Tardive Dyskinesia and Extrapyramidal Symptoms in Schizophrenia

William Glazer, MD
William Glazer, MD
(Moderator)
President
Glazer Medical Solutions
Key West, Florida and Menemsha, Massachusetts



Antipsychotic medications that block dopamine receptor properties have the potential to produce acute or short-term reversible neurological side effects such as dystonia, tremor akathisia, and parkinsonism, collectively termed extrapyramidal symptoms (EPS). In addition, late occurring and potentially irreversible involuntary movement disorders such as tardive dyskinesia (TD) can also occur with these drugs. The risk of EPS and TD is greater with first generation antipsychotic (FGA) (or typical antipsychotic) agents than with second generation antipsychotic (SGA) (or atypical) agents.[1-3] Not surprisingly, patient Tom experienced an acute dystonic reaction in the emergency room after being administered an FGA agent intramuscularly.

Prior to the development of atypical antipsychotic agents, the treatment approach adopted for acutely psychotic patients like Tom had been the administration of a combination of an FGA medication and a benzodiazepine. The intent of combining both medications in the same syringe was to diminish the patient's exposure to high doses of the antipsychotic agent and, consequently, reduce the neurologic toxicity of the agent.[4] Because of the high risk of EPS and TD with the FGA agents, efforts were channeled into producing agents having a lower risk for these side effects, leading to the development of the SGA medications.

This article reviews the incidence, etiology, and management of EPS and TD in patents with schizophrenia treated with FGA and SGA agents and speculates on the future of these conditions.

Etiology and Clinical Expression of EPS

Antipsychotics work primarily by blocking dopamine neurotransmission in the brain. There are 4 dopamine pathways in the brain that play a role in the pathophysiology of schizophrenia as well as the therapeutic effects and side effects of antipsychotic agents.[5] Activity in each of them has a unique set of physical, cognitive, and psychological effects. Thus, blockade of dopamine in one pathway may be beneficial in controlling symptoms of schizophrenia, but dopamine blockade in another pathway may cause side effects.

EPS arises as a result of dopamine blockade in the nigrostriatal dopamine pathway, which is part of the extrapyramidal nervous system.[5] Blockade of dopamine neurotransmission in this pathway by medications, or by neurodegeneration as in Parkinson's disease, creates an imbalance between the inhibitory actions of dopamine and the excitatory actions of acetylcholine in the striatum. In the absence of the inhibitory action of dopamine, the excitatory actions cause movement disorders. Herein lies the rationale for the use of anticholinergic agents (or antiparkinsonian agents) for the treatment of movement disorders in schizophrenia.

Several movement disorders are associated with antipsychotic use. These include dystonia [muscular spasms, eg, of the neck (torticollis), eyes (oculogyric crisis), tongue, or jaw], parkinsonism (muscle stiffness, shuffling gait, or tremor), tics, and myoclonic jerks and twitches. These movement disorders are distinguished from one another based on the frequency and quality of the involuntary movements associated with each condition (Table 1).[6]

Table 1. Differentiating Involuntary Movements Associated with
Neuroleptic Therapy

Differentiating Involuntary Movements Associated with Neuroleptic Therapy
Adapted from Glazer W. TD Monitor. Multi Health Systems, Toronto, 1992.[6]

Akathisia, another movement disorder associated with antipsychotic medication use and thought to be related to dopamine receptor blockade, is characterized by an internal sense of motor restlessness. It is often described as an inability to resist the urge to move. The most common form of akathisia involves pacing and an inability to sit still. Akathisia is often very distressing and debilitating to the patient, reducing the patient's ability to perform everyday tasks. Severe akathisia, in addition, has been associated with an increased likelihood of medication nonadherence in schizophrenia.[7]

There is a direct relationship between the degree of dopamine blockade and the incidence of EPS, with greater blockade leading to higher incidence.[8] As the SGA agents block nigrostriatal dopamine receptors to a lesser degree than the FGA agents, the former are associated with a lower incidence of EPS.[9] The implications of EPS reduction touch virtually every domain of pathology in schizophrenia, including short- and long-term movement disorders, negative symptoms, noncompliance, relapse rate, cognitive dysfunction, and dysphoria.[10]

Decreasing Incidence of EPS from FGA to SGA Agents

Up to 60% of patients treated with FGA agents experience some form of EPS.[11,12] Meta-analyses indicate that all atypical agents are associated with a lower incidence of EPS than typical neuroleptics.[1,2] However, it is important to note that EPS can still occur with SGAs and that it may be dose related in some instances. When EPS does occur with the SGA medications, it often manifests as akathisia. Thus, clinicians must continue to monitor patients for EPS even with the SGA agents.

