Persistent Tardive Dyskinesia Research Articles

Diagnostic and Treatment Fundamentals for Tardive Dyskinesia.

Tardive dyskinesia (TD) consists of involuntary movements of the tongue, lips, face, trunk, and extremities that occur in patients treated long-term with dopamine antagonist medications. TD can be associated with significant functional impairment and be socially stigmatizing. TD, once established, has proved to be often irreversible and remains a significant treatment issue. An accurate and early diagnosis of TD is crucial because the risk of permanence increases over time. Clinicians should be educated on which patients are most at risk for TD and conduct assessments through clinical examination or through the use of a structured evaluative tool such as the Abnormal Involuntary Movement Scale (AIMS). Patients and caregivers need to be educated about the risks of and alternatives to antipsychotic medication and early signs of TD. New treatment approaches to persistent TD are available and approved by the US Food and Drug Administration: the vesicular monoamine transporter-2 (VMAT2) inhibitors, deutetrabenazine and valbenazine. When treatment is initiated, a baseline assessment should be obtained by clinicians using the AIMS and follow-up assessments should be done on a regular basis. In this educational activity, Drs Correll and Citrome offer a review of the diagnostic and treatment fundamentals for TD.

Amisulpride withdrawal dyskinesia: a case report

BackgroundThe effects of antipsychotic drug withdrawal have been inadequately studied. Case reports have described dyskinesia occurring in patients with several antipsychotics withdrawn, but studies on amisulpride withdrawal dyskinesia are lacking.Case presentationA 63-year-old man, who was diagnosed with schizophrenia at age 49, received amisulpride treatment since age 62. The dosage of amisulpride was reduced from 200 to 50 mg/day because of occurrence of akathisia during one admission. Severe withdrawal dyskinesia, mixed with dystonia and akathisia, was noted immediately after the dosage reduction. The abnormal involuntary movement showed improvement 2 weeks later when the dosage was increased to 100 mg/day.ConclusionsWithdrawal dyskinesia and other abnormal involuntary movements could be noted in a patient with reduction of amisulpride dosage or sudden termination. Withdrawal dyskinesia may subsequently lead to persistent tardive dyskinesia. Therefore, withdrawal-emergent dyskinesia should be promptly identified, and appropriate medical interventions should be given early.

Comparing the risk of tardive dyskinesia in older adults with first-generation and second-generation antipsychotics: a systematic review and meta-analysis.

The advent of second-generation antipsychotics (SGAs) in the 1990s brought optimism that neuroleptic-induced tardive dyskinesia (TD) may become relegated to history. Whether or not this is the case remains inconclusive, and this review aims to compare the risk of TD in older adults treated with first-generation antipsychotics (FGAs) versus SGAs. Relevant papers were sourced via a range of electronic databases, with a date range from 1957 to January 2015. Included studies used both a validated rating scale and research diagnostic criteria to report on the prevalence or incidence of TD in older adults exposed to antipsychotic medications. For FGAs, the prevalence estimate was 53% (95% confidence interval [CI] [39.0, 68.4]) for mild TD and 38% (95% CI [25.9, 50.3]) for probable TD. Incidence estimates for probable TD with FGAs were 23% (95% CI [15.3, 30.6]) at 1 year, 42% (95% CI [24.8, 58.4]) at 2 years and 57% (95% CI [45.3, 69.1]) at 3 years. For SGAs, the incidence estimates at 1 year were 7% (95% CI [4.4, 10.2]) for probable TD and 3% (95% CI [1.5, 4.2]) for persistent TD. The risk of probable TD is more than three times lower in older adults receiving SGAs in comparison with FGAs after 1 year of treatment (23% vs 7%). The risk of persistent TD at 1 year with SGAs is particularly low. Evidence is lacking in regard to the longer-term risk of TD with SGAs, although the rates associated with the prolonged use of FGAs are high. Caution is therefore still required, particularly with the protracted use of both FGAs and SGAs.

Incidence of tardive dyskinesia: a comparison of long-acting injectable and oral paliperidone clinical trial databases.

