The primacy of neuroleptic-Induced D2 receptor hypersensitivity in tardive dyskinesia
Central Michigan University
During the past 50 years, little research has been devoted to examining the neurological underpinnings of tardive dyskinesia. Currently, the majority of available evidence suggests that neuroleptic-induced D2 receptor hypersensitivity in the nigrostriatal pathway best accounts for the disorder. Although the D2 hypersensitivity hypothesis may have several weaknesses, competing theories focusing on GABAergic and cholinergic transmission have little empirical support. Conversely, functional reserve may play an important moderating factor in determining who will be susceptible to the disorder. Ultimately, more research on neuroleptic side effects is needed in order to improve treatment outcomes and facilitate informed consent.
The primacy of neuroleptic-induced D2 receptor hypersensitivity in tardive dyskinesia
Tardive dyskinesia refers to a delayed onset movement disorder, generally secondary to prolonged neuroleptic (antipsychotic) medication use. Among people taking conventional (typical, first-generation) neuroleptics, tardive dyskinesia tends to occur at a rate of 5% per year, with rates plateauing after approximately 5-8 years; unfortunately, the elderly are particularly at risk, with initial annual rates of 25-30% (Correll, Leucht, & Kane, 2004; Nasrallah, 2006; Sachdev, 2000). Symptoms include rapid or jerking movements, facial spasms, dystonia, and stereotyped movements. Oral and facial muscles are particularly affected, and as symptoms increase the tongue may writhe and thrust about outside of the mouth, commonly referred to as “fly catching;” fingers may appear to move uncontrollably in a manner similar to “piano playing” (Sachdev, 2000, p. 356). Often, symptoms are irreversible. The stigma of tardive dyskinesia lowers life satisfaction and creates difficulties in reintegrating into society (Correll et al., 2004; Margolese, Chouinard, Kolivakis, Beauclair, & Miller, 2005).
Evidently, the rate of tardive dyskinesia is lower among those using atypical (second-generation) neuroleptics, but many patients still take conventional neuroleptics to treat their schizophrenia symptoms. Surprisingly little research attention has been devoted to tardive dyskinesia over the past 50 years, and the precise mechanisms of the disorder are not perfectly understood. Currently, the neurological underpinnings of tardive dyskinesia are best explained by the dopamine receptor hypersensitivity hypothesis.
Specifically, neuroleptic medications treat positive symptoms of schizophrenia, primarily by blocking dopamine receptors. Conventional neuroleptics, in particular, are known to have a high affinity for postsynaptic dopamine receptors in the nigrostriatal pathway. The long-term use of these medications is thought to cause postsynaptic D2 receptor hypersensitivity. Three lines of evidence support this hypothesis. Foremost, between-group comparisons show higher base rates of tardive dyskinesia among those treated with conventional neuroleptics, as opposed to atypical neuroleptics. Secondly, within-subject data showing medication-related symptom changes are also consistent with this hypothesis. Finally, additional support from genetic polymorphism studies in encouraging, though not yet conclusive. Alternative theories of tardive dyskinesia are relatively unsupported; however, decreased functional reserve may play a key moderating role. Although additional research is needed, current evidence implicates neuroleptic-induced D2 receptor hypersensitivity as the central cause of tardive dyskinesia.
Atypical vs. Conventional Neuroleptics
In comparison to atypical neuroleptics, conventional neuroleptics have a greater affinity for the D2 dopamine receptor, which accounts for the higher base rate of tardive dyskinesia for conventional neuroleptics. Strange (2001) summarized existing findings on neuroleptic drug affinities for dopamine binding sites. Conventional neuroleptics have a much lower affinity for the D2 receptor than do atypical neuroleptics, whereas atypicals have a greater affinity for the D3 and D4 receptors. Importantly, extrapyramidal symptoms are significantly more likely to occur when occupancy of D2 receptors exceeds 80% (Remington, 2007, p 134). Conventional neuroleptics, such as haloperidol, have been shown to occupy approximately 85% of D2 receptors in the striatum, whereas atypical neuroleptics have been shown to generally occupy 35-75% of these D2 receptors (Margolese et al., 2005; Remington, 2007; Strange, 2001). Given the role of the striatum in controlling movement, if D2 receptor occupancy leads to hypersensitivity, then conventional neuroleptics should be associated with higher rates of tardive dyskinesia than atypical neuroleptics.
