typical antipsychotic, like chlorpromazine. Unlike higher potency antipsychotics, thioridazine has a lower incidence of extrapyramidal side effects. However, lower potency antipsychotics are more likely to be associated with antimuscarinic, antihistaminic, and antiadrenergic side effects. Thioridazine is metabolized through the liver with a half-life of 24 hours and is excreted in the urine, bile, and feces. The hepatic cytochrome P450 CYP2D6 metabolism of thioridazine is important because it assists in identifying different drug-drug interactions. Thus, it is necessary to evaluate patients and identify medications that may increase or decrease thioridazine levels.[15]

Enhancing Healthcare Team Outcomes

The use of thioridazine has declined significantly because of the availability of safer and more effective atypical antipsychotics. When it is used, the entire interprofessional healthcare team needs to be actively involved in therapy. In the current medical environment, its use is almost exclusively limited to refractory schizophrenia that has failed to respond to other therapeutic agents. However, all clinicians (MDs, DOs, NPs, PAs) who prescribe thioridazine should first consult with a psychiatrist for a better option. If the drug is prescribed, its adverse effects must be closely monitored. This is where nursing staff and pharmacists can be of particular benefit. The pharmacist can also check for drug-drug interactions and report these to the prescriber if present. Nurses can serve as a contact point to the prescriber for other interprofessional healthcare team members and patients, offer patient counseling regarding medication administration and side effects, and document any concerns in the patient's medical record.

Further, the patient requires education about the side effects and potential drug interactions. Although a rare but serious side effect of thioridazine is agranulocytosis, each patient should be evaluated for abnormal white blood cell counts before use because this medication may exacerbate this problem. If all members of the interprofessional healthcare team collaborate and share information about the patient during thioridazine therapy, the patient is more apt to derive therapeutic benefit leading to improved outcomes with fewer adverse effects. [Level 5]