BackgroundTo assess the tardive dyskinesia (TD) rate in studies of once-monthly long-acting injectable (LAI) paliperidone palmitate (PP) and once-daily oral paliperidone extended release (Pali ER).MethodsCompleted schizophrenia and bipolar studies for PP and Pali ER (≥ 6 month duration with retrievable patient-level data) were included in this post hoc analysis. Schooler–Kane research criteria were applied using Abnormal Involuntary Movement Scale (AIMS) scores to categorise probable (qualifying AIMS scores persisting for ≥ 3 months) and persistent TD (score persisting ≥ 6 months). Spontaneously reported TD adverse events (AEs) were also summarised. Impact of exposure duration on dyskinesia (defined as AIMS total score ≥ 3) was assessed by summarising the monthly dyskinesia rate.ResultsIn the schizophrenia studies, TD rates for PP (four studies, N = 1689) vs. Pali ER (five studies, N = 2054), were: spontaneously reported AE, 0.18% (PP) vs. 0.10% (Pali ER); probable TD, 0.12% (PP) vs. 0.19% (Pali ER) and persistent TD, 0.12% (PP) vs. 0.05% (Pali ER). In the only bipolar study identified [Pali ER (N = 614)], TD rate was zero (spontaneously reported AE reporting, probable and persistent TD assessments). Dyskinesia rate was higher within the first month of treatment with both PP (13.1%) and Pali ER (11.7%) and steadily decreased over time (months 6–7: PP: 5.4%; Pali ER: 6.4%). Mean exposure: PP, 279.6 days; Pali ER, 187.2 days.ConclusionsRisk of TD with paliperidone was low (< 0.2%), regardless of the formulation (oral or LAI), in this clinical trial dataset. Longer cumulative exposure does not appear to increase the risk of dyskinesias.

Incidence of tardive dyskinesia in older adult patients treated with olanzapine or conventional antipsychotics.

The risk of persistent tardive dyskinesia (TD) was compared in patients with acute psychosis or agitation aged 55 years or older who were treated with olanzapine (OLZ) or conventional antipsychotic (CNV) drug therapy. Patients without TD were randomized to treatment with OLZ (2.5-20 mg/d; n = 150) or CNV (dosed per label; n = 143). Following a 6-week drug tapering/initiation period, patients without TD were treated with OLZ or CNV for up to 1 year. The a priori defined primary outcome end point was persistent TD defined as Abnormal Involuntary Movement Scale (AIMS) scores = 2 on at least 2 items or ≥3 on at least 1 item (items 1-7) lasting at least for 1 month (Criterion A). Post hoc analyses assessed persistent TD meeting the criterion of moderate severity defined as AIMS score ≥3 on at least 1 item persisting for 1 month (Criterion B) and probable TD defined as elevated AIMS scores (Criterion A or B) not persisting for 1 month. Treatment groups were compared using Kaplan-Meier curve with log-rank exact test. On average, patients were 78 years of age; the predominant diagnosis was dementia (76.7% in the OLZ group and 82.5% in the CNV group). Approximately, 40.6% of patients in the CNV group received haloperidol. No significant difference in time to developing persistent TD was observed during treatment with OLZ or CNV (cumulative incidence: OLZ, 2.5% [95% confidence interval [95% CI]: 0.5-7.0]; CNV, 5.5% [95% CI: 2.1-11.6], P = .193). The exposure-adjusted event rates per 100 person-years were not significantly different between treatment groups: OLZ (2.7) and CNV (6.3; ratio: 0.420; 95% CI: 0.068-1.969). Post hoc analyses revealed a significantly lower risk of at least moderately severe persistent TD persisting for 1 month (P = .012) and probable TD not persisting for 1 month (Criterion A, P = .030; Criterion B, P = .048) in OLZ-treated patients. For those patients without significant extrapyramidal symptoms at baseline, significantly more patients in the CNV treatment group developed treatment-emergent parkinsonism than for patients in the OLZ treatment group (CNV: 70%, 35 of 50 patients; OLZ 44%, 25 of 57 patients; P = .011). No significant difference between the groups was observed for treatment-emergent akathisia (CNV: 6%, 7 of 117 patients; OLZ: 10%, 13 of 130 patients; P = .351). The cumulative incidence of persistent TD was low and the risk of persistent TD did not differ significantly among predominantly older adult patients having dementia with acute psychosis or agitation treated with OLZ or CNV.

