Rael D. Strous

A Highly Significant Association between a COMT Haplotype and Schizophrenia

Several lines of evidence have placed the catechol-O-methyltransferase (COMT) gene in the limelight as a candidate gene for schizophrenia. One of these is its biochemical function in metabolism of catecholamine neurotransmitters; another is the microdeletion, on chromosome 22q11, that includes the COMT gene and causes velocardiofacial syndrome, a syndrome associated with a high rate of psychosis, particularly schizophrenia. The interest in the COMT gene as a candidate risk factor for schizophrenia has led to numerous linkage and association analyses. These, however, have failed to produce any conclusive result. Here we report an efficient approach to gene discovery. The approach consists of (i) a large sample size-to our knowledge, the present study is the largest case-control study performed to date in schizophrenia; (ii) the use of Ashkenazi Jews, a well defined homogeneous population; and (iii) a stepwise procedure in which several single nucleotide polymorphisms (SNPs) are scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. We found a highly significant association between schizophrenia and a COMT haplotype (P=9.5x10-8). The approach presented can be widely implemented for the genetic dissection of other common diseases.

Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior.

We have recently characterized a functional polymorphism in the catechol-O-methyltransferase (COMT) gene that is responsible for substantial variability in COMT enzymatic activity found in humans. A common low-activity variant of the enzyme contains a methionine residue at amino acid 158 of membrane-bound COMT whereas the common high activity variant has a valine at this site. Considering the role of COMT in dopamine metabolism and the involvement of dopaminergic pathways in the pathogenesis of schizophrenia and violence, we screened 37 patients with schizophrenia to determine whether or not a behavioral association with the COMT polymorphism exists. Patients were assessed for dangerousness on the basis of a history of violent and threatening behavior, crime, cocaine and alcohol abuse, and other antisocial behaviors. We found that schizophrenic patients who were homozygous for the low activity allele were judged by their psychiatrists to be at higher risk for aggressive and dangerous behavior than those who were homozygous for the high activity allele (Kruskal-Wallis statistic = 10.43; P = 0.003).

COMT: A common susceptibility gene in bipolar disorder and schizophrenia

A variety of psychiatric illnesses, including schizophrenia and bipolar disorder, have been reported in patients with microdeletion on chromosome 22q11—a region which includes the catechol‐O‐methyltransferase (COMT) gene. The variety of psychiatric manifestations in patients with the 22q11 microdeletion and the role of COMT in the degradation of catecholamine neurotransmitters may thus suggest a general involvement of the COMT gene in psychiatric diseases. We have previously reported on a significant association between a COMT haplotype and schizophrenia. In this study, we attempt to test for association between bipolar disorder and the polymorphisms implicated in schizophrenia. The association between COMT and bipolar disorder was tested by examining the allele and haplotype found to be associated with schizophrenia. A significant association between bipolar disorder and COMT polymorphisms was found. The estimated relative risk is greater in women, a result consistent with our previous findings in schizophrenia. We suggest that polymorphisms in the COMT gene may influence susceptibility to both diseases—and probably also a wider range of behavioral traits.

Elevation of the cortisol/dehydroepiandrosterone ratio in schizophrenia patients.