In fact, the results of clinical trials do reliably show higher base rates of tardive dyskinesia among those taking conventional neuroleptics over those taking atypicals. Studies consistently show that among adults taking conventional neuroleptics, approximately 5% annually will develop tardive dyskinesia during the first 5-8 years of treatment, with rates subsequently leveling off (Correll et al., 2004; Nasrallah, 2006; Remington, 2007; Sachdev, 2000). Among elderly patients, the rate of tardive dyskinesia is approximately 25-30% annually among those taking conventional neuroleptics (Sachdev, 2000; Correll et al., 2004; Nasrallah, 2006; Remington, 2007). Alternatively, atypical neuroleptics are associated with much lower rates of tardive dyskinesia. Because most atypical neuroleptics are relatively new, long-term data on annual tardive dyskinesia rates are not yet available. However, Correll et al. (2004) systematically reviewed the results of 11 existing studies of at least 1-year in duration, reporting on the frequency of tardive dyskinesia among those in clinical trials for atypicals. Across studies, the average rate of tardive dyskinesia among adults was approximately 1%, with a higher rate of 5% among elderly participants; rates among those taking haloperidol were similar to those cited in past research (Correll et al., 2004, p. 418). Thus, among adults and elderly adults, conventional neuroleptics appear to be approximately five times more likely than atypical neuroleptics to cause tardive dyskinesia. Future research examining longer-term differences would be helpful for expanding on this finding.
Additionally, to determine the generalizability and replicability of findings from clinical trials, it is also important to examine data gathered in the naturalistic setting. Studies examining medication side effects require large samples for adequate power, due to the relatively low base rate of conditions, such as tardive dyskinesia, limiting the number of available studies. In one study (de Leon, 2007), a group of inpatients who had only taken atypicals (n = 48) were compared to a group who had taken conventional neuroleptics for fewer than five years (n = 94). Surprisingly, in both groups, 19% of patients were diagnosed with tardive dyskinesia, and severe cases were more common among those taking atypicals. However, the study is limited in that those in the conventional neuroleptic group were allowed to have had a previous history of atypical neuroleptics use. Additionally, those in the atypical neuroleptic group may have been on the medication longer than those in the conventional neuroleptic group, which could confound the results. This unexpected finding is limited due to the small sample size.
In contrast, a study involving 8,500 schizophrenia outpatients found results remarkably similar to those in the clinical trials (Diederik, van Harten, Slooff, Belger, & van Os, 2005). Although the final results of the 3-year study have not yet been published, results after 6-months indicate that 0.9% of those on atypicals had tardive dyskinesia, compared to 3.8% of those on conventional neuroleptics. These results indicate that those on conventional neuroleptics were 4.2 times more likely to have tardive dyskinesia than those on atypicals, concurring with the approximate risk statistics from clinical trials. Given that in the naturalistic setting patients are not randomly assigned to treatments, it is likely that some discrepant results will occur, particularly when sample size is small (de Leon, 2007). The study conducted by Diederik et al. (2005) was much larger and reaffirms the results of clinical trials documenting that conventional neuroleptics increase the risk of tardive dyskinesia over that of atypicals. These results support the neuroleptic-induced D2 receptor hypersensitivity hypothesis because conventional neuroleptics are associated with greater D2 affinity and greater risk of tardive dyskinesia.
Although the between-group results are convincing, additional evidence for the D2 receptor hypersensitivity hypothesis also comes from within-subject data examining the dose-response relationship between neuroleptic medication and tardive dyskinesia. Nasrallah (2006) notes that it can be difficult to establish the dose-response rate between neuroleptics and tardive dyskinesia for several reasons: symptoms of tardive dyskinesia wax and wane, ceiling effects may occur due to overly high doses, some patients are presumably immune to developing tardive dyskinesia, and demographic characteristics associated with risk for the disorder may mask results. Thus, it is all the more impressive that several recent longitudinal studies have found a relationship between dose of conventional neuroleptic and probability of developing tardive dyskinesia (for a review, see Sachdev, 2000, p. 361). Furthermore, although tardive dyskinesia can occasionally develop after brief exposure to neuroleptics, rates of the disorder do increase steadily during the first 5-8 years of treatment (Correll et al., 2004; Nasrallah, 2006; Remington, 2007; Sachdev, 2000). Sachdev (2000) concluded that, “taken together, the total neuroleptic load can be considered to be a risk factor” for tardive dyskinesia (p. 361). These results are consistent with the D2 receptor hypersensitivity hypothesis.
Stronger support comes from studies examining how symptoms of tardive dyskinesia increase or decrease in response to changes in treatment. If tardive dyskinesia is caused by D2 receptor hypersensitivity, then symptoms might be expected to temporarily decrease by increasing the neuroleptic medication dosage, thereby blocking more of the hypersensitive receptors. This type of suppression effect has been noted in research studies and case reports (Ananth, 1982; Bressan, Jones, & Pilowski, 2004; Nasrallah, 2006). Similarly, medication changes that tend to increase dopamine transmission—withdrawing neuroleptics, administering L-dopa, and administering amphetamines—tend to exacerbate dyskinetic symptoms, at least in the short-run (Ananth, 1982; Sachdev, 2000; Bressan et al., 2004; Nasrallah, 2006). Thus, the functional relationship between changes in medications, dopamine transmission, and modification of short-term symptoms of tardive dyskinesia can be explained by the D2 receptor hypersensitivity hypothesis.
