P.N. van Harten

Antipsychotic-induced tardive dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2 and MnSOD genes: a meta-analysis of pharmacogenetic interactions

Despite accumulating evidence pointing to a genetic basis for tardive dyskinesia, results to date have been inconsistent owing to limited statistical power and limitations in molecular genetic methodology. A Medline, EMBASE and PsychINFO search for literature published between 1976 and June 2007 was performed, yielding 20 studies from which data were extracted for calculation of pooled estimates using meta-analytic techniques. Evidence from pooled data for genetic association with tardive dyskinesia (TD) showed (1) in COMTval158met, using Val–Val homozygotes as reference category, a protective effect for Val–Met heterozygotes (OR=0.63, 95% CI: 0.46–0.86, P=0.004) and Met carriers (OR=0.66, 95% CI: 0.49–0.88, P=0.005); (2) in Taq1A in DRD2, using the A1 variant as reference category, a risk-increasing effect for the A2 variant (OR=1.30, 95% CI: 1.03–1.65, P=0.026), and A2–A2 homozygotes using A1–A1 as reference category (OR=1.80, 95% CI: 1.03–3.15, P=0.037); (3) in MnSOD Ala–9Val, using Ala–Ala homozygotes as reference category, a protective effect for Ala–Val (OR=0.37, 95% CI: 0.17–0.79, P=0.009) and for Val carriers (OR=0.49, 95% CI: 0.24–1.00, P=0.047). These analyses suggest multiple genetic influences on TD, indicative of pharmacogenetic interactions. Although associations are small, the effects underlying them may be subject to interactions with other loci that, when identified, may have acceptable predictive power. Future genetic research will take advantage of new genomic knowledge.

The prevalence of tardive dystonia, tardive dyskinesia, parkinsonism and akathisia The Curaçao extrapyramidal syndromes study: I

A prevalence study of extrapyramidal syndromes was conducted among all psychiatric inpatients of the Netherlands Antilles (n = 194; mean age 53.1). The Netherlands Antilles are very suitable for epidemiological research as it is a well-defined catchment area with only one psychiatric hospital and a health care system based on western principles. In this mainly chronic population, the prevalence was measured of tardive dystonia, tardive dyskinesia, parkinsonism and akathisia using respectively the Fahn-Marsden rating scale, the Abnormal Involuntary Movement Scale, the Unified Parkinson Disease Rating Scale and the Barnes Akathisia Rating Scale. The prevalence numbers were for tardive dystonia 13.4%, tardive dyskinesia 39.7%, parkinsonism 36.1%, akathisia 9.3% and pseudoakathisia 12.9%. The most important conclusions were: (1) The prevalence of tardive dystonia was higher than reported in most other studies and (2) extrapyramidal syndromes are very common in this predominantly Negroid population, with three out of four patients suffering of one or more extrapyramidal syndromes.

The role of dopamine D3, 5-HT2A and 5-HT2C receptor variants as pharmacogenetic determinants in tardive dyskinesia in African-Caribbean patients under chronic antipsychotic treatment

Abstract Tardive dyskinesia (TD) is associated with polymorphisms of the dopamine D3, serotonin 2A and 2C receptors (DRD3, HTR2A and HTR2C, respectively). This study investigated the possible relationship between TD and the polymorphisms Ser9Gly (DRD3), 102T>C (HTR2A), −1438G>A(HTR2A) and Cys23Ser (HTR2C) in African-Caribbean inpatients. One hundred and twenty-six patients under chronic antipsychotic treatment were genotyped. The assessment of TD was carried out with the abnormal involuntary movement scale (AIMS). The relationships between the carriership of the least frequent alleles and the respective orofaciolingual dyskinesia (TDof) (sum of the items 1-4 of the AIMS), limb-truncal dyskinesia (TDlt) (sum of items 5-7 of the AIMS) and TD (sum of items 1-7 of the AIMS) were analyzed with ANCOVA, comparing means with age as a covariate and stratification for carriers and non-carriers of the mutations. In addition, we conducted pre-planned t-tests to compare AIMS values of carriers of the combinations of alleles versus the corresponding non-carriers. In the study population, females with 9Ser carriership exhibited higher AIMS values than non-carriers. Male subjects with 9Ser carriership in combination with 23Ser or −1438A carriership exhibited higher AIMS values. In male patients also, the combination of 23Ser and −1438A carriership increased TD. The study clearly shows that the African-Carribean population differs from the Caucasian population with regard to the association of TD with the polymorphisms studied and suggests that the association of TD with the studied polymorphisms of the 5-HT2C and probably of the 5-HT2A receptor are the result of a changed susceptibility of the patients, independent of the action of the antipsychotics on these receptors.

Incidence and persistence of tardive dyskinesia and extrapyramidal symptoms in schizophrenia.

Although it has been suggested that second-generation antipsychotics (SGA) may reduce the rate of prevalent tardive dyskinesia (TD), little is known about the incidence and outcome of TD in those exposed exclusively to SGA. The incidence and subsequent persistence of TD and extrapyramidal symptoms (EPS) was calculated in a cohort of patients with schizophrenia treated predominantly with SGA. This cohort of more than 10,000 patients with schizophrenia was seen six times over a period of two years. Dichotomous measures of EPS and TD were used to calculate the yearly incidence rates of TD and EPS as well as their subsequent cumulative persistence rate in a subset of 9104 and 6285 patients at risk for TD and EPS, respectively. Of 9104 individuals who did not present with TD at baseline, 138 developed TD, yielding a TD incidence rate of 0.74% (95% CI: 0.62, 0.87) and a subsequent cumulative persistence rate of 80%. Of 6285 individuals without EPS at baseline, 464 developed EPS yielding an incidence rate of 3.7% (95% CI: 3.4, 4.0) and a subsequent cumulative persistence rate of 82%. Incidence rates of TD and EPS may be low in the SGA era. However, once emerged, these disorders prove persistent, suggesting strong moderators effects of underlying predisposing factors.

Movement disorders are associated with schizotypy in unaffected siblings of patients with non-affective psychosis.

BACKGROUND Movement disorders and schizotypy are both prevalent in unaffected siblings of patients with schizophrenia and both are associated with the risk of developing psychosis or schizophrenia. However, to date there has been no research into the association between these two vulnerability factors in persons with an increased genetic risk profile. We hypothesized that unaffected siblings of patients with non-affective psychosis have more movement disorders and schizotypy than healthy controls and that these co-occur. METHOD In a cross-sectional design we assessed the prevalence and inter-relationship of movement disorders and schizotypy in 115 unaffected siblings (mean age 27 years, 44% males) and 100 healthy controls (mean age 26 years, 51% males). Movement disorders were measured with the Abnormal Involuntary Movement Scale (AIMS), the Unified Parkinson Disease Rating Scale (UPDRS), the Barnes Akathisia Rating Scale (BARS), and one separate item for dystonia. Schizotypy was assessed with the Structured Interview for Schizotypy--Revised (SIS-R). RESULTS There were significant differences in the prevalence of movement disorders in unaffected siblings versus healthy controls (10% v. 1%, p<0.01) but not in the prevalence of schizotypy. Unaffected siblings with a movement disorder displayed significantly more positive and total schizotypy (p=0.02 and 0.03 respectively) than those without. In addition, dyskinesia correlated with positive schizotypy (r=0.51, p=0.02). CONCLUSIONS The association between movement disorders (dyskinesia in particular) with positive and total schizotypy in unaffected siblings suggests that certain vulnerability factors for psychosis or schizophrenia cluster in a subgroup of subjects with an increased genetic risk of developing the disease.

The course of tardive dystonia in Afro Caribbean patients, a population-based study: the Curacao extrapyramidal syndromes study: VII.

Tardive dystonia (TDt) is a severe side effect of long-term use of antipsychotics. Previous publications suggested that TDt persist but the results are distorted by referral bias. In a population-based nine-year follow-up study (one baseline, six follow-ups) of chronic psychiatric patients (N=194) on a Caribbean island, the course of prevalent and incident TDt was measured with the Fahn-Marsden rating scale. Of the 26 patients (mean age 53.3 yrs) with TDt at baseline, 64% recovered, 20% persisted, and in 16% the course was intermittent. The severity of baseline TDt was significantly higher in persistent cases versus those who recovered (t=3.01, P<0.008). Of the 27 incident cases (cumulative 9-year incidence: 16.1%; mean age 57.6 yrs), 80% recovered, 8% persisted, and in 12% the course was intermittent. Predominantly affected were hands, eyes (blepharospasm), neck and mouth. The natural course of TDt is better than previously suggested but severe cases tend to persist.

Predicting the incidence of antipsychotic-induced movement disorders in long-stay patients: A prospective study.

Tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia are antipsychotic-induced movement disorders that remain a cause for concern in the treatment of patients with psychotic disorder. Movement disorders secondary to antipsychotics constitute a major reason for non-compliance, which results in an increased risk of psychotic relapse (Robinson et al. 2002; Lambert et al. 2004; Casey, 2006). Although second generation antipsychotics (SGAs) may be associated with a lower incidence of movement disorders, these medications nevertheless still carry risk. We further refer to our previous publication (Bakker et al. 2011). A high-risk group for movement disorders consists of patients with chronic mental illness and therefore chronically exposed to antipsychotic medication, particularly long-stay patients (i.e. patients institutionalized for long periods) with supervised medication regimes (Bakker et al. 2011). Antipsychotic-induced movement disorders (Owens, 1999; Factor et al. 2005) can be divided into acute syndromes, such as parkinsonism and akathisia, that occur within hours/days or weeks after initiating antipsychotic treatment or increasing the antipsychotic dose (or cessation of anticholinergics), and tardive syndromes, such as TD and tardive dystonia, that develop after months or years of treatment. Given that combinations of acute and chronic movement disorders occur in patients undergoing long-term treatment with antipsychotics, prediction models should include both syndromes, i.e., the four major types of movement disorders (TD, parkinsonism, akathisia and tardive dystonia). Given the above considerations, the aim of the current prospective study of movement disorders was to provide clinicians with risk information regarding new occurrences of movement disorders for prevention purposes in the population currently most at risk: long-stay patients with chronic mental illness requiring long-term antipsychotic treatment.

Movement disorders associated with neuroleptics : the Curaçao extrapyramidal syndromes study

This thesis concerns extrapyramidal syndromes (EPS) and is divided into three parts because each part has its own study design. The focus of part 1 is on the epidemiology of the EPS tardive dyskinesia, tardive dystonia, parkinsonism, and akathisia. Part 2 focuses on tardive dystonia. It starts with a review of this syndrome and then reports the results of a clinical trial with clozapine. Part 3 opens with a review of acute dystonia and then the results are given of a prospective study that investigated whether the use of cocaine is a risk factor for neuroleptic induced acute dystonia.

Novel instrumental devices measuring movement disorders in psychiatry : a paradigm shift (Poster)

Background: Cardiovascular and metabolic problems combined with a bad lifestyle are a major cause of a shortened life expectancy in chronic psychotic disorders. While the incidence of cannabis use is twice as high in psychosis compared to the general population, use of cannabis has been associated with better outcomes on cardiometabolic risk factors. This study investigates whether this effect is mediated by the AKT1 gene, as activation of the related enzyme by cannabis may cause changes in metabolism. Methods: Patients with a recent onset psychosis (n=623) were included from a cohort study (GROUP). Cannabis use, based on self-report and urine screening, was related to Body Mass index (BMI). Next the mediating effects of six AKT1 polymorphisms (rs1130214, rs1130233, rs2494732, rs2498784, rs3730358 and rs3803300) were investigated. Results: There was a strong, negative association between BMI and cannabis use. Moreover, two SNPs (rs1130233 and rs2494732) showed an association with cannabis use, but did not mediate the effect of cannabis on BMI. Conclusion: In conclusion, cannabis use results in a lower body weight in patients with a psychosis. While AKT1 is related to cannabis use, it does not affect body mass via AKT1. Instead, AKT1 risk alleles may increase the incidence of cannabis use. Future studies may investigate whether other genes mediate the effect between cannabis and metabolic risk factors.

W11-01 European portal for high quality links selected by colleagues: www.psychiatrynet.eu

The internet makes it possible to search in an endless variety of information. However, not all information is valid and reliable. Googling the term schizophrenia gives over 10 million hits. Among these hits there are some high quality websites, but also many sites with useless or even misleading or false information. With this workshop the editors-in-chief of the website www.psychiatrynet.eu will present search strategies for the participants, which they can apply in their daily practice. In June 2008 the English version of www.psychiatrynet.eu has been launched modelled after the Dutch website www.psychiatrienet.nl (launched in 2001). The lead of the website is ‘An independent selection of high quality links by your colleagues’. Independency is a basic value and the financial support comes from the Foundation of the Netherlands and Flemish Journal of Psychiatry. The current editorial board consists of over 50 mainly Dutch and Flemish psychiatrists, who select links and provide a short description of the links. In the forthcoming years members from different European countries will be selected to join the European editorial board. The goal is to become a key website for psychiatrists in Europe.