Electroconvulsive Therapy for a Patient With Persistent Tardive Dyskinesia

Tardive dyskinesia (TD) is a movement disorder that presents with abnormal, involuntary, and irregular choreoathetoid movements involving mouth, tongue, face, trunk, or extremities after prolonged use of dopamine receptor-blocking agents. Currently, there is still a lack of effective treatment for it. Here, we report a female patient with paranoid schizophrenia, who has had persistent TD for 8 years. After electroconvulsive therapy (ECT) was performed, both of her psychotic symptoms and dyskinetic movements were improved. The efficacy and potential clinical variables of ECT in the treatment of TD were reviewed.

Does Tardive Dysmentia Really Exist?

Tardive dysmentia has been described as the behavioral equivalent of tardive dyskinesia in patients with schizophrenia. Its association with tardive dyskinesia and psychopathology has been controversial. The authors assessed 123 inpatients with chronic schizophrenia for presence of tardive dysmentia symptoms/signs. Psychopathology and tardive dyskinesia were also assessed. Of the group, 24 patients (19.5%) had at least one tardive dysmentia symptom/sign, whereas only 1 patient (0.8%) fulfilled the syndromal criteria for tardive dysmentia. Those with tardive dysmentia had higher psychopathology scores, higher Abnormal Involuntary Movement Scale total scores, higher number of women and family psychiatric illness, and higher rates of persistent tardive dyskinesia. Tardive dysmentia symptoms/signs are frequently seen in chronic schizophrenia, but the complete syndrome may be rare.

Analysis of genetic variations in the dopamine D1 receptor (DRD1) gene and antipsychotics-induced tardive dyskinesia in schizophrenia

Dyskinesia is a kind of abnormal involuntary movement disorder that increases with age. The pathogenesis of dyskinesia may result from divergent changes in dopamine D1 receptors (DRD1) and dopamine D2 receptors (DRD2) in the brain while aging. Tardive dyskinesia (TD), a kind of dyskinesia, may develop after long-term antipsychotic treatment. Because the prevalence of TD also steadily increased with age, TD has been suggested to be the consequence of an imbalance between DRD1 and DRD2. We supposed that patients who develop TD may have genetic variants of DRD1 that cause the excitatory effects of DRD1 overwhelming the attenuated inhibitory effects of DRD2 after antipsychotic treatment. In the present study, schizophrenic inpatients receiving long-term antipsychotic treatment were first assessed using the Abnormal Involuntary Movement Scale (AIMS), and only patients who were either free of any abnormal involuntary movements (non-TD group, AIMS =0) or who showed persistent TD (TD group) were enrolled. Finally, 382 patients were recruited (TD=220, non-TD=162) and three single nucleus polymorphisms (SNPs; rs5326, rs4532 and rs265975) of DRD1 were genotyped for each subject. Genotype frequency (%; AA/AG/GG) of rs4532 (TD: non-TD) was 61.4/35.8/2.8: 74.2/24.5/1.3. After genetic analyses, genotype GG showed significant association with TD (if OR=2.0, power (%)=98.5; if OR=1.5, power (%)=63.7; P=0.033). Haplotype frequency (%) CGC of rs5326-rs4532-rs265975 (TD: non-TD) was 19.0:13.7; and after haplotype-based analyses, haplotype CGC also showed significant association with TD (OR=1.4, permutation P=0.027). Our results indicate that the genotypic variants of DRD1 might play a role in the susceptibility of TD. Further replication in other countries or other populations is highly expected.