Although increasing conventional neuroleptic dose may temporarily suppress symptoms of tardive dyskinesia, such an approach is not recommended for long-term management of dyskinetic symptoms (Sachdev, 2000). As expected according to the D2 receptor hypersensitivity hypothesis, and as supported by research on the dose-response relationship, increasing conventional neuroleptic dosage increases the risk and severity of tardive dyskinesia in the long run. Similarly, though withdrawal of conventional neuroleptics may temporarily increase dyskinetic symptoms, such a strategy stabilizes or decreases dyskinetic symptoms in the long-run, presumably because hypersensitivity of the D2 receptors is allowed to dwindle. If fact, switching patients from conventional neuroleptics to atypicals (with lower D2 affinities) has also been shown to decrease symptoms of tardive dyskinesia in some patients; whether this decrease in dyskinetic symptoms is due to merely to the withdrawal of conventional neuroleptics or due to some restorative factor of atypicals is not presently known (Margolese et al., 2005). Thus, both the short-term and long-term impact of medication changes on tardive dyskinesia symptoms can be explained by the D2 receptor hypersensitivity hypothesis.
According to a diathesis model, genetic factors may cause some people to be more susceptible to developing tardive dyskinesia than others, which is consistent with the finding that some patients develop tardive dyskinesia readily, whereas others appear to be relatively immune. Genetic polymorphisms coding for dopamine receptors may explain differences in susceptibility to tardive dyskinesia. Genetic polymorphisms for dopamine receptors may impact dopamine binding affinity, which would potentially make some patients on neuroleptic medications more susceptible to tardive dyskinesia than others. Several studies have shown that variations in the dopamine receptor D2 gene result in differential rates of tardive dyskinesia among patients (Chen, Wei, Koong, & Hsiao, 1997; Liou et al. 2006). However, other studies have found inconsistent results (Kaiser, Tremblay, Klufmoller, Roots, Brockmoller, 2002; Lattuada, Cavallero, Serretti, Lorenzi, & Smeraldi, 2004).
Additional studies have examined genetic polymorphisms for other dopamine receptor genes, but results have similarly been inconsistent (Bakker, van Harten, & van Os, 2006; Liao et al., 2001; Rietschel et al., 2000). Bakker et al. (2006) have suggested that a publication bias may be present; for example, large studies tend to be published regardless of the study results, and small studies tend to only be published when results are statistically significant. Many of the larger studies have shown no important impact of dopamine receptor gene polymorphisms, whereas the significant findings in smaller studies may represent alpha errors. Alternatively, these genetic polymorphisms may interact with demographic characteristics, such as ethnicity or gender, as results tend to differ across these groups (Sachdev, 2000; Liao et al., 2001; Bakker, van Harten, & van Os, 2006; Nasrallah, 2006).
In addition, Kaiser et al. (2002) added that, “it is typical of many genetic polymorphisms, that their medical impact alone is mostly only moderate, but may become important in specific gene–gene or gene–environment interactions” (p. 703). Thus, the inconsistent results may be due to unmeasured genetic and environmental moderators, such as other genetic polymorphisms, environmental toxins, duration of treatment, or type of medication used. Given the earlier findings that conventional and atypical neuroleptics differ in terms of their D2, D3, and D4 binding site affinities, it may be important for future researchers to examine the interactions between genetic polymorphisms for these binding sites, rather than merely looking at main effects. For example, genetic polymorphisms coding for higher binding affinity at the D2 receptor may only function to increase susceptibility to tardive dyskinesia when present in combination with polymorphisms for D3 and D4 that decrease their binding site affinities. Thus, while several initial studies provide results in support of the D2 receptor hypersensitivity hypothesis, more research is needed, using large sample sizes, with potential moderating variables measured, in order to resolve discrepant results. In summary, the D2 receptor hypersensitivity hypothesis is supported both by studies examining group differences in tardive dyskinesia resulting from conventional or atypical neuroleptic medication as well as by studies examining treatment effects within-subject, but more genetic polymorphism research is needed.