Dehydroepiandrosterone (DHEA) and its sulfate derivative DHEA-S are neurosteroids, produced in the brain, and neuroactive steroids, produced in the adrenals and affecting the brain. We compared the ratios of serum cortisol/DHEA or DHEA-S in schizophrenia patients with normal subjects, and determined the correlation of these ratios with psychopathology and distress. Early morning plasma concentrations of DHEA, DHEA-S, and cortisol were determined by radioimmunassay in 40 medicated schizophrenia inpatients, and 15 healthy subjects with similar age and sex distribution. Subjects were assessed for psychopathology using the Positive and Negative Syndrome Scale (PANSS) and the Montgomery and Asberg Depression Rating Scale (MADRS), anxiety, anger, emotional and somatic distress levels. Schizophrenia inpatients demonstrated significantly higher levels of state and trait anxiety, anger expression index, emotional and somatic self-reported distress scores. Cortisol/DHEA and cortisol/DHEA-S ratios were significantly higher in schizophrenia patients than in healthy comparison subjects. Both ratios correlated positively with age and duration of illness; cortisol/DHEA-S ratio also showed positive association with age of illness onset. When age, illness duration and age of onset were controlled, cortisol/DHEA-S ratio significantly correlated with severity of depression (MADRS, r=0.33, p=0.048), state and trait anxiety (r=0.43, p=0.008 and r=0.40, p=0.014, respectively), trait anger (r=0.41, p=0.012), angry temperament (r=0.46, p=0.004), anger expression index (r=0.36, p=0.033), and hostility (r=0.42, p=0.010). No significant association was found between these ratios and severity of psychopathology, and type or dosage of antipsychotic agents. Thus, elevated cortisol/DHEA and/or cortisol/DHEA-S ratios in schizophrenia patients are positively associated with higher scores for anxiety and anger, depression and hostility, age and age of onset/duration of illness, but are independent of severity of psychopathology (PANSS) and antipsychotic treatment.

Alcohol and cannabis use in schizophrenia: effects of clozapine vs. risperidone

BACKGROUND Alcohol and cannabis use disorders worsen the course of schizophrenia. While the typical antipsychotics are of limited value in controlling substance use in schizophrenic patients, previous studies suggest that the novel antipsychotic clozapine (CLOZ) may decrease their substance use. We describe a retrospective study of the effects of the novel antipsychotics risperidone (RISP) and clozapine on alcohol and cannabis use in patients with schizophrenia or schizoaffective disorder and comorbid alcohol and/or cannabis use disorder. METHOD This study involved retrospective assessment of abstinence (cessation of alcohol and cannabis use) in 41 patients treated with either risperidone (n=8) or clozapine (n=33) for at least 1 year. In 32 of these 41 patients, information was available on whether abstinence occurred during the 1-year period. RESULTS Abstinence rates were significantly higher in patients treated with clozapine than in those treated with risperidone (54% vs. 13%, p=0.05). The nine patients treated for at least 1 year, but excluded from the analysis because time of cessation of use was not known, had all stopped alcohol/cannabis use during clozapine treatment. DISCUSSION While the limitations of this retrospective study must be recognized, the data suggest that comorbid patients treated with clozapine are more likely to abstain from alcohol and cannabis use than are those treated with risperidone. Further prospective studies will be required to confirm these intriguing results.

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.

Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: a replication study

We have previously reported that increased aggressive behavior in schizophrenic patients may be associated with a polymorphism at codon 158 of the catechol O‐methyltransferase (COMT) gene that encodes a low enzyme activity variant. The finding has been replicated by one group, but not others. The discordant findings could be due to statistical errors or methodological issues in the assessment of aggressive/violent behavior. Consequently, additional studies are needed. Patients with schizophrenia (SZ) were assessed for violent behavior using the Lifetime History of Aggression (LHA) scale, an 11‐item questionnaire that includes Aggression, Self‐Directed Aggression, and Consequences/Antisocial Behavior subscales. DNA was genotyped for the COMT 158 polymorphism, as well as a functional polymorphism in the monoamine oxidase A (MAOA) gene promoter. Similar to our previously reported findings, a statistically significant association was found between aggressive behavior in SZ and the COMT 158 polymorphism; mean LHA scores were higher in subjects homozygous for 158Met, the low enzyme activity COMT variant (F(2,105) = 5.616, P = 0.005). Analysis of the major LHA subscales revealed that the association with 158Met was due to high scores on the Aggression, and Self‐Directed Aggression subscales, but not the Consequences/Antisocial Behavior subscale. No significant association was detected for the MAOA gene alone. Our findings provide further support that COMT is a modifying gene that plays a role in determining interindividual variability in the proclivity for outward and self‐directed aggressive behavior found in some schizophrenic patients.

