Baruch Spivak

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.

Elevated levels of serum interleukin-1β in combat-related posttraumatic stress disorder

Levels of serum interleukin-1 beta (IL-1 beta) and soluble interleukin-2 receptor (sIL-2R) were assessed in 19 male patients with combat-related posttraumatic stress disorder (PTSD) in comparison to 19 age- and sex-matched healthy volunteers. Serum IL-1 beta levels (but not sIL-2R) were significantly higher (p < .001) in the PTSD patients than in the controls. IL-1 beta levels did not correlate with cortisol levels, severity of PTSD, anxiety, depressive symptoms, or alexithymia score; however, they did correlate significantly (r = .54, p < .005) with the duration of PTSD symptoms. It is possible that desensitization of the hypothalamic-pituitary-adrenal axis in chronic PTSD patients counteracts the stimulatory effect of IL-1 beta on cortisol secretion.

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.

Elevated circulatory level of GABA(A)--antagonistic neurosteroids in patients with combat-related post-traumatic stress disorder.

BACKGROUND Post-traumatic stress disorder (PTSD) is a multisystem neurobiological disorder with chronic alterations in various neurochemical systems. Levels of the GABA(A)--antagonistic neurosteroids plasma dehydroepiandrosterone (DHEA) and its sulphate derivate, dehydroepiandrosterone sulphate (DHEAS) may be relevant to depressive and anxiety disorders, including PTSD. METHODS We assessed the circulatory levels of morning plasma DHEA and DHEAS in 21 male outpatients with untreated chronic combat-related PTSD (CR-PTSD), and 18 healthy control male subjects. RESULTS Compared with the control subjects, the PTSD patients showed significantly higher plasma DHEA and DHEAS levels. CONCLUSIONS Chronic CR-PTSD may be associated with increased circulatory level of neuroactive steroids with inhibitory activity at the GABA(A) receptors. Neurosteroid-induced decreased GABAergic tone may be relevant to the symptomatology and pathophysiology of chronic PTSD, as well as to the frequent co-morbidity of PTSD with depression and anxiety disorders.

Circulatory levels of catecholamines, serotonin and lipids in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) may be associated with a dysregulation of the catecholaminergic and serotonergic systems. Furthermore, ADHD is frequently complicated by aggressive impulsive behaviour, which is suggested to be related to low serum cholesterol levels. We examined the relationship between blood serotonin, norepinephrine, dopa and lipid levels and the degree of hyperactivity, impulsiveness, lack of concentration, and aggressiveness in boys with ADHD of low and high severity as determined by a specially designed formulated scale based on the DSM‐IV criteria for ADHD. No differences were noted between the groups in any of the peripheral biological parameters except blood serotonin, for which a tendency (P =0.08) towards lower levels was observed in the children with more severe disorder. We conclude that children with severe ADHD may have a different serotonin turnover compared to children with mild ADHD. These results may have implications for our understanding of the pathogenesis of ADHD, at least the more severe type.

Combined electroconvulsive-clozapine therapy.

We reviewed 36 reported psychiatric patients who were treated with a combination of electroconvulsive therapy (ECT) and clozapine. The indication of the ECT-clozapine treatment was resistance to classical antipsychotic agents, clozapine, or ECT alone. Sixty-seven percent of the patients benefited from the combined treatment. In most of the patients, the combined treatment was safe and well tolerated. Adverse reactions occurred in 16.6% of the patients and included prolonged ECT-induced seizures (one case), supraventricular (one case) and sinus tachycardia, and blood pressure elevation. It seems that combined ECT-clozapine treatment is effective and safe. This strategy may be a therapeutic option in treatment-resistant patients.