Although the D2 receptor hypersensitivity hypothesis is both long-standing and well-supported, it also has several weaknesses, which suggest that alternative or complimentary theories may be needed to account for the neurophysiological underpinnings of tardive dyskinesia. One of the central problems with the D2 receptor hypersensitivity hypothesis is that although tardive dyskinesia overwhelmingly occurs in patients treated with dopamine antagonists, cases have also been reported in patients who were taking medications that do not directly impact dopamine. For example, several patients who were not on neuroleptics reported dyskinetic symptoms in reaction to antihistamines, diphenhydramine, cough syrup, ephedrine, doxylamine, alcohol, acetaminophen, and various other drugs (Ananth, 1982; Sachdev, 2000). Further, tardive dyskinesia occasionally occurs spontaneously in unmedicated people, for unknown reasons (Sachdev, 2000). Due to the difficulty of diagnosing tardive dyskinesia and previous lack of diagnostic criteria, some of these case reports may be erroneous; furthermore, several of these medications may impact the D2 receptors in the striatum indirectly. Yet, given these weaknesses, several alternatives to the D2 receptor hypersensitivity hypothesis should be considered. The most popular alternative theories involve GABA and acetylcholine.
One alternative theory is that degeneration in GABA-generating neurons plays a significant role in tardive dyskinesia. Several studies involving animal models of tardive dyskinesia have shown that long-term administration of neuroleptic medication leads to decreased activity of GAD (a rate-limiting enzyme involved in GABA production) in the subthalamic nucleus, globus pallidus, and substantia nigra (Ananth, 1982; Margolese et al., 2005; Sachdev, 2000). Although these findings are consistent with the hypothesis that degeneration of the GABAergic nigrostriatal pathway leads to tardive dyskinesia, results may not generalize to humans. Although GABA agonists have been successful in preventing and treating tardive dyskinesia in rats, they have not proven to be consistently effective in humans (Ananth, 1982; Margolese et al., 2005).
A second alternative theory posits that acetylcholine plays an important role in tardive dyskinesia. Specifically, in autopsies of patients treated with neuroleptics who developed tardive dyskinesia, Miller and Chouinard (1993) noted degeneration of the striatal cholinergic neurons. Based on this, choline agonists have occasionally been used to treat tardive dyskinesia in humans and in animal models, and professionals have been advised to avoid prescribing anti-cholinergics to patients with tardive dyskinesia (Ananth, 1982; Nasrallah, 2006). However, a recent meta-analysis involving 11 available controlled trials examining the effects of choline precursors and agonists on tardive dyskinesia concluded that these agents serve no benefit (Tammenmaa, Sailas, McGrath, Soares-Weiser, & Wahlbeck, 2004). Nasrallah (2006) argued that professionals might observe a relationship between anti-cholinergics and worsening dyskinetic symptoms merely due to an illusory correlation. Often, anti-cholinergics are prescribed when initial extrapyramidal symptoms present, and later symptoms progress into tardive dyskinesia, though it is merely coincidental that aggravated symptoms occur after prescribing the anti-cholinergics. Thus, although there are potential limitations of the D2 receptor hypersensitivity hypothesis, competing theories are generally supported more by anecdotal observations than by empirical evidence.
Although D2 receptor hypersensitivity is hypothesized to explain the primary neurological basis for tardive dyskinesia, decreased functional reserve also plays an important complimentary role as a moderating factor. That is, although decreased functional reserve may not be a necessary component for development of tardive dyskinesia, it does help to explain differences in susceptibility. Mental retardation and traumatic head injuries noth increase the likelihood of developing tardive dyskinesia (Nasrallah, 2006). Furthermore, older adults are much more likely to develop tardive dyskinesia, perhaps due to higher levels of oxidative stress, which is also associated with tardive dyskinesia (Margolese et al., 2005; Sachdev, 2000). Enlarged ventricles, usually a result of neurodegeneration, are also related to increased risk (Sachdev, 2000). Finally, alcohol abuse also increases the likelihood of one developing tardive dyskinesia (Nasrallah, 2006). Although most of these factors only play a small role in increasing susceptibility for developing tardive dyskinesia (Ananth, 1982), they overwhelmingly support the complementary role of decreased functional reserve in explaining outcomes.
Although tardive dyskinesia has not received the research attention it deserves, existing studies indicate that neuroleptic-induced D2 receptor hypersensitivity in the nigrostriatal pathway plays a primary role in the development of tardive dyskinesia. Alternative theories lack strong empirical evidence, though the D2 receptor hypersensitivity hypothesis too has noted weaknesses. Decreased functional reserve also plays an important role in exacerbating symptoms. However, beyond this, a comprehensive, integrative theory of tardive dyskinesia is lacking, and more research is needed, particularly in the area of genetic polymorphisms for dopamine receptors. Ultimately, this line of research can be used to prevent or treat additional cases of tardive dyskinesia, and may help guide the development of new drugs with fewer side effects. An understanding of neuroleptic side effects is also important for facilitating the informed consent process and guiding treatment decisions (Sachdev, 2000).
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Firts Published December 2007
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