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Relationship Between Adverse Effects of Antipsychotic Treatment And Molecular Psychiatry (2002) 7, 695–705 2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Relationship between adverse effects of antipsychotic treatment and dopamine D2 receptor polymorphisms in patients with schizophrenia R Kaiser1,2, P-B Tremblay1, F Klufmo¨ller1, I Roots1 and J Brockmo¨ller1,2 1Institute of Clinical Pharmacology, Universita¨tsklinikum Charite´, Humboldt Universita¨t zu Berlin, Berlin, Germany; 2Institute of Clinical Pharmacology, Universita¨tsklinikum der Georg-August-Universita¨t Go¨ttingen, Go¨ttingen, Germany Extrapyramidal adverse symptoms (EPS) represent a major type of adverse events in treat- ment with typical antipsychotic drugs which share high affinity to the dopamine D2 receptor (DRD2). Genetic variants of this receptor may modulate the therapeutic response and the severity of adverse symptoms of antipsychotics. We analyzed nine known polymorphisms of the DRD2 in 665 schizophrenic patients with European Caucasian ethnic background and compared the intensity of acute dystonia, extrapyramidal symptoms, akathisia, and tardive dyskinesia between carriers of different DRD2 genotypes. In a subgroup of 40 patients with most severe extrapyramidal symptoms we sequenced the coding region including the exon- intron junctions of the DRD2 gene. Functionally relevant DRD2 amino acid variants (Ser310, Cys311) were rare or were not found at all (Ala96). Complete sequence analysis of sufferers from the most severe adverse effects revealed two new intronic polymorphisms and a silent polymorphism in exon 7, but no new amino acid variants beyond those which are already known. We found no significant association between these polymorphisms and the intensity of the different types of adverse neurologic effects of the antipsychotics. These results were obtained by correlating adverse events with each of the nine single nucleotide polymorphisms and by correlation with the estimated haplotypes. In conclusion, genetic variations in the DRD2 gene were no major predictors of the individually variable adverse effects from antipsy- chotic treatment in Caucasian schizophrenic patients. Molecular Psychiatry (2002) 7, 695–705. doi:10.1038/sj.mp.4001054 Keywords: dopamine D2 receptor; DRD2; polymorphism; schizophrenia; adverse effects; BARS; AIMS; EPS; dyskinesia; akathisia Introduction striatal dopamine resulting in an increased oxidative cellular stress.6,7 Administration of typical antipsychotics in the treat- Akathisia is a frequent adverse effect of antipsy- ment of schizophrenia is associated with a high rate of chotic treatment and is characterized by periodic undesirable neurologic effects such as acute dystonia, movements of the legs and inner restlessness. A dopa- pseudoparkinsonism (EPS), akathisia and tardive dys- minergic misbalance may be the underlying mech- kinesia. These may be observed in up to 50–75% of anism since the occurrence of akathisia was related to patients and may require discontinuation of treatment D and D receptor occupancy.8–10 in up to 10% of patients.1,2 1 2 Tardive dyskinesia is a later and most pronounced Antidopaminergic drugs produce acute dystonia and adverse event appearing as abnormal, involuntary, pseudo-parkinsonian symptoms and in a subgroup of irregular, repetitive movements of the orofacial muscu- long-term or high-dose treated patients these symp- lature and limbs found in approximately 25% of toms may persist after discontinuation of the medi- patients. Alteration in the dopamine D or D receptor cation in the form of tardive dyskinesia.3,4 It has been 1 2 mediated striatonigral or striatopallidal pathways and hypothesized that neuroleptics irreversibly desensitize a loss of striatal neurons might be involved in the and depopulate dopaminergic receptors5 or that they pathogenesis indicating a neurotoxic effect of long- increase the neuronal firing rates and release of nigro- term antipsychotic treatment.11,12 The dopamine D2 receptor (DRD2) is the primary binding target of all typical antipsychotics. It belongs Correspondence: Prof Dr J Brockmo¨ller, Abteilung fu¨ r Klinische to the family of receptors coupled to heterotrimeric Pharmakologie, Universita¨tsklinikum der Georg-August-Universi- cyclic guanine nucleotide binding regulatory proteins ta¨tGo¨ttingen, Robert Koch Str 40, D-37075 Go¨ttingen, Germany. E-mail: jurgen.brockmollerȰmed.uni-goettingen.de (G-proteins). The DRD2 activates intracellular signaling Received 3 July 2001; revised 31 July 2001; accepted 30 Nov- by inhibition of cAMP synthesis through interaction ember 2001 with Gi-like proteins. As shown in Figure 1, the DRD2 Dopamine D2 receptor polymorphisms and adverse events R Kaiser et al 696 Figure 1 The genomic structure and the examined polymorphisms of the DRD2 receptor gene. Boxes represent the exons. Shadowed boxes represent the coding sequences within the exons. Transmembrane domains (I–VII) were characterized by black boxes. All polymorphisms are indicated with their respective localization according to the published sequence.13 