Analysis of neurosteroid levels in attention deficit hyperactivity disorder

Neurosteroids are important neuroactive substrates with demonstrated involvement in several neurophysiological and disease processes. Attention deficit hyperactivity disorder (ADHD) has been associated with dysregulation of the catecholaminergic and serotonergic systems, however its relationship to irregularities or changes in neurosteroid levels remains unknown. We examined the relationship between blood levels of dehydroepiandrosterone (DHEA), its principal precursor pregnenolone and its principal metabolite dehydroepiandrosterone sulphate (DHEAS) in 29 young male subjects aged 7-15 years with DSM-IV criteria of ADHD. Subjects were evaluated by a specially designed scale, following which patients were divided into two groups according to severity of symptomatology. Results indicated significant inverse correlations between clinical symptomatology and levels of DHEA and pregnenolone in the total group. These inverse correlations were particularly evident in the less severe group of subjects. Levels of DHEA and DHEAS were inversely correlated with the hyperactivity subscale. Furthermore, using median blood levels as a cut-off indicator, higher blood levels of DHEA and DHEAS were associated with fewer ADHD symptoms, in particular hyperactivity symptomatology. Our findings suggest a possible protective effect of various neurosteroids on the expression of ADHD symptomatology.

Reduction of Aggressiveness and Impulsiveness during Clozapine Treatment in Chronic Neuroleptic-Resistant Schizophrenic Patients

Aggressive and impulsive behavior is frequently observed in schizophrenic patients. Previous studies suggest that impulsive aggression may be the most common behavioral correlate of central serotonergic system dysfunction. This study was aimed to determine if clozapine, an atypical antipsychotic agent with potent serotonergic antagonistic properties, can reduce impulsiveness and aggression in neuroleptic-resistant chronic schizophrenic patients. Fourteen neuroleptic-resistant chronic schizophrenic patients were treated with clozapine and prospectively evaluated for aggressiveness and impulsiveness for 18 weeks. Clozapine treatment induced a marked decrease in impulsiveness (32% on the Impulsivity Scale; p < 0.0001) and aggressiveness (98% on the Overt Aggression Scale; p < 0.0001). We conclude that clozapine treatment may be effective in reducing psychotic symptoms as well as in controlling aggressive and impulsive behavior in neuroleptic-resistant chronic schizophrenic patients.

Lowered DHEA-S plasma levels in adult individuals with autistic disorder

The aim of this study was to determine for the first time neurosteroid levels, dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) in particular, in a group of adult patients with autistic disorder and compare these levels with normal healthy individuals. Levels of DHEA, DHEA-S and cortisol were compared between 15 adult drug-free patients with autistic disorder and 13 healthy controls. The Ritvo-Freeman Real-Life Rating Scale (RLRS) and the Overt Aggression Scale (OAS) were assessed as a measure of symptom severity. Significant lower DHEA-S levels were observed in the group with autistic disorder as compared to controls (p < 0.05). DHEA-S levels appear to be low in patients with autistic disorder and, while speculative, may play a role in the etiopathophysiology of the disorder.

The impact of clozapine treatment on serum lipids in chronic schizophrenic patients

The aim of this retrospective study is to determine whether lipid levels rise in neuroleptic-resistant chronic schizophrenic patients during clozapine treatment and if this rise is correlated with a decrease in aggressive and suicidal behavior. Seventy neuroleptic-resistant schizophrenic patients treated with clozapine for at least 6 months were compared with 30 chronic schizophrenic patients treated with classic antipsychotic agents for the same length of time. Data on serum levels of cholesterol and triglycerides and on aggressive and suicidal behavior, as measured by the Overt Aggression Scale (OAS), were collected in both groups before treatment and 6 months later. A significant reduction in aggressive and suicidal behavior was noted in the clozapine-treated group but not in the classical antipsychotic-treated group. Clozapine treatment was associated with an elevation in serum triglyceride level, whereas classic antipsychotic treatment was associated with an increase in serum cholesterol level. We conclude that serum cholesterol level does not play a role in the clozapine-induced attenuation in aggressive and suicidal behavior in neuroleptic-resistant schizophrenic patients, though the accompanying elevation in triglycerides may be relevant to a behavioral effect.