Future of EPS

Prompted in part by healthcare payer interest in reducing pharmaceutical costs, healthcare policy makers have revisited the use of FGA agents as first-line treatments. It is also likely that as the incidence of EPS has decreased considerably, since the introduction of the atypical antipsychotics, concerns about EPS with antipsychotic medications may have dwindled. This lessened vigilance toward EPS may have indirectly led to the renewed interest in the possible use of FGA agents. Images of patients with EPS have perhaps faded from the minds of many policy makers, the general public, and from newer clinicians, who may have less experience with EPS. Lastly, the results of a meta-analysis that evaluated whether the newer atypical antipsychotic drugs induce fewer EPS than low potency conventional antipsychotics could also have contributed to a return to the use of FGA medications. This meta-analysis had reported that "Optimum doses of low-potency conventional antipsychotics might not induce more EPS than new generation drugs."[13] However, the same meta-analysis also showed that the atypical drugs were more effective than the older, low potency drugs, regardless of dose. Thus, clinicians should keep in mind that lowering the dose of the typical antipsychotics might lead to a reduction in EPS but the lower dose might not be effective in controlling psychotic symptoms, which is the intent of antipsychotic treatment.

Table 2. Past, Present, and Future of Extrapyramidal Symptoms

Past, Present, and Future of Extrapyramidal Symptoms

It is hoped that the continued search for newer compounds with antipsychotic properties will culminate in the development of antipsychotic agents that act via different mechanisms, other than the dopamine system, and which may eradicate the EPS issue entirely (Table 2). Meanwhile, the SGA agents offer a viable alternative for patients like Tom.

The Relationship between EPS and TD

Tom illustrates another concern about using FGA agents. TD usually appears after prolonged use of antipsychotic medications and appears to be related to the total lifetime dose of medication. It is a mostly irreversible neurological disorder with a symptom spectrum that can include tongue protrusion, grimacing, rapid eye blinking, lip smacking, pursing or puckering, rapid movement of the arms or legs, and other involuntary movements of the head, face, neck and tongue muscles.[14]

George Crane, in 1972, suggested that TD is more likely to occur in patients who experience early EPS.[15] Shortly thereafter, Klawans proposed that the pathogenesis of TD appeared to be related to chronic striatal dopaminergic receptor site blockade, and the pathophysiology of TD appeared to be related to the resultant denervation hypersensitivity. He hypothesized that in patients who develop EPS, the brain compensates for the basic action of antipsychotics (blocking dopamine) by producing more dopamine receptors. This upregulation of dopamine receptors in areas of the brain connected to movement results in overactive signals, producing excessive movements, typically involving the face (lips, tongue, and jaw), extremities, and trunk.[16]

A number of prospective studies have now provided direct support for the relationship between EPS and TD.[17-20] A study that investigated the incidence of and risk factors for TD in elderly individuals beginning treatment with antipsychotic drugs concluded that the presence of EPS early in treatment was associated with increased TD vulnerability (Figure 1).[17] In this study, the incidence of neuroleptic-induced dyskinesia was 31% after 43 weeks of cumulative neuroleptic treatment.

Figure 1. Extrapyramidal symptoms (EPS) early in the treatment course predicts tardive dyskinesia (TD) occurrence in the elderly

Extrapyramidal symptoms (EPS) early in the treatment course predicts tardive dyskinesia (TD) occurrence in the elderly
Reprinted with permission from Saltz BL, et al. JAMA. 1991;266:2402-2406.[17]

Neuroleptic-naive patients were monitored for the occurrence of EPS and TD upon initiation of neuroleptic therapy at 3-month intervals for periods ranging from 3 to 119 weeks. Vertical bars indicate 95% confidence intervals.

As EPS early in the treatment course is prognostic for TD, clinicians should evaluate antipsychotic agents for their EPS liability before prescribing. Thus, if Tom were to be continued on an FGA, he would be considered at high risk for TD because he developed an acute EPS picture.

Clinical Commentary

As EPS is a risk factor for TD, clinicians might think that suppression of EPS with anticholinergic agents would reduce the risk of TD. This, however, is not true. Balancing cholinergic effects with anticholinergic agents (eg, antiparkinsonian agents) does not reduce the risk of TD. Moreover, current evidence indicates that antiparkinsonian agents themselves are a risk factor for TD. Clinicians who practice prophylactic anticholinergic use should be aware of this risk. Moreover, current evidence indicates that chronic use of anticholinergic agents has a negative effect on cognitive function that may impair daily functioning.[21]

TD: Then and Now

Our current understanding of TD has evolved since the first documented use of the atypical antipsychotic agent chlorpromazine about a half century ago.[22] During the era of the FGA agents, the etiology of TD was unknown (Table 3). Although the etiology of TD still remains elusive during the present era of SGA agents, genetic studies have identified several gene polymorphisms—manganese superoxide dismutase gene,[23,24] dopamine D3 receptor gene Ser9Gly,[25] and dopamine and serotonin receptor and transporter gene[26]—to be associated with TD.

