New Hope for Patients With Tardive Dyskinesia

Stanley Caroff, M.D.

Tardive dyskinesia (TD) represents unfinished business in psychopharmacology. TD (involuntary and repetitive movements associated with chronic use of antipsychotics) became a major concern and the impetus driving new drug development shortly after the introduction of antipsychotics that block dopamine receptors.

Interest in TD waned in recent years because newer antipsychotics have a lower risk of TD, concern shifted to metabolic and cardiovascular side effects, and specific treatment for TD remains elusive.

Today, the need to review knowledge about TD is increasing because antipsychotics are more widely prescribed, many patients already have TD resulting from chronic treatment, and new research findings on genetics, pathophysiology, and novel drug treatments offer hope for developing a rational management strategy for TD (1).

When examining treatments for TD, it is important for you to consider the following questions:

• Does the treatment affect the natural course of TD?

• Does the treatment actively or passively reverse brain pathology underlying TD or simply mask the symptoms?

• How does the treatment fit in with ongoing psychopharmacological management?

Preventive measures are important for limiting the risk of TD. Clinicians should always confirm the indication for antipsychotics; use conservative doses, opting for low-risk agents; inform patients and caregivers of risk; and monitor for incipient signs of TD.

Once TD is detected, guidelines encompass a series of step-wise decision points (1). First, the diagnosis and treatment options should be discussed with patients and caregivers. The differential diagnosis of TD should be investigated, including neurological consultation if necessary. Contrasting a relatively mild case of TD within the context of a serious psychiatric condition may justify a period of close observation to determine the course of illness before specific interventions for TD are considered.

The next logical step in attempting to reduce symptoms of TD is to reexamine antipsychotic treatment. Although antipsychotic drug discontinuation was recommended in the past, up to 50 percent of patients experience worsening of TD initially, while up to 50 percent may show improvement over time (1). It is unclear how often and how long it might take for complete resolution of TD to occur after drug cessation, but patients with psychotic disorders incur a high risk of psychotic relapse.

If alternative treatments are available and dopamine-receptor blocking antipsychotics are not essential, they should be discontinued.

If you have a patient experiencing TD who is stable on an antipsychotic regimen you may want to consider gradual dose reduction with careful monitoring, although evidence is limited as to whether lowering the dose ameliorates TD symptoms. While TD may worsen in some patients it does not appear to progress in most patients, even with continued antipsychotic treatment. An alternative is to switch antipsychotics; potent first-generation antipsychotics suppress symptoms of TD in up to two-thirds of patients, although potentially limiting recovery from TD and exacerbating acute extrapyramidal symptoms.

After switching to less potent second-generation antipsychotics, most patients continue to experience a persistent or fluctuating course of TD. Among patients randomized to second-generation antipsychotics in a clinical trial, we found that one-third showed significant improvement in TD, while less than 10 percent showed significant worsening in TD (2). Clozapine has been shown to suppress TD, and should be considered in patients with treatment-resistant psychotic symptoms.

Dose reduction or switching antipsychotics risks destabilizing psychiatric status, so close follow-up is advisable. Existing data are inconclusive as to whether recovery rather than simply suppression occurs during antipsychotic treatment.

If anticholinergic drugs have been prescribed, you and your patient need to decide whether to continue the medication or gradually taper. Anticholinergic drugs worsen TD generally, such that improvement has been noted in two-thirds of patients withdrawn from these agents. However, anticholinergic drugs may have been prescribed for concurrent acute extrapyramidal symptoms or for tardive dystonia, which may worsen after anticholinergic withdrawal (1).

Once psychopharmacological treatment has been optimized, specific antidyskinetic drugs ought to be considered. If antipsychotics are discontinued, antidyskinetic drugs can serve as “a bridge to recovery”—suppressing symptoms of TD without dopamine-receptor blockade, while theoretically allowing TD to resolve. If antipsychotics are essential for treatment and have been optimized in suppressing psychosis and TD, any persistent TD symptoms may be further reduced by antidyskinetic drugs prescribed adjunctively.

Speculations on mechanisms underlying TD have generated investigations of numerous antidyskinetic agents, but none has received approval for TD. For example, increasing evidence showing the beneficial effects of specific cholinergic agonists on dyskinesias in animal models suggests that clinical trials of these drugs for TD may be worthwhile (3).

Observational studies have shown improvement in TD with tetrabenazine, which depletes presynaptic dopamine by inhibiting vesicular monoamine transporter-2 (VMAT-2). These findings prompted the development of two novel, highly selective VMAT-2 inhibitors that have proven to be effective and safe in reducing TD symptoms in pivotal trials and appear to have superior pharmacokinetic properties and tolerability compared with tetrabenazine (4,5).

The emergence of new and approved treatments for TD is likely to renew interest in TD by instilling a greater sense of therapeutic optimism and hope among patients, caregivers, and clinicians. ■