Tardive Dyskinesia and the 3-Year Course of Schizophrenia

The objective of this study was to compare the 3-year course of schizophrenia between persons with tardive dyskinesia (TD) and persons without TD on multiple outcome measures. Data were drawn from a large, prospective, naturalistic study of persons treated for schizophrenia-spectrum disorders (DSM-IV criteria) in the United States, conducted between July 1997 and September 2003. Treatment outcomes were assessed at enrollment and at 12, 24, and 36 months postenrollment using measures of symptoms, functioning, productivity, activity, and quality of life. Participants who had TD at enrollment (fulfilling Schooler-Kane criteria, N = 637) were compared with those who did not (N = 1538) on clinical and functional measures at enrollment and across the 3 years of follow-up. Additional analyses examined those with persistent TD compared to those without persistent TD. With adjustment for known correlates of TD, participants with TD compared to those without TD had significantly more severe psychopathology, were less likely to experience symptom remission, had more severe extrapyramidal side effects, and had lower levels of quality of life and functioning, lower productivity, and fewer activities (all p < .001) across the 3-year follow-up. Findings were essentially unchanged when the subgroup of participants with persistent TD (at enrollment and at 1 year) was examined. These results indicate that, in the long-term treatment of schizophrenia, persons with TD have a significantly more severe and more refractory course of illness than those without TD, suggesting poorer prognosis and the need for specialized interventions.

Analysis of genetic variations in the RGS9 gene and antipsychotic‐induced tardive dyskinesia in schizophrenia

Some patients treated chronically with antipsychotics develop tardive dyskinesia (TD), an abnormal involuntary movement disorder. Typical antipsychotics block D(2) dopamine receptors (D(2)DR) and produce D(2)DR supersensitivity. On contrary, regulators of G-protein signaling (RGS) can enhance the signal termination of G-protein-coupled D(2)DR. Besides, after prolonged inhibition of dopaminergic transmission, dopaminergic agonists induced severe dyskinesia only in RGS9 knock-out mice but not in normal mice. Therefore, variety in the human RGS9 gene may be related to susceptibility to TD. In this study, schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale twice over a 3-month interval. Only patients in whom abnormal involuntary movements were absent (non-TD group) and those who showed persistent TD (TD group) were enrolled. There were 407 patients in the study sample (TD = 252; non-TD = 155) and seven single nucleus polymorphisms (SNPs) in the RGS9 gene were genotyped for each subject. Genotype and allelic distributions of SNPs did not differ between the TD and non-TD groups in this study, with the exception that a weak trend of allelic association was seen with rs4790953 (P = 0.0399). In the haplotype analysis, a significant association of the AGG haplotype (rs8077696-rs8070231-rs2292593) of the RGS9 gene was found (permutation P = 0.007), and this is worthy of replication and further study.

Association of Serotonin 2A Receptor and Lack of Association of CYP1A2 Gene Polymorphism with Tardive Dyskinesia in a Turkish Population

The aim of this study was to investigate the possible association of serotonin 2A receptor gene (HTR2A) -1438 G/A polymorphism and CYP1A2 gene 163C/A polymorphism with tardive dyskinesia (TD) in a Turkish population. A total of 47 patients with persistent TD, 80 patients who were consistently without TD, and 100 healthy controls were included in this study. The polymorphic regions of -1438 G/A polymorphism of HTR2A receptor gene (rs6311) and 163C/A of CYP1A2 (rs762551) gene were amplified using polymerase chain reaction (PCR), followed by digestion with restriction enzymes MspI and Bsp1201. Genotype and allele frequencies were calculated by the chi(2)-test. Crude and adjusted odds ratios (ORs) were estimated, and 95% confidence intervals (CIs) were computed by multivariate logistic regression analysis. The genotype and allele frequencies of HTR2A and CYP1A2 gene were similar in schizophrenia with TD, schizophrenia without TD, and healthy controls. The logistic regression analysis showed that cumulative exposure to antipsychotic drugs for every year (p = 0.003; OR = 1.15; CI = 1.07-1.23), and AA genotype of HTR2A gene (p = 0.0258; OR = 4.34; CI = 1.19-15.81) are risk factors for TD. The same logistic regression model showed no association between CYP1A2 polymorphism and TD. The results of the present study seem to indicate that HTR2A gene polymorphism influences the tendency to express TD following prolonged antipsychotic drug exposure in Turkish schizophrenia patients.

Botulinum toxin as a treatment for tardive dyskinesia

Two older female patients with a history of psychotic depression were treated with a combination of an antipsychotic and an antidepressant. Both developed persistent tardive dyskinesia with severe tongue protrusion. Botulinum toxin was injected into the genioglossal area and the embarrassing tongue protrusion practically disappeared. Both patients chose to continue taking botulinum toxin.

Can Medication-Free Research Ever Be Ethical in Older People With Psychotic Disorders?

Can Medication-Free Research Ever Be Ethical in Older People With Psychotic Disorders?

Negative association between Catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and persistent tardive dyskinesia in schizophrenia

Chronic administration of typical antipsychotic agents, which mainly act on the dopamine receptors, implicates a role of dopamine system on the susceptibility of tardive dyskinesia (TD). In the present study, the association between a functional Val158Met polymorphism of Catechol-O-methyltransferase (COMT) gene and TD occurrence and TD severity was investigated in 299 Chinese schizophrenic patients with long-term antipsychotic treatment (TD: 166, non-TD: 133). After adjusting the effects of confounding factors, there was no significant association between COMT genotype and TD occurrence (p=0.367). Among TD patients, we found no significant correlation between COMT genotypes and the total scores of abnormal involuntary movement scale (AIMS) (p=0.629). We concluded that this COMT polymorphism might not play a major role in the susceptibility of TD nor on the severity of TD.

Ethnicity and the Course of Tardive Dyskinesia in Outpatients Presenting to the Motor Disorders Clinic at the Maryland Psychiatric Research Center

Although newly emergent tardive dyskinesia (TD) is less of a concern, about one-fourth to one-third of patients on or previously on chronic first-generation antipsychotic agents have TD. The long-term course and outcome, as well as their predictors, are unknown. Earlier studies identify ethnicity as one of the risk factors for the development of TD, and case reports have noted a preponderance of African-American males in cohorts of patients with tardive dystonia. The current study examines the anatomic distribution and course of TD in a cohort of schizophrenia patients of European and African descent with TD who were referred to the Motor Disorders Clinic (MDC). We evaluated data collected on 1149 TD patients who were given a focused neurologic examination for movement disorders. Movements were evaluated with the MPRC Scale for Involuntary Movements (IMS). All patients met RDC-TD criteria for diagnosis of persistent TD. One to 10-year follow-up data on 528 patients were evaluated to examine the course of TD following recommendations made to referring primary clinicians. Suggested interventions to referring primary clinicians included dose reduction of first-generation antipsychotic medication, or switching to a second-generation antipsychotic. Initial evaluation included 701 European American (EA) patients and 448 African-American (AA) patients. AA patients had a significantly higher proportion of males [chi(1) = 7.50, P < 0.05]. EA subjects had a higher mean age than AA patients 42.8 +/- 11.2 and 39.8 +/- 10.4, respectively [F(1,1147) = 22.27, P < 0.05]. Mean neuroleptic exposure (chlorpromazine equivalents) was similar in both groups after controlling for differences in age.Follow-up data analyzed in 528 patients (329 EA and 199AA) showed a significant ethnicity by TD interaction [F(1,504) = 4.26, P < 0.05]. Examination of body distribution of dyskinetic movements showed an effect of ethnicity. Subsequent analyses suggest EA patients experienced more improvement in TD over the course of follow up [F(1,319) = 22.39, P < 0.05] compared with AAs [F(1,189) = 1.58, P > 0.05]. These findings were unchanged when age, change in antipsychotic drug dose, and duration of follow-up were covaried. Reports from earlier studies note ethnicity (African descent) as a risk factor in the development of TD. Our study findings suggest ethnicity might be an important factor in predicting a poor course of TD.

Olanzapine treatment for tardive dyskinesia in schizophrenia patients: a prospective clinical trial with patients randomized to blinded dose reduction periods

Background: Tardive dyskinesia (TD) is a potentially persistent and disabling abnormal involuntary movement disorder. The aim of this 8-month study was to determine if olanzapine treatment could lead to a significant and persistent reduction in preexisting TD. Methods: Eligible schizophrenia patients met restricted Research Diagnosis criteria of TD requiring, in part, a rating of at least moderate severity (score≥3) in one or more of seven body regions on the Abnormal Involuntary Movement Scale (AIMS). Patients received olanzapine, 5–20 mg/day, for 8 months. During this period, they underwent one to two dose reduction periods under blinded conditions. Concurrent changes in TD, psychopathology, parkinsonism and akathisia were assessed with the AIMS, the Positive and Negative Syndrome Scale (PANSS), and the Simpson-Angus and Barnes Akathisia Scales, respectively. Results: A significant reduction in mean AIMS total score was demonstrated at endpoint ( n=92; p<0.001) as well as at each visit ( p<0.001) and as early as Week 1 on olanzapine. Approximately 70% of patients no longer met the restricted Research Diagnostic criteria for persistent TD (RD-TD) after 8 months of treatment. No statistically significant rebound worsening of TD was found during either blinded drug reduction period. Significant improvement in psychopathology ( p=0.001) and parkinsonism ( p<0.001) was observed. Conclusions: Improvement in the severity of preexisting TD was achieved with olanzapine and persisted throughout the 8-month study and during each dose reduction period. Overall improvement in clinical status suggests that olanzapine may be effective for the long-term management of schizophrenia patients with preexisting TD.

Cytochrome P-450 2D6*10 C188T Polymorphism Is Associated with Antipsychotic-Induced Persistent Tardive Dyskinesia in Chinese Schizophrenic Patients

Typical antipsychotic treatment had been postulated to be a risk factor for the susceptibility to tardive dyskinesia (TD). The cytochrome P-450 debrisoquine/sparteine hydroxylase (CYP2D6) metabolizes a majority of antipsychotics and exhibits various phenotypes on enzymatic activities from poor metabolizers to ultrarapid metabolizers. The various phenotypes are encoded by polymorphic genetic variants on the CYP2D6 gene. Although several studies had explored the association between the CYP2D6*10 C188T polymorphism, which encodes the phenotype intermediate metabolizers, and TD in Orientals, the findings were inconclusive. In the present study, we examined the relationship between the CYP2D6*10 C188T polymorphism and the TD occurrence in 216 Chinese schizophrenic patients (113 patients with TD and 103 patients without TD) and explored the correlation between the TD severity assessed by the Abnormal Involuntary Movement Scale (AIMS) and each C188T genotype in the 113 TD patients. Using logistic regression analysis, we found a modest association (p = 0.045) between TD and C188T genotypes. This positive finding was only observed in male patients (p = 0.001), but not in females. Our findings also support the correlation between AIMS scores and C188T polymorphism within the TD group after adjusting for confounding effects with the multiple regression analysis (p = 0.033). We concluded that the CYP2D6*10 C188T polymorphism may be associated with the susceptibility to the occurrence of TD induced by typical antipsychotics, especially in male patients, and may also be correlated with AIMS scores in TD patients.

Incidence of tardive dyskinesia in first-episode psychosis patients treated with low-dose haloperidol.

Previous studies suggest that the risk of tardive dyskinesia is increased with higher doses of conventional antipsychotics. This study evaluates the 12-month incidence of tardive dyskinesia in subjects with first-episode psychosis who were treated with very low doses of haloperidol. Fifty-seven subjects with first-episode psychosis and a DSM-IV diagnosis of schizophreniform disorder, schizophrenia, or schizoaffective disorder were treated according to a fixed protocol with a mean dose of haloperidol of 1.68 mg/day and prospectively studied for 12 months. Subjects were assessed for extrapyramidal symptoms and psychiatric symptoms at 3-month intervals. Data were gathered from 1999 to 2001. Twelve-month incidence of probable or persistent tardive dyskinesia according to Schooler and Kane criteria was 12.3% (N = 7). Subjects with tardive dyskinesia did not differ from the rest of the sample regarding gender, race, duration of untreated psychosis, or baseline clinical characteristics. Subjects with tardive dyskinesia were older compared with subjects without tardive dyskinesia (37.14 +/- 9.23 vs. 27.30 +/- 8.09 years, respectively; t = -2.77, df = 30, p = .01) and received higher mean doses of haloperidol at 12 months (2.80 +/- 1.64 vs. 1.39 +/- 0.69 mg/day, respectively; t = -3.13, df = 25, p = .004). Cox regression analysis revealed that age at inclusion (p = .031), percentage change in negative symptoms (p = .028), and dose of haloperidol at 12 months (p = .016) were significant predictors of risk for tardive dyskinesia. Incidence of tardive dyskinesia was at least as high as in other samples treated with standard doses of conventional antipsychotics. Subjects at risk for tardive dyskinesia could not be identified on the basis of initial clinical features or acute treatment response. Risk of tardive dyskinesia was related to age, antipsychotic dose, and worsening of negative, depressive, and parkinsonian symptoms.

CYP2D6 polymorphism and tardive dyskinesia in schizophrenic patients.

Antipsychotic drug-induced tardive dyskinesia (TD) is a serious problem during psychopharmacologic treatment of schizophrenic patients. In search of genetic factors contributing to TD, there is a lack of consensus regarding the role of the polymorphic isozyme cytochrome P450 CYP2D6, which is involved in the oxidative metabolism of antipsychotic drugs. In the present case-control study, we tested the putative influence of the CYP2D6 genotype on the development of TD. Out of 157 patients, 109 were retrospectively selected meeting DSM IV criteria for schizophrenia or schizoaffective disorder, and 50 of them persistently presenting with TD. Genotyping detected the functional allele CYP2D6 *1, the known major defective alleles CYP2D6 *3, *4, *5, *6, and gene duplication. According to their number of functional CYP2D6 alleles, subjects were divided into carriers of none, one, or at least two functional CYP2D6 alleles. The proportions of these categories did not differ between patients and an ethnically homogenous control population (n = 195, p = 0.99) or between patients with and without TD (p = 0.818). Schizophrenic patients were carriers of gene duplication more often than healthy probands, without revealing statistical significance (p = 0.10). Out of seven patients with gene duplication, three developed persistent TD. Furthermore, patients with and without TD were comparable according to age, age of onset, gender, and duration of illness, but subjects with TD had taken more lifetime chlorpromazine equivalents (CPZ) than had patients without TD (chi 2-test, Student's t-test). Forward as well as backward logistic regression analyses confirmed that the presence of TD was influenced by lifetime CPZ but not by age, age of onset, gender, duration of illness, or CYP2D6 genotype. In contrast to the relevance of lifetime CPZ, the lifetime dose of antipsychotic drugs known to be metabolized by CYP2D6 did not significantly influence the presence of TD. In conclusion, our results provide no evidence for the contribution of CYP2D6 genotype to the development of TD in schizophrenic patients receiving long-term antipsychotic medication.

Treatment predictors of extrapyramidal side effects in patients with tardive dyskinesia: results from Veterans Affairs Cooperative Study 394.

Predictors for the development of tardive dyskinesia (TD) have been studied extensively over the years, yet there are few studies of predictors of the course of TD after it has developed. Moreover, few studies have examined predictors of the course of other extrapyramidal side effects (EPS) in patients maintained on neuroleptics. The purpose of this study was to determine which modifiable variables are important in the prediction of EPS in patients with persistent TD over a period of as long as 2 years. One hundred fifty-eight patients enrolled in the Veterans Affairs Cooperative Study 394 were included in this study. A linear mixed-effects (LME) analysis to estimate the Abnormal Involuntary Movement Scale score (for TD severity), Simpson-Angus Scale (for parkinsonism severity), and Barnes Akathisia Scale at any given time after intake assessment was performed. The severity of each of the TD and EPS outcomes at any given visit was predicted by their respective baseline severity scores. Additional predictors of a favorable course of TD included lower doses of antipsychotic medications and use of anticholinergic medications. Other predictors of a favorable course of EPS included younger age and the use of atypical antipsychotic medication (for rigidity) and the use of anticholinergic medication (for tremor). These findings indicate that clinician-modifiable factors related to medication usage can influence the outcome of TD and EPS in patients with persistent TD.