Nimrod Grisaru

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.

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.

Effect of transcranial magnetic stimulation in posttraumatic stress disorder: a preliminary study

BACKGROUND Transcranial magnetic stimulation (TMS) has become, over the last few years, a promising avenue for new research in affective disorders. In this study we have evaluated the clinical effect of slow TMS on posttraumatic stress disorder (PTSD) symptoms. METHODS Ten PTSD patients were given one session of slow TMS with 30 pulses of 1 m/sec each, 15 to each side of the motor cortex. RESULTS Symptoms of PTSD were assessed by using three psychological assessment scales, at four different time points. In this first, pilot, open study, TMS was found to be effective in lowering the core symptoms of PTSD: avoidance (as measured by the Impact of Event Scale), anxiety, and somatization (as measured by the Symptom Check List-90). A general clinical improvement was found (as measured by the Clinical Global Impression scale); however, the effect was rather short and transient. CONCLUSIONS The present study showed TMS to be a safe and tolerable intervention with possibly indications of therapeutic efficacy for PTSD patients.

Slow magnetic stimulation of prefrontal cortex in depression and schizophrenia.

1. The authors used transcranial magnetic stimulation (TMS) of pre-frontal cortex to study mood changes in 10 depressed patients and 10 schizophrenic patients. 2. A slow rate of stimuli was used, one per 30 seconds; maximal intensity of about 2 Tesla was given for 30 stimuli, 15 on each side of the brain. 3. No side effects were seen and at least three depressed patients and two schizophrenic patients appeared to improve, at least transiently. 4. These results suggest that rapid rate TMS may not be necessary to elicit mood effects.

Magnetic Stimulation of the Brain in Animal Depression Models Responsive to Ecs

Studies in humans show antidepressant potential for transcranial magnetic stimulation (TMS). We therefore studied TMS in animal models of depression and compared its effects with those of ECS. ECS in rats has several robust behavioral effects, including enhancement of apomorphine-induced stereotypy, reduction of immobility time in the Porsolt swim test, and increases in seizure threshold for subsequent stimulation. Seven or 10 days of daily TMS consistently enhanced apomorphineinduced stereotypy, whereas a single session of TMS did not. Two TMS treatments markedly reduced immobility in the Porsolt swim test, as does ