Tardive syndromes (TDS), including tardive dyskinesia, are a serious side effect in patients taking neuroleptic (antipsychotic) medications. Frequently, these syndromes occur in individuals taking neuroleptics for schizophrenia, schizoaffective disorder, or bipolar disorder, but there has been no consensus to date on how clinicians should manage these conditions.
Some reports claim that the newer atypical, or second-generation, antipsychotics cause fewer tardive symptoms, but that evidence has been less uniform, and the finding has been a matter of debate. What is clear is that the use of these second-generation antipsychotics is skyrocketing, especially in children and nursing home residents. In the first quarter of 2013 alone, aripiprazole (Abilify) was the number 1 selling drug, and duloxetine (Cymbalta) ranked number 3, with sales at approximately $1.5 million and $1.3 million, respectively, according to data from US National Sales.
Now, the Guideline Development Subcommittee of the AAN has published the first official evidence-based review of TDS in the July 30 issue of Neurology. For the review, Roongroj Bhidayasiri, MD — associate professor of neurology and director of the Chulalongkorn Parkinson's Disease and Related Disorders Center of Excellence at Chulalongkorn University Hospital in Bangkok, Thailand — and colleagues conducted an extensive evaluation of all studies relating to the treatment of TDS published between 1966 and 2011.
Patients who develop TDS typically have at least three months of neuroleptic exposure and experience abnormal involuntary movements that are not explained by other existing medical conditions. “Reports of the prevalence of tardive syndromes vary, partly depending on the study populations and methodology; however, it is estimated that 30 percent of outpatients with schizophrenia treated with neuroleptics [have TDS], ” Dr. Bhidayasiri said.
In an interview with Neurology Today, Dr. Bhidayasiri discussed the most important conclusions of the AAN's review, as well as the limitations of current data on TDS.
WHY DID THE AAN DECIDE TO CONDUCT THIS EVIDENCE-BASED REVIEW OF TARDIVE SYNDROMES?
There is currently no official guideline or consensus on the management of tardive syndromes. The current evidence for the management of TDS is based on a vast amount of literature starting from 1966 and covering different interventions used to treat tardive syndromes. These studies utilized different outcome measures and there is a lack of uniformity in the reporting of the results. Therefore, it is difficult for clinicians to draw a conclusion on the efficacy of each intervention. But by utilizing AAN classification of evidence for therapeutics, we are able to rate the evidence for each intervention and make recommendations that we hope will benefit those practicing physicians who frequently encounter patients with tardive syndromes.
WHAT ARE THE MOST IMPORTANT RECOMMENDATIONS FROM THE PAPER? HOW CAN THESE FINDINGS BE APPLIED IN CLINICAL PRACTICE?
Despite the limitations of this evidence due to the lack of uniform data and measures, the most important messages of this study include the finding that clonazepam and ginkgo biloba are probably effective in decreasing tardive syndromes (Level B). The studies were short-term for both agents, and because the ginkgo biloba evidence is restricted to inpatients with schizophrenia, both agents should be considered for short-term treatment, with the additional limitation considered for ginkgo biloba.
We found that amantadine and tetrabenazine have less evidence of efficacy (Level C), so they may be considered to treat tardive syndromes only for the short term. We do believe that both amantadine and tetrabenazine are promising agents in the treatment of tardive syndromes, but more studies are needed to confirm their efficacy.
We also found evidence against the use of diltiazem (Level B) and galantamine and eicosapentaenoic acid (Level C), so they should not be considered as treatment for TDS.
The treatment of tardive syndromes needs to be individualized and a holistic approach is necessary in order to have comprehensive management of this syndrome.
WHAT FACTORS MIGHT INCREASE OR DECREASE A PATIENT'S LIKELIHOOD OF DEVELOPING TARDIVE SYNDROMES?
Regardless of age or background, people who take antipsychotics are at risk of developing tardive syndromes. However, the risk is greatest for people who are 55 years or older, women (especially those who have gone through menopause), people with a history of alcohol or substance abuse, and those with HIV/AIDS.
Second-generation antipsychotics are believed to have a lower propensity to cause tardive dyskinesia than first-generation antipsychotics. However, this evidence is still conflicting and not uniform. Therefore, a definite conclusion cannot be made on the lesser risk with second-generation antipsychotics.
Since tardive syndromes are potential long-term complications associated with the use of antipsychotics, clinicians should always exercise their judgment if these agents are indicated in patients.
ARE THERE ANY STRATEGIES FOR PREVENTION OF TARDIVE SYNDROMES?
The important point in the management of tardive syndromes is that they are iatrogenic disorders. Therefore, one should avoid using antipsychotics if possible, and treating physicians should always balance the risks and benefits associated with neuroleptic use in each individual patient. Patients should be forewarned of the risk of tardive syndromes before being placed on any neuroleptic drug.
WHAT FUTURE RESEARCH IS NECESSARY FOR MANAGING TDS?
From the therapeutic perspective, well-designed, double-masked, randomized controlled trials with specific inclusion criteria are needed to determine which interventions are most effective for reducing the symptoms of tardive syndromes. Furthermore, separation of studies of certain forms of tardive syndromes may be necessary since not all tardive syndromes are treated in the same way.
QUESTIONS ADDRESSED IN THE AAN'S EVIDENCE-BASED REVIEW OF TARDIVE SYNDROMES
In order to provide comprehensive, evidence-based recommendations for the management of tardive syndromes (TDS), the AAN's Guideline Development Subcommittee set out to answer the following five questions in their recent paper published in the July 30 issue of Neurology:
- Is withdrawal of dopamine receptor blocking agents (DRBAs) an effective TDS treatment?
- There were insufficient data to support or refute TDS treatment by DRBA withdrawal (Level U).
- Does switching from typical to atypical DRBAs reduce TDS symptoms?
- There were insufficient data to support or refute TDS treatment by changing to atypical antipsychotics (Level U).
- What is the efficacy of pharmacologic agents in treating TDS?
- Clonazepam and ginkgo biloba are probably effective in decreasing tardive syndromes (Level B).
- Diltiazem probably does not reduce tardive dyskinesia and should not be considered as treatment (Level B).
- Tetrabenazine may be considered in treating TDS (Level C) and amantadine with neuroleptics may be considered for short-term use (Level C).
- Eicosapentaenoic acid (EPA) and galantamine are possibly ineffective in treating TDS and might not be considered (Level C).
- Data are insufficient to support or refute the use of acetazolamide, thiamine, thiopropazate, molindone, sulpride, fluperlapine, flupenthixol, reserpine, neuroleptics, α-methyldopa, bromocriptine, anticholinergic drugs, vitamin B6, selegiline, yi-gan san, baclofen, levetiracetam, buspirone, nifedipine, biperiden discontinuation, or electroconvulsive therapy in treating TDS (Level U).
- Do patients with TDS benefit from chemodenervation with botulinum toxin?
- Data are insufficient to support or refute chemodenervation with botulinum toxin use to treat TDS symptoms (Level U).
- Do patients with TDS benefit from surgical therapy?
- Data are insufficient to support or refute pallidal deep brain stimulation use in treating TDS (Level U).
•. Bhidayasiri R, Fahn S, Weiner W, et al. Evidence-based guideline: Treatment of tardive syndromes. Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013; 81:463–469; E-pub 2013 July 30.