Table 3. Past and Present Understanding of Tardive Dyskinesia

Past and Present Understanding of Tardive Dyskinesia

The incidence of TD has been estimated at 5% per year with FGA medications.[27] This rate is cumulative and after 20 years of treatment with FGA agents, it is estimated that almost 70% of patients will develop TD.[28] As SGA agents are associated with lower rates of EPS compared to FGA agents, the expectation is that SGA agents cause less TD than FGA agents. The results of a study that compared the cumulative incidence of definitive TD among high-risk patients (> 45 years) who had borderline TD at baseline found that the use of SGA agents was associated with a significantly lower risk of developing definitive TD compared with FGA agents (Figure 2).[29] However, it should be noted that although patients are less likely to develop TD with atypical antipsychotics, the condition remains a concern with all SGA agents.[9]

Figure 2. Cumulative incidence of definitive tardive dyskinesia (TD) in patients > 45 years with borderline dyskinesia treated with typical versus atypical antipsychotics

Cumulative incidence of definitive tardive dyskinesia (TD) in patients > 45 years with borderline dyskinesia treated with typical versus atypical antipsychotics
Reprinted with permission from Dolder CR, Jeste DV. Biol Psychiatry. 2003;53:1142-1145.[29]

Patients treated with atypical antipsychotics had a significantly reduced risk of developing definitive TD compared with patients prescribed typical antipsychotics [P = .0005].

At present there is a more sophisticated understanding of the risk factors for TD. In the past, females were believed to be at greater risk than males in developing TD. More recent analyses suggest that gender may not be a risk factor for TD.[30] Aging is a critical risk factor for developing TD; the incidence of TD is 5-6 times greater in persons > 45 years compared with younger adults.[1,17] Race also appears to be an important risk factor: African Americans have a 2-fold higher risk than Caucasians.[30] Other risk factors that have been implicated include right-handedness, treatment with anticholinergics, alcohol abuse, mood disturbance, decreased cognitive functioning, development of EPS early in the course of antipsychotic therapy, and the presence of diabetes and other chronic medical illnesses.[9,30]

With the introduction of the SGA agents, there has been a change in the monitoring and managing practices for TD. Since TD is still a concern with SGA agents, the recommendation is that all patients taking antipsychotic agents (FGA or SGA agents) should be monitored weekly for TD and other EPS adverse effects during acute treatment and for at least 2 weeks after the dose is stabilized. Then, patients who are receiving conventional antipsychotics should be assessed for TD at least every 6 months, while patients taking atypical agents should be assessed annually.[2] As a change in medication can induce EPS and TD, Tom should be closely monitored for at least 2 weeks after his second discharge from the hospital. Once his condition stabilizes, and if he does not develop EPS or TD, further monitoring for EPS may be performed annually. Furthermore, as global and time-dependent Abnormal Involuntary Movement Scale (AIMS) scores have been shown to be significant predictors of TD risk,[31] assessment of AIMS throughout the course of antipsychotic treatment would be judicious.

The general principle of managing patients with TD taking FGA agents is to lower the dose to a minimum effective dose, thereby reducing the side effect. But this practice exposes patients to the risk of psychosis relapse; patients in whom the course of illness may already be more severe and more refractory than those without TD. A recent study that compared the 3-year course of schizophrenia between patients with TD and those without TD found that patients with TD had significantly worse Positive And Negative Syndrome Scale (PANSS) total score, negative symptoms, positive symptoms, general psychopathology, were less likely to experience symptom remission, had more severe EPS, and poorer level of functioning compared to their counterparts without TD.[32]

Our treatment approach to TD has remained empirical over the years and there is currently no specific treatment for TD. Given the more severe course of illness, specialized interventions are needed in patients with TD. A preliminary study that evaluated bilateral deep brain stimulation of the globus pallidus as a treatment for severe TD has reported a 50% mean reduction in the EPS Rating Scale score when stimulation was applied compared with the absence of stimulation.[33] Bilateral globus pallidus deep brain stimulation may thus offer a much-needed new treatment option for disabling TD.

TD in the Year 2020

The most optimistic future for patients with schizophrenia will be one where antipsychotic treatment will address only the psychotic symptoms and not cause any adverse effects. Although we are far from achieving this ideal, new diagnostic procedures under development such as imaging [eg, functional magnetic resonance imaging (fMRI) and positron emission tomography (PET)],[34,35] genetic testing,[36] and biochemical testing (eg, plasma homovanillic acid),[37] hold the promise of the development of precise medications tailored for each individual patient's neurobiological genotype. For example, in Tom's case, the antipsychotic treatment will treat specifically his hallucinations, delusions, and agitation, but will not produce EPS. If this can be achieved then TD will be eradicated. However, movement disorders associated with the psychotic condition per se may still be observable.

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