Increased circulatory dehydroepiandrosterone and dehydroepiandrosterone-sulphate in first-episode schizophrenia: relationship to gender, aggression and symptomatology

Dehydroepiandrosterone (DHEA) is a major circulating neurosteroid in humans and its administration has demonstrated efficacy in the improvement of mood, with increased energy, interest, confidence and activity levels. Since recent findings have suggested the role of neurosteroids in general, and DHEA in particular, in the symptomatology and pharmacotherapy of schizophrenia patients with chronic illness, we investigated DHEA and DHEA-S blood levels in individuals in their first-episode of psychosis in order to exclude effects of age, chronic illness, long-term treatment and institutionalization. Blood levels for DHEA, DHEA-S and cortisol were obtained for 37 first-episode schizophrenia subjects and 27 normal age- and sex-matched controls and correlated with a range of clinical and side-effect rating scales. Baseline DHEA and DHEA-S levels were significantly higher in schizophrenia patients (p<0.05 and p<0.001, respectively). No gender differences were noted in DHEA levels; however, DHEA-S levels were significantly higher in male patients. DHEA-S levels inversely correlated with severity of illness (p<0.05) and aggressive behavior (p<0.05). Patients with higher DHEA-S levels tended to have shorter hospitalizations. Results suggest that individuals in their first-episode of schizophrenia psychosis may develop a neurosteroid response to the first onset of psychosis, which may be associated with a reduction in various adverse clinical features including aggression. Such a putative mechanism may become desensitized with the onset of chronic illness. While preliminary, these results further imply the role of these neurosteroids in the pathophysiology and management of schizophrenia.

Dopaminergic regulation of immune cells via D3 dopamine receptor: a pathway mediated by activated T cells

Neuro‐immune interactions enable mutual regulation of the nervous and immune systems. To date, evidence exists for manipulations of immune cells by neurotransmitters in the periphery. In this study, we suggest the existence of a pathway by which the brain affects immune cells. The pathway we describe here is mediated by dopamine receptors expressed on activated T cells, termed blasts. Blasts can cross the blood brain barrier regardless of antigen specificity and can therefore encounter neurotransmitters in the brain. We show that blasts have a unique response to dopaminergic activation, which has no counterpart in resting T cells. Dopaminergic activation of blasts induces a Th1 bias in their cytokine profile and causes changes in surface marker expression. We further suggest that these changes can subsequently be transferred to peripheral T cells. We have tested this pathway in two in vivo systems: in rats exogenously administered with L‐dopa, and in schizophrenia, which is characterized by a central nervous system‐restricted increase in dopamine. In both models, peripheral T cells exhibit similar features to those of dopaminergically activated blasts. The existence of such a pathway by which the brain can regulate immune cells opens a conceptually new direction in neuro‐immune interactions.

Reduced language lateralization in first-episode schizophrenia: An fMRI index of functional asymmetry

Patients with schizophrenia exhibit a decrease or loss of normal anatomical brain asymmetry that also extends to functional levels. We applied functional magnetic resonance imaging (fMRI) to investigate language lateralization in patients with schizophrenia during their first episode of illness, thus excluding effects of chronic illness and treatment. Brain regions activated during language tasks of verb generation and passive music listening were explored in 12 first-episode patients with schizophrenia and 17 healthy controls. Regions of interest corresponded to Brocas area in the inferior frontal gyrus (IFG) and Wernickes area in the superior temporal sulcus (STS). Patients with schizophrenia had significantly smaller lateralization indices in language-related regions than controls. A similar effect was observed in their IFG and STS regions. There was no difference between the groups in the auditory cortex for the music task. Patients with schizophrenia demonstrated greater activation than the controls in temporal regions: the difference was larger in patients with more severe positive symptom subscores. In conclusion, patients with schizophrenia demonstrated loss of normal functional brain asymmetry, as reflected in diminished lateralization of language-related activation in frontal and temporal regions. This phenomenon was already present during their first episode of psychosis, possibly reflecting developmental brain abnormalities of the illness.