P. Roberto Bakker

Antipsychotic-induced tardive dyskinesia and the Ser9Gly polymorphism in the DRD3 gene: A meta analysis

BACKGROUND A polymorphic site in the gene encoding the dopamine 3 receptor (DRD3) resulting in a serine (Ser) into glycine (Gly) substitution has been shown to affect dopamine binding affinity, and may contribute to individual differences in susceptibility to antipsychotic-induced tardive dyskinesia (TD). METHODS A Medline, EMBASE and PsychINFO search of literature published between 1976 and March 2005 yielded 11 studies from which data were extracted for calculation of pooled estimates using meta-analytic techniques. RESULTS The Gly allele increased the risk relative to the Ser allele (OR=1.17; 95% CI: 1.01-1.37) with evidence of publication bias. No significant genotype effects were apparent. CONCLUSIONS TD may be associated with functional variation in the DRD3 allele. However, caution is required in interpreting this finding, as there is evidence of publication bias, genetic methodology has shortcomings, and the relation between antipsychotics, schizophrenia and TD is complex.

Long-Stay Psychiatric Patients: A Prospective Study Revealing Persistent Antipsychotic-Induced Movement Disorder

Objective The purpose of this study was to assess the frequency of persistent drug-induced movement disorders namely, tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia in a representative sample of long-stay patients with chronic severe mental illness. Method Naturalistic study of 209, mainly white, antipsychotic-treated patients, mostly diagnosed with psychotic disorder. Of this group, the same rater examined 194 patients at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. Results The frequencies of persistent movement disorders in the sample were 28.4% for TD, 56.2% for parkinsonism, 4.6% for akathisia and 5.7% for tardive dystonia. Two-thirds of the participants displayed at least one type of persistent movement disorder. Conclusions Persistent movement disorder continues to be the norm for long-stay patients with chronic mental illness and long-term antipsychotic treatment. Measures are required to remedy this situation.

Candidate Gene-Based Association Study of Antipsychotic-Induced Movement Disorders in Long-Stay Psychiatric Patients: A Prospective Study

Objective Four types of antipsychotic-induced movement disorders: tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia, subtypes of TD (orofacial and limb truncal dyskinesia), subtypes of parkinsonism (rest tremor, rigidity, and bradykinesia), as well as a principal-factor of the movement disorders and their subtypes, were examined for association with variation in 10 candidate genes (PPP1R1B, BDNF, DRD3, DRD2, HTR2A, HTR2C, COMT, MnSOD, CYP1A2, and RGS2). Methods Naturalistic study of 168 white long-stay patients with chronic mental illness requiring long-term antipsychotic treatment, examined by the same rater at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. The authors genotyped 31 SNPs, associated with movement disorders or schizophrenia in previous studies. Genotype and allele frequency comparisons were performed with multiple regression methods for continuous movement disorders. Results Various SNPs reached nominal significance: TD and orofacial dyskinesia with rs6265 and rs988748, limb truncal dyskinesia with rs6314, rest tremor with rs6275, rigidity with rs6265 and rs4680, bradykinesia with rs4795390, akathisia with rs4680, tardive dystonia with rs1799732, rs4880 and rs1152746. After controlling for multiple testing, no significant results remained. Conclusions The findings suggest that selected SNPs are not associated with a susceptibility to movement disorders. However, as the sample size was small and previous studies show inconsistent results, definite conclusions cannot be made. Replication is needed in larger study samples, preferably in longitudinal studies which take the fluctuating course of movement disorders and gene-environment interactions into account.

Antipsychotic-Induced Movement Disorders in Long-Stay Psychiatric Patients and 45 Tag SNPs in 7 Candidate Genes: A Prospective Study

Objective Four types of antipsychotic-induced movement disorders: tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia, subtypes of TD (orofacial and limb truncal dyskinesia), subtypes of parkinsonism (rest tremor, rigidity, and bradykinesia), as well as a principal-factor of the movement disorders and their subtypes, were examined for association with variation in 7 candidate genes (GRIN2B, GRIN2A, HSPG2, DRD3, DRD4, HTR2C, and NQO1). Methods Naturalistic study of 168 white long-stay patients with chronic mental illness requiring long-term antipsychotic treatment, examined by the same rater at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. The authors genotyped 45 tag SNPs in 7 candidate genes, associated with movement disorders or schizophrenia in previous studies. Genotype and allele frequency comparisons were performed with multiple regression methods for continuous movement disorders. Results Various tag SNPs reached nominal significance; TD with rs1345423, rs7192557, rs1650420, as well as rs11644461; orofacial dyskinesia with rs7192557, rs1650420, as well as rs4911871; limb truncal dyskinesia with rs1345423, rs7192557, rs1650420, as well as rs11866328; bradykinesia with rs2192970; akathisia with rs324035; and the principal-factor with rs10772715. After controlling for multiple testing, no significant results remained. Conclusions The findings suggest that selected tag SNPs are not associated with a susceptibility to movement disorders. However, as the sample size was small and previous studies show inconsistent results, definite conclusions cannot be made. Replication is needed in larger study samples, preferably in longitudinal studies which take the fluctuating course of movement disorders and gene-environment interactions into account.

Effect of Antipsychotic Type and Dose Changes on Tardive Dyskinesia and Parkinsonism Severity in Patients With a Serious Mental Illness: The Curaçao Extrapyramidal Syndromes Study XII

OBJECTIVE To test the efficacy of current treatment recommendations for parkinsonism and tardive dyskinesia (TD) severity in patients with severe mental illness (SMI). METHODS We present an 18-year prospective study including all 223 patients with SMI (as defined by the 1987 US National Institute of Mental Health, which were based on DSM-III-R diagnostic criteria) receiving care from the only psychiatric hospital of the former Netherlands Antilles. Eight clinical assessments (1992-2009) focused on movement disorders and medication use. Tardive dyskinesia was measured by the Abnormal Involuntary Movement Scale and parkinsonism by the Unified Parkinsons Disease Rating Scale. Antipsychotics were classified into first-generation antipsychotic (FGA) versus second-generation antipsychotic (SGA) and high versus low dopamine 2 (D₂) affinity categories. The effect that switching has within each category on subsequent movement scores was calculated separately by using time-lagged multilevel logistic regression models. RESULTS There was a significant association between reduction in TD severity and starting/switching to an FGA (B = -3.54, P < .001) and starting/switching to a high D₂ affinity antipsychotic (B = -2.49, P < .01). Adding an SGA to existing FGA treatment was associated with reduction in TD severity (B = -2.43, P < .01). For parkinsonism, stopping antipsychotics predicted symptom reduction (B = -7.76, P < .01 in FGA/SGA-switch model; B = -7.74, P < .01 in D₂ affinity switch model), while starting a high D₂ affinity antipsychotic predicted an increase in symptoms (B = 3.29, P < .05 in D₂ affinity switch model). CONCLUSIONS The results show that switching from an FGA to an SGA does not necessarily result in a reduction of TD or parkinsonism. Only stopping all antipsychotics reduces the severity of parkinsonism, and starting an FGA or a high D₂ affinity antipsychotic may reduce the severity of TD.

Movement Disorders and Psychosis, a Complex Marriage

Most clinicians relate parkinsonism and dyskinesia directly to acute and tardive drug-induced movement disorders. However, parkinsonism and dyskinesia are also present in antipsychotic-naive patients with psychotic disorders. In this paper, we want to highlight the clinical value of these spontaneous movement disorders and want to discuss the concept of “non-mental signs.”

Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10−5 and c.2702T > G [p.V901G], MAF 2.51 × 10−3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05–13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10−8), viability (P = 8.9 × 10−7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10−4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10−5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia.

Asymmetric Drug-Induced Parkinsonism and Psychopathology: A Prospective Naturalistic Study in Long-Stay Psychiatric Patients

Background Drug-induced parkinsonism (DIP) is the most common movement disorder induced by antipsychotics. Although DIP is mostly symmetric, asymmetric DIP is reported in a substantial part of the patients. We investigated the frequency of motor asymmetry in DIP and its relationship to the severity of psychopathology in long-stay psychiatric patients. Methods We obtained data from a cohort study of 207 long-stay psychiatric patients on the frequency and risk factors of tardive dyskinesia, akathisia, tardive dystonia, and DIP. From July 2003 to May 2007 (mean follow-up, 1.1 year) drug-induced movement disorders were assessed at least two times in each patient, with a frequency of persistent DIP of 56.2%. All patients who had at least one time parkinsonism in the upper/lower limb(s) were included for analyses (190 patients, 79 women; mean age, 48.0 ± 12.9 years). The Unified Parkinson Disease Rating Scale motor scale was used to calculate the frequency of asymmetric parkinsonism. Multilevel mixed models were built to explore the relationship between asymmetry in parkinsonism and the severity of psychopathology, measured on the Clinical Global Impression-Schizophrenia scale severity index (CGI-SCH SI). Results The frequency of asymmetric parkinsonism was 20.8%. Asymmetry in parkinsonism was associated with symptom severity on all CGI-SCH SI scales (β range, 0.37–3.74) and significantly associated with the positive symptom scale (β, 3.74; 95% CI, 0.35–7.31). Conclusion DIP is asymmetric in a substantial part of patients. Asymmetric presentation of DIP is of clinical relevance as it is related to the severity of psychopathology and may alert the clinician of more severe psychopathology. Future research is recommended to provide insight into the neuropsychopathology and clinical value of asymmetric parkinsonism for psychiatric patients.

Likelihood of mechanistic roles for dopaminergic, serotonergic and glutamatergic receptors in tardive dyskinesia: A comparison of genetic variants in two independent patient populations

Objectives: An established theory for the pathogenesis of tardive dyskinesia is disturbed dopaminergic receptor sensitivity and/or dopaminergic intracellular signaling. We examined associations between genetic variants of neurotransmitter receptors and tardive dyskinesia. Methods: We assessed tardive dyskinesia in Caucasian psychiatric inpatients from Siberia (N = 431) and a long-stay population from the Netherlands (N = 168). These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared. Results: Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations. This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population. After reviewing the literature, we propose that the constitutive stimulatory activity of serotonergic type 2 receptors may be relevant. Conclusions: Inactivity of the serotonergic, type 2C receptor or blockade of these receptors by atypical antipsychotic drugs may decrease the vulnerability to develop tardive dyskinesia.

F191. THE GENETICS OF DRUG-RELATED MOVEMENT DISORDERS AN UMBRELLA REVIEW OF META-ANALYSES

Abstract Background Treatment with antipsychotics can provoke drug-related movement disorders (DRMD) (also known as extrapyramidal symptoms (EPS)), i.e. tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia. DRMD remain a cause for concern in the treatment of patients with psychotic disorders, especially because the DRMD can become irreversible (Correll and Schenk, 2008). There are lower percentages in younger patients (32%) (Mentzel 2017), but the prevalence is substantial in chronic patients (68%) (Bakker 2011), with around a quarter of chronic patients showing two different types of DRMD (Bakker 2011). DRMD can cause severe impairment in quality of life (Fujimaki 2012. In addition, a meta-analysis (Ballesteros 2000) and two recent studies showed a higher mortality in patients with tardive dyskinesia (Chong 2009, Dean and Thuras 2009). It is therefore important to find ways of preventing DRMD. Pharmacogenetic studies may identify genetic risk factors, which underlie individual vulnerability for DRMD in response to antipsychotics (Reynolds 2007; Ohmori 2003; Lerer 2002), in theory paving the way for individually tailored medication prescriptions (Lerer and Segman 2006). To date, many different papers have been written on the subject and they have presented inconsistent results. The aim of this umbrella review is to provide clinicians and patients with evidence-based information regarding the genes that are thought to be associated with DRMD and to use this umbrella review on the genetics of DRMD as a basis for recommendations for future prevention programs and research. Methods To identify all relevant meta-analyses a Medline, Embase, and Psychinfo literature search was performed. Titles and abstract were screened using predetermined criteria by two independent authors. The methodological quality of included meta-analyses was assessed by two overview authors using ‘assessment of multiple systematic reviews’ (AMSTAR) critical appraisal checklist. Reference lists of included papers and those of reviews were cross-checked and no new publications were found. Results The search yielded 14 meta-analysis studies and consensus was obtained. The DRD3, DRD2, CYP2D6, 5-HT2A, COMT and MnSOD genes all contain variants that increase the odds ratio of TD. However meta-analyses showed diminishing significance over time and meta-analyses on the same subject were difficult to compare due to differences in patient population and methods used. Discussion For now it appears that TD is a complex disease with multiple genes that are involved in its phenotype and more studies (eg. Genome wide associatio studies), on a larger scale, are required to develop a genetic test kit to predict the chance of TD. To achieve this multiple research groups need to work together, a DRMD genetic database needs to be in place to overcome publication bias and results need to be stratified by patient characteristics. The result could be test that undoubtedly will be of great clinical value in treating patients and by prospectively preventing debilitating DRMD.