Thank you for your interest in CCO content. As a guest, please complete the following information fields. These data help ensure our continued delivery of impactful education.
Become a member (or login)? Member benefits include accreditation certificates, downloadable slides, and decision support tools.
Professor of Psychiatry and of Neurology
Departments of Psychiatry and of Neurology
Case Western University School of Medicine
Director, Neurological and Behavioral Outcomes Center
University Hospitals of Cleveland
Martha Sajatovic, MD, has disclosed that she has received research funds from Alkermes, Nuromate, and Otsuka; has received consulting fees from Alkermes, Health Analytics, Janssen, Myriad, and Otsuka.
Burden of Schizophrenia and Tardive Dyskinesia (TD) Is Extensive
Worldwide, schizophrenia is ranked in the top 20 causes of disability.1 The humanitarian and financial burden of schizophrenia also is extensive, with an estimated cost of more than $150 billion annually in the United States based on 2013 data.2 Schizophrenia typically has onset in early adulthood, and long-term or lifetime treatment often is required. A cornerstone of treatment in people with schizophrenia is the use of evidence-based antipsychotic medications. Although highly effective in treating the positive symptoms of schizophrenia for many individuals, persistent residual negative or cognitive symptoms and/or medication-related complications such as adverse events tend to be the rule rather than the exception. An important potential drug-related complication is the presence of tardive syndromes, defined as persistent abnormal involuntary movement disorders caused by sustained exposure to antipsychotic medications. TD, tardive dystonia, and tardive akathisia are the most common tardive syndromes the in clinical setting. Unfortunately, tardive syndromes may be permanent, even when antipsychotic medication is reduced or discontinued—often not a practical consideration for those with schizophrenia. TD can cause functional impairment and worsening of stigma, and it may contribute to social isolation and overall schizophrenia burden.
Recommendations for Managing TD Among Patients With Schizophrenia
The 2021 American Psychiatric Association (APA) practice guideline update on this topic—the first since 2004—reflects the advancements in pharmacologic and psychosocial treatments that have emerged over the past 15 years.3 It is important to note that the APA practice guidelines include 3 key categories of recommendations for healthcare professionals (HCPs): (1) assessment and determination of a treatment plan, (2) pharmacotherapy, and (3) psychosocial interventions.
A strength of the APA recommendations is that they are based on the overall body of evidence in systematic reviews of the scientific literature, formulated by panels of experts, and informed by input from relevant stakeholders. The pharmacotherapy recommendations section of the schizophrenia practice guidelines comprises 11 separate statements or recommendations based on the strength of the available evidence.
The first 3 pharmacotherapy recommendations (statements 4-6) are specific to the use of antipsychotic medication and support long-term or maintenance use of antipsychotic drugs for individuals who respond to standard therapies. Statements 7-10 provide guidance on the use of the antipsychotic clozapine, along with recommendations for the use of long-acting injectable antipsychotics. Reflective of both the relatively common occurrence of drug-related adverse events and the potential to add to schizophrenia burden, statements 11-14 specifically address the management of adverse events, including parkinsonian symptoms, akathisia, and TD. The guidelines recommend that patients who have moderate to severe or disabling TD associated with antipsychotic therapy be treated with a reversible inhibitor of the vesicular monoamine transporter 2 (VMAT2).
TD Assessment and Management Suggestions From the APA Guidelines
Ongoing evaluation for TD in patients receiving antipsychotic drugs is stressed in the guidelines, which note the importance of a comprehensive assessment that includes physical examination and the use of a structured evaluative tool such as the Abnormal Involuntary Movement Scale (AIMS) or the Dyskinesia Identification Syndrome: Condensed User Scale (DISCUS), which can help HCPs accurately identify TD, clarify a likely etiology within the differential diagnoses of movement syndromes, and inform subsequent treatment planning and monitoring.3 Although the guidelines note that VMAT2 inhibitors are recommended for moderate to severe TD symptoms, they do not specifically provide cutoff thresholds for when VMAT2 inhibitors should be administered. This is an acknowledgment that total scores on standardized scales can be associated with dramatically different levels of patient burden depending on various factors, including patient awareness of movements, types and locations of movements, and patient functional status. The guidelines note the importance of assessing for TD at every clinical visit and underscore the value of receiving input from family or support persons in complementing the patient’s experience/report.
The APA guidelines provide detailed information on 3 reversible VMAT2 inhibitors—deutetrabenazine, tetrabenazine, and valbenazine—with respect to available formulations, dosing, bioavailability, metabolism, special considerations for patients with renal or hepatic impairment, food effect, and common adverse events. HCPs may find the APA Pocket Guide to be particularly useful in providing a quick, targeted summary of the relative benefits and burdens of these 3 available agents.4 The guidelines note that deutetrabenazine or valbenazine is preferred over tetrabenazine because of a stronger evidence base with respect to benefit vs burden in supporting their use.3,4
The APA guidelines also note that various factors may influence HCP choice of a VMAT2 inhibitor.3,4 With respect to hepatic or renal function, the guidelines note that tetrabenazine and deutetrabenazine are contraindicated in individuals with hepatic impairment, whereas valbenazine is not recommended for use in individuals with severe renal impairment. It should be noted, however, that the prescribing information for valbenazine states that dose adjustments are not necessary for those with mild, moderate, or severe renal impairment, although dose reduction is recommended for those with moderate or severe hepatic impairment.5 The adverse events of treatment with VMAT2 inhibitors include sedation and, with tetrabenazine, extrapyramidal effects, akathisia, insomnia, anxiety, nausea, and falls. However, despite these caveats, the guidelines note that most patients with moderate to severe or disabling TD have a greater likelihood of experiencing the benefits of a VMAT2 inhibitor than experiencing harm or burden. In addition, patient preferences to reduce motor symptoms or impairment are likely to favor treatment.
In summary, the 2021 APA guideline recommendations on the use of VMAT2 inhibitors for disabling TD, specifically deutetrabenazine and valbenazine, reflect ongoing advances in care for the management of patients with schizophrenia.
Tell us about your knowledge and use of the APA practice guidelines. Do you refer to the guidelines when considering your treatment plan for patients with TD? Are there other guidelines on TD that you find useful? Does your approach to treating patients with TD differ based on the severity of symptoms?