Association of diabetes with dyskinesia in older psychosis patients

Rationale Older patients treated with antipsychotics are more likely to develop tardive dyskinesia (TD) than younger individuals. Advanced age is also an important risk factor for diabetes, which may be associated with TD. These observations suggest that older diabetic patients may be particularly vulnerable to developing TD.Objective To examine whether older psychosis patients with diabetes exhibit more severe dyskinesia than well-matched patients without diabetes and to test whether there are differences in dyskinesia severity between diabetic patients treated with conventional versus atypical antipsychotics versus those not taking antipsychotic medications.Method Sixty-one psychosis patients with diabetes and 122 case-matched non-diabetic comparison patients were studied. Observer-based and quantitative instrumental measures were administered to assess prevalence and severity of dyskinesia. Raters were unaware of patients diabetes status.Results Diabetic patients exhibited significantly more severe TD than non-diabetic comparison patients. Groups did not differ in terms of severity of parkinsonism. Significantly more diabetic (27.9%) than non-diabetic (14.6%) patients met research diagnostic criteria for TD. Diabetic patients treated with atypical antipsychotics at the time of assessment had significantly more severe TD than all other patient subgroups, including patients treated with conventional antipsychotics. Results from the instrumental measures of force steadiness were consistent with observer-based severity ratings.Conclusion The deleterious effect of diabetes on TD in the absence of any effect of parkinsonism supports preclinical studies of glucose-related dopamine hyperfunction and has implications for the pharmacologic management of psychosis in patients with pre-existing diabetes.     

The life expectancy of schizophrenic patients with tardive dyskinesia

Relationships between tardive dyskinesia (TD) and the life expectancy of schizophrenic patients who suffer it were examined in two studies over a 50-month period. In a prospective study, the mortality rate was found to be higher in patients with TD than in those without. This suggests either that TD is a factor tending to precipitate death, or else that it is an indication that the final period of life has been reached. The failure in the prospective study to detect medical factors which would discriminate between those TD patients who died and those who remained alive, as well as the finding of a significantly older age at death of patients with TD in the retrospective study may both support this idea. No significant differences were observed in the retrospective study in the prevalence of TD between 35 pairs of age-matched deceased and living patients. The effects of TD on life expectancy are subtle; the present results are consistent with the possibilities both that TD reduces life expectancy and that it appears at the end-stage of life.     

Non-functional CYP2D6 alleles and risk for neuroleptic-induced movement disorders in schizophrenic patients

The use of classic anti-psychotic drugs in the long-term treatment of schizophrenia is associated with risk for extrapyramidal side-effects, such as akathisia, parkinsonism and tardive dyskinesia (TD). Approximately 5–10% of European Caucasians lack the cytochrome P450 enzyme CYP2D6 (so-called poor metabolizers; PM), which normally metabolizes several drugs including many neuroleptics. PM subjects may achieve high or toxic plasma levels upon standard drug therapy. In this study we have examined 100 subjects from the Nithsdale cohort of schizophrenic patients in South-west Scotland receiving long-term neuroleptic medication, which enabled us to perform both a cross-sectional and longitudinal evaluation of extrapyramidal side-effects in relation to the genetically impaired CYP2D6 metabolism. We identified ten (10%) schizophrenic subjects with the PM genotype. In the cross-sectional study, the prevalence of TD, parkinsonism and akathisia was 51%, 38% and 15%, respectively. Patients with TD or parkinsonism were significantly older than patients without these side-effects. In contrast, patients with akathisia were significantly younger than patients without akathisia. There was a non-significant tendency for PM subjects to have more severe ratings for TD and parkinsonism. In the long-term evaluation based on repeated ratings since 1981, there was a non-significant 3-fold higher frequency of PM subjects among schizophrenic patients with longitudinal TD, as compared with the group of patients with fluctuating or no TD. These results indicate that genetically impaired CYP2D6 metabolism may be a contributing factor for the development of persistent TD. Received: 16 October 1996 /Final version: 5 January 1997     

Extrapyramidal syndromes in neuroleptic-treated patients: prevalence, risk factors, and association with tardive dyskinesia.

Prevalence and risk factors for extrapyramidal syndromes (EPS) were investigated in a sample of 1,559 patients. The overall prevalence of EPS was 29.4% (N = 458). Among the EPS-diagnosed patients, parkinsonism as assessed by the presence of core parkinsonian symptoms (rigidity, tremor, bradykinesia) was present in 65.9% of patients (N = 302), akathisia in 31.8% (N = 145), and acute dystonia in 2.1% (N = 10). Old age and long-term neuroleptic drug (NL) treatment were significantly associated with EPS in both the univariate and the multivariate analyses, whereas no relationship was observed with average NL daily doses and current NL treatment. EPS was diagnosed in 50.2% of 285 patients with persistent tardive dyskinesia (TD). Distribution of EPS in patients with TD showed that tremor and akathisia were more frequent in peripheral TD cases than in orofacial TD cases. Furthermore, there was a stronger association of NL-induced parkinsonism with peripheral TD than with orofacial TD. This study suggests that the association between EPS and TD may be limited to specific subtypes of TD. Peripheral TD showed a higher association with parkinsonism and with akathisia, suggesting that these symptoms may share a common pathophysiology.     

Tardive dyskinesia and diabetes mellitus.

Two studies examine the prevalence of tardive dyskinesia (TD) in neuroleptic-treated diabetic patients. Study 1 compared 38 diabetic patients with 38 nondiabetic patients treated for psychotic disorders with low to moderate doses of neuroleptics (mean chlorpromazine equivalents = 300 mg/day) for an average of 18 years. Study 2 compared 24 diabetic and 27 nondiabetic patients treated for an average of 2.6 years with a mean 31 mg/day of metoclopramide for gastrointestinal disease. Patients were examined for TD using standardized scales by raters blind to all treatment and illness variables. In both studies, there were no differences between the diabetic and nondiabetic groups in age, sex, type of psychiatric illness, and dose and duration of neuroleptic treatment or severity of parkinsonism. In both studies, the diabetic patients had significantly greater prevalence and severity of TD. No measures of diabetes severity were associated with TD in either study. Possible pathophysiologic mechanisms for the increased prevalence of TD in neuroleptic-treated patients with diabetes will be discussed.     

Diabetes is not a risk factor for tardive dyskinesia: a retrospective observational study

The aim of this observational study was to compare the prevalence of tardive dyskinesia (TD) in diabetic and non diabetic patients. We compared 34 diabetic patients with 34 non diabetic controls, matched by sex, age and time of admission, who had received a complete neuropsychiatric evaluation and who had been exposed to antidopaminergic treatment for at least 3 months. Among them, 8 of 24 diabetic (33.3%) and 6 of 15 (40.0%) non diabetic patients presented TD. The prevalence of TD in the diabetic group is numerically lower than in the controls but the difference is not statistically significant (chi(2) = 0.006; fd = 1; p = 0.937). These results suggest that diabetes is unlikely to play a major role in the pathogenesis of TD.     

Pharmacy-based screening program for tardive dyskinesia

An ongoing screening program using pharmacists to detect tardive dyskinesia (TD) was developed, and a pharmacy-based prevalence survey of TD in chronic hospitalized psychiatric patients was undertaken to determine the extent of abnormal involuntary movements. The results show that older patients and women in particular are at higher risk for developing abnormal movements. Higher doses of neuroleptics were used in non-TD patients, indicating a possible masking effect caused by these drugs. By using a standardized rating method such as the Abnormal Involuntary Movement Scale, pharmacists can and should be utilized in the surveillance of TD.     

Relationship of symptomatology of schizophrenia and tardive dyskinesia.

The role of drug factors and patient factors in the development of tardive dyskinesia (TD) was examined in 31 TD patients and 31 non-TD patients matched by age and sex. TD patients achieved significantly lower total scores on the anxiety-depression factor of Brief Psychiatric Rating Scale (BPRS) (5.2 +/- 1.4 vs. 6.5 +/- 2.2; less than P) and significantly higher total scores on the activation factor (6.4 +/- 2.2 vs. 5.3 +/- 2.5; less than P). The finding that TD patients were less depressed may be explained by a hypermonoaminergic state developing in TD. Based on the findings of this study it is suggested that catatonic schizophrenic patients are more vulnerable to the development of TD.     

Clozapine versus typical antipsychotics a retro- and prospective study of extrapyramidal side effects

Schizophrenic patients in long-term neuroleptic monotherapy with clozapine (n=100) and perphenazine, flupenthixol or zuclopentixol (controls,n=100) were evaluated for extrapyramidal side effects (EPS) (blind) as well as other side effects and mental condition (non-blind). In both groups the patients had received neuroleptic treatment for a total of 14 years (median) and the present antipsychotic (clozapine or control drug) for 5 years. Thus the clozapine-treated patients had previously received traditional neuroleptics for 9 years (median). The study was both retrospective (0.3–19 years for clozapine, 0.3–24 years for control drug, by means of chart information) and prospective (1 year, with video-controlled evaluation of EPS). There was a significantly lower prevalence of tardive dyskinesia (TD) in clozapine treated patients than control patients, although prior to this treatment there were more TD patients in the clozapine group (P<0.05). This lower level of TD in the clozapine group was related to a lower induction of new cases (P<0.001) and a tendency towards greater disappearance of TD in the clozapine than in the control group (P=0.07). Clozapine treated patients without TD had started clozapine and ceased traditional neuroleptics at an earlier age than those with TD. Parkinsonian signs were seen in 33% of the clozapine patients versus 61% of the control patients, mainly as hypokinesia; tremor in 3% versus 11% and rigidity in 0 versus 19%. Psychic akathisia was found in 14% versus 40% and motor akathisia in 7% versus 29% of the patients, all differences significantly in favor of clozapine. Clozapine treated patients also had less neuroleptic-induced emotional indifference and depression, but more autonomic side effects than controls.     

Tardive dyskinesia in schizophrenia is associated with prolactin-related sexual disturbances.

Tardive dyskinesia (TD) may occur in never-medicated patients with psychotic illness, indicating the existence of non-medication, possibly disease-related, causes. We tested the hypothesis that, independent of the antipsychotic-induced rise in prolactin, the incidence of TD would be associated with the incidence of prolactin-related sexual disturbances (PRSD), which would be suggestive of a common pathology involving multiple dopamine tracts. Simple, global measures of TD and PRSD (loss of libido, amenorrhea, gynaecomastia, impotence, and galactorrhea) were rated in a prospective, observational European Health Outcomes Study (SOHO). New onset of TD and new onset of PRSD at 3, 6, and 12 months was analyzed in a risk set of 4263 patients using a Cox proportional hazard model yielding adjusted hazard ratios (aHR). Incidence of TD was significantly and linearly comorbid with the incidence of PRSD in both men and women. Compared to those with no PRSD, the risk for TD was 2.0 (95% CI: 1.1, 3.7) with one PRSD, 2.4 (95% CI: 1.3, 4.5) with two PRSD, and 3.6 (95% CI: 1.1, 11.8) with three PRSD. Associations were stronger in those who only had received prolactin-sparing medications (aHR per unit PRSD increase=2.0, 95% CI: 1.2, 3.3) than in those who only had received prolactin-raising medications (aHR=1.3, 95% CI: 0.9, 1.9). In people with schizophrenia, TD and PRSD show comorbidities that are independent of antipsychotic-induced alterations in plasma prolactin. This may suggest a shared, pandopaminergic pathological mechanism associated with schizophrenia itself, rather than only a medication effect.     

Awareness of tardive dyskinesia in Asian patients with schizophrenia

While ethnocultural differences in risk of tardive dyskinesia (TD) have been suggested, no previous studies have examined whether this factor also plays a role in lack of awareness of TD. This study examined this question in an Asian population with schizophrenia. Six hundred seven patients in a state mental hospital in Singapore were assessed using the Abnormal Involuntary Movement Scale (AIMS) and the Simpson-Angus Rating Scale. Of the 607 patients, 242 (39.9%) met criteria for TD, and 163 (67.4%) patients were not aware of the presence of TD. No significant differences in terms of age, gender, and duration of illness were found between those aware of their TD and those not aware. Daily neuroleptic doses and scores for the AIMS and Simpson-Angus Rating Scale were significantly different, although after logistic regression, only the Simpson-Angus Rating Scale scores remained significant. The finding that a large proportion of our patients lacked awareness of their TD is consistent with other reports in the West and provides evidence that this feature is characteristic of the illness rather than of a specific ethnocultural group. We found an association between lack of awareness and greater severity of extrapyramidal symptoms (EPS), suggesting that there may be a subtype of TD in which lack of awareness and greater vulnerability of developing EPS are features.     

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype

Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A) receptor gene (HTR(2A)) with TD in a large, multicentre patient sample. The design employed case-control analysis controlling for possible confounders using pooled, original data from published and available unpublished samples and employing logistic regression, analysis of variance and meta-analysis. The study sample consisted of 635 patients with schizophrenia or schizoaffective disorder (256 with TD and 379 without TD) drawn from five research centres, divided into six groups based on population origin. The main outcome measure was association of a categorical diagnosis of TD based on the Research Diagnostic Criteria for TD with HTR(2A) T102C and His452Tyr genotypes and haplotypes. The findings indicate significant association of TD with HTR(2A) T102C genotype (p=0.002) over and above the effect of population group, also when controlling for age and gender (p=0.0008), but not with His452Tyr genotype. The T102C genotype was significantly associated with TD in older (>median age 47 yr, p=0.002) but not younger patients and in patients with non-orofacial (limb-truncal) (p=0.001) but not orofacial TD. By meta-analysis the Mantel-Haenszel (M-H) pooled odds ratio (OR) across all the available data was 1.64. A T102C-His452Tyr haplotype was significantly associated with TD (p=0.0008). These findings confirm that genetic variability in HTR(2A) contributes a small but significant degree of risk for the expression of TD, particularly in older patients and specifically for the non-orofacial (limb-truncal) type. Together with other genetic variants associated with TD the findings could be used to assess risk in patients who are candidates for treatment with typical antipsychotic medications.     

Antipsychotic-Induced movement disorders in the elderly: epidemiology and treatment recommendations

We reviewed the epidemiological aspects of antipsychotic-induced movement disorders as they pertain to older patients. The incidence and prevalence of drug-induced parkinsonism and tardive dyskinesia (TD) are significantly greater in the older patient than in the younger patient whereas akathisia seems to occur evenly across the age spectrum and dystonia is uncommon among older patients. The literature on risk factors associated with treatment-emergent movement disorders is highly variable. Treatment practices vary across the age range and the interaction between age and antipsychotic dosage confounds our understanding of the relative importance of treatment-related risk factors. However, there is general agreement that pre-existing extrapyramidal signs (EPS) increase the vulnerability of the patient to developing significant drug-induced movement disorders. Elderly patients with dementia are at greater risk than patients without dementia for persistent drug-induced EPS. Management of drug-induced movement disorders in the older patient requires careful consideration of the contraindications imposed by such agents as anticholinergics and beta-blockers. At present, well-controlled double-blind studies of second-generation antipsychotics such as clozapine, risperidone. olanzapine or quetiapine for reducing the risk of treatment-emergent movement disorders in the elderly have not been published. However, open-label studies of atypical antipsychotics demonstrate a markedly lower incidence of both EPS and TD compared with conventional antipsychotic treatment in the elderly. There is emerging literature in support of atypical antipsychotics for the treatment of existing drug-induced movement disorders. More controversial is the use of adjunctive antioxidants in newly treated patients who are vulnerable to drug-induced movement disorders. While the evidence is mixed in support of antioxidants for the treatment of TD, the possibility remains that prophylactic use of antioxidants may help reduce the incidence of TD. The development of a drug-induced movement disorder often reduces the quality of life in an elderly patient. Effective pharmacological management requires cooperation from the patient and family, which can be fostered early in the patient's care through proper informed consent. The risks and benefits of antipsychotic treatment in the elderly patient need to be communicated to the patient and family. At the present time, there is no consistently effective treatment for patients with TD once it develops. Therefore, attention should focus on its prevention and close monitoring.     

Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia

OBJECTIVE: Neuroleptic-induced tardive dyskinesia (TD) is an involuntary movement disorder that develops in patients who have undergone long-term treatment with antipsychotic medications, and its etiology is unclear. In this study, a genome-wide association screening was done to identify the pathway(s) in which genetic variations influence susceptibility to neuroleptic-induced TD. METHODS: Screening with Sentrix Human-1 Genotyping BeadChip (Illumina, San Diego, California, USA) was done for 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD. A total of 40 573 single nucleotide polymorphisms that were not in linkage disequilibrium with each other and were located in the exonic and intronic regions of 13 307 genes were analyzed. After gene-based corrections, P values for allelic associations were subjected to canonical pathway-based analyses with Ingenuity Pathway Analysis software (Ingenuity Systems, Inc., Redwood City, California, USA). RESULTS: Eight genes (ABAT, ALDH9A1, GABRA3, GABRA4, GABRB2, GABRAG3, GPHN, and SLC6A11) contained polymorphisms with gene-based corrected allelic P values of less than 0.05. They were aggregated significantly in 33 genes belonging to the gamma-aminobutyric acid (GABA) receptor signaling pathway (P=0.00007, corrected P=0.01). Associations were replicated in an independent sample of 36 patients with TD and 136 patients without TD for polymorphisms in SLC6A11 (GABA transporter 3) (P=0.0004 in the total sample), GABRB2 (beta-2 subunit of GABA-A receptor) (P=0.00007 in the total sample), and GABRG3 (gamma-3 subunit of GABA-A receptor) (P=0.0006 in the total sample). CONCLUSION: The results suggest that the GABA receptor signaling pathway may be involved in genetic susceptibility to treatment-resistant TD, at least in a subgroup of Japanese patients with schizophrenia. The present results suggest that benzodiazepines may be considered as possible treatment option for TD.     

Double-blind trial of the effects of tryptophan depletion on depression and cerebral blood flow in smokers

Studies of clinically depressed patients have documented left frontal lobe hypoactivity. Smokers also show an increased prevalence of depression and evidence that nicotine normalizes qEEG indices of left frontal lobe activity. Tryptophan depletion (TD) has been shown to increase negative mood in smokers, particularly those with recurrent depression. Thus, in smokers, we expected that increased depression during TD would be associated with decreased cerebral blood flow, specifically in the left frontal lobe. Hamilton depression scores and relative regional cerebral blood flow (rCBF) were measured with SPECT using (99m)Tc-hexamethylpropyleneamineoxime in seven smokers after TD and after a control procedure. Decreased bilateral cerebral blood flow to the inferior frontal (IF) lobe following TD relative to placebo was associated with increased depressed mood (r= -.653, P<.05). Among smokers, a decrease in brain serotonin is associated with increased depressed mood and with focal bilateral decreases in IF activity. Chronic nicotine exposure appears to be associated with cortical responses suggestive of depressive vulnerability.     

Tardive dyskinesia in the course of antidepressant therapy: a prevalence study and review of the literature

The authors present a prevalence study of tardive dyskinesia (TD) in the course of antidepressant therapy. Of the 50 patients evaluated, three developed TD. TD developed rapidly and in a short period of time. Withdrawal of antidepressant improved TD in two patients. The literature on TD developing in the course of antidepressant therapy is reviewed, and the different etiological theories are examined.     

Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia.

In 112 schizophrenic patients previously treated with typical neuroleptics, we investigated the putative role of the dopamine D3 receptor gene (DRD3) in tardive dyskinesia (TD). Patients were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS) and were subsequently genotyped for the MscI polymorphism that identifies a serine to glycine substitution in DRD3. A modified analysis of covariance model, which incorporated several clinical risk factors for TD, was utilized to detect differences in TD severity among the various genotypic groups. The glycine allele of DRD3 was found to be associated with typical neuroleptic-induced TD (F[2,95] = 8.25, p < .0005). Higher mean AIMS scores were found in patients homozygous for the glycine variant of the DRD3 gene, as compared to both heterozygous and serine homozygous patients. Although replication is necessary, this finding supports a role for the dopamine D3 receptor in the pathogenesis of TD.     

Evidence that lithium protects against tardive dyskinesia: the Cura?ao Extrapyramidal syndromes study VI.

Lithium may have neuroprotective properties and therefore could affect the occurrence of tardive dyskinesia (TD). We conducted a nine-year follow-up study with one baseline and six follow-up assessments including all psychiatric inpatients in Cura?ao (N=194). TD was measured with the Abnormal Involuntary Movement Rating Scale (AIMS). There were 758 follow-up observations in the 166 patients (mean age 54.4 yrs, SD 16.0) with at least one follow-up assessment. Most patients (74%) had schizophrenia. The mean baseline score of the AIMS was 4.1 (SD 4.7). Sixteen patients (9.6%) used lithium at baseline and eight patients started lithium during follow-up. Prevalent and incident lithium significantly reduced the severity of existing TD with respectively 2.3 and 2.9 point reduction on the AIMS (AIMS score range: 0-23) and a standardised effect size of 0.5 for prevalent TD and 0.6 for incident TD. In the restricted sample of those with a baseline score of zero on the AIMS, prevalent lithium significantly lowered the risk of new abnormal movements (standardised effect size of 0.7). In conclusion, the use of lithium was significantly negatively associated with both persistence and onset of TD. These results suggest a beneficial effect on TD of lithium in some patients using long-term antipsychotics.     

The effect of vitamin E treatment on tardive dyskinesia and blood superoxide dismutase: a double-blind placebo-controlled trial

Free radicals may be involved in the pathogenesis of tardive dyskinesia (TD). Vitamin E, a free radical scavenger, has been reported to improve symptoms of TD. The present study was designed to replicate this finding in a group of Chinese patients with TD, and to examine the effect of vitamin E treatment on blood superoxide dismutase (SOD), a critical enzyme in the detoxification of free radicals. Forty-one inpatients with TD completed a double-blind, placebo-controlled, parallel-group study of vitamin E. Twenty-two of the patients were randomly assigned to receive a fixed dose of 1200 IU/d vitamin E, and 19 were assigned to a placebo for 12 weeks. Patients were assessed primarily using the Abnormal Involuntary Movement Scale (AIMS) at baseline, weeks 6 and 12. Blood SOD levels were measured by radioimmunometric assay before and after treatment. The results showed that the reduction in AIMS score from baseline was significantly higher with vitamin E treatment compared with placebo (45.9% vs. 4.3%). Blood SOD levels were significantly increased after treatment with vitamin E (P = 0.001), but no change with placebo treatment (P < 0.05). These results support earlier findings of the efficacy of vitamin E in the treatment of TD. Moreover, the efficacy of vitamin E may be due to its ability to increase SOD level, which may reduce oxidative injure in tardive dyskinesia.     

Enzyme studies in tardive dyskinesia. III. Noradrenergic hyperactivity in a subgroup of dyskinetic patients

This study was undertaken to test a hypothesis that tardive dyskinesia (TD) patients with high plasma dopamine-beta-hydroxylase (DBH) activity would also have other enzymatic alterations suggestive of noradrenergic hyperactivity. Plasma renin activity was chosen as a peripheral indicator of noradrenergic function. We measured plasma renin activity in three groups of female psychiatric inpatients over the age of 50: a TD group with high plasma DBH activity, a TD group with low plasma DBH activity, and a non-TD group. The high-DBH TD group had significantly greater plasma renin activity than the other two groups. Our results are consistent with the hypothesis that a subgroup of TD patients has relative noradrenergic hyperactivity.