Polymor- phisms indicated by * have been found by sequencing in the subgroup of 40 individuals with the severest EPS. gene has eight exons and spans at least 270 kb. The kum Benjamin Franklin) and from three community presumed promoter sequence is separated by the large psychiatric hospitals (Wilhelm-Griesinger Kranken- (greater than 250 kb) first intron from the protein- haus, Kliniken im Theodor Wenzel Werk, Urban- coding sequence.13,14 Several variants of the DRD2 gene Krankenhaus). Only subjects of German Caucasian are known: one substitution (Val96Ala) within the descent were included. second transmembrane domain and two substitutions Patients with organic or drug-induced psychosis as (Pro310Ser, Ser311Cys) within the third transmembrane revealed by clinical history, magnetic resonance tom- domain and a number of silent polymorphisms.15 Pre- ography, computerized tomography, or toxicological vious studies using positron emission tomography laboratory findings and patients younger than 18 or (PET) have shown that a threshold DRD2 occupancy of older than 70 years were excluded. Not all patients about 65–75% during antipsychotic treatment is neces- could be evaluated by the rating scales given below sary to obtain a therapeutic effect.16 Individuals with because they were either not able to participate in the the TaqIA1 and TaqIB1 allele were shown to have a neurological tests for adverse effects or were dismissed decreased striatal DRD2 density and showed a better prior to the respective test dates from the hospitals clinical response to a DRD2 antagonist.17–20 In contrast, within a few days after admission to the hospital. In individuals with the −141C insertion allele of the pro- addition, we excluded all patients with repeated moter showed an increased DRD2 density.17 Moreover, admission to the hospital during the study period. Of in vitro the Ala96 variant had a 50% reduced binding the 665 patients initially recruited, we could analyze affinity for clozapine, chlorpromazine and dopamine the different scores for the adverse effects from 584 whereas the Cys311 and Ser310 variants were markedly patients at observation point day 2–4, from up to 518 less effective in inhibiting cAMP synthesis than the patients at day 12–16 and from up to 390 patients at 21,22 wild-type or the Ala96 variant. day 26–30. To explore the bias possibly caused by Therefore, these variations in the DRD2 receptor those who could not be explored for adverse events, gene might explain individual differences in the sus- we compared the genotype frequencies in both groups ceptibility to develop adverse drug effects in schizo- (those who completed the evaluation and those who phrenic patients. We tested this hypothesis in a multi- did not complete the evaluation), but no significant dif- center prospective trial in patients receiving typical ferences were found by use of the chi-square test. This antipsychotic drugs. result excludes at least a major selection bias. Informed consent was obtained from all subjects. The study was approved by the Ethics Committee of the Universitats- Materials and methods ¨ klinikum Charite´ (Humboldt-Universita¨t zu Berlin) and Subjects the Universita¨tsklinikum Benjamin Franklin (Freie A hospital-based, multicenter, naturalistic, prospec- Universita¨t Berlin). tive, non-interventional study was performed with All 665 patients were acute hospitalized patients unrelated schizophrenic patients from Berlin, Ger- with schizophrenia according to DSM-IV criteria, many. We recruited 665 schizophrenic patients (53.6% including 368 schizo-paranoid (DSM-IV 295.3), 134 male, 46.4% female) with a mean age of 38.3 years schizo-affective (295.7), 45 residual (295.6), 41 cata- (range 18–70 years, SD = 12.1) and a median age of tonic (295.2), 23 disorganized (295.1), 11 schizophrenic onset of 28.7 years (range 14–66 years, SD = 9.1) from form (295.4), six undifferentiated (295.9), and 37 other two university psychiatric hospitals in Berlin and unclassified subtypes. Diagnosis was assigned on (Universita¨tsklinikum Charite´ and Universita¨tsklini- the basis of interviews and medical records according Molecular Psychiatry Dopamine D2 receptor polymorphisms and adverse events R Kaiser et al 697 to DSM-IV criteria. All psychiatrists involved in the for 1 min 50 s; TaqIB: 94°C for 1 min, 60°C for 1 min, study received detailed instructions on how to apply 72°C for 1 min 50 s; TaqID: 94°C for 1 min, 60°C for 1 ° ° ° the DSM-IV criteria prior to the study. Age at first epi- min, 72 C for 1 min 20 s; Val96Ala: 94 C for 30 s, 58 C ° ° ° sode, duration, familial predisposition, number of for 1 min, 72 C for 45 s; Pro310Ser: 94 C for 1 min, 60 C ° ° recurrent exacerbations, smoking behavior and current for 1 min, 72 C for 1 min 30 s; Ser311Cys: 94 C for 1 therapeutic response (using the positive and negative min, 60°C for 1 min, 72°C for 1 min 30 s; and for the Ͼ ° symptoms scale), and medication were documented. Leu141Leu (423G A) polymorphism: 94 C for 30 s, Incident cases were 131 patients and 534 patients suf- 54°C for 30 s, 72°C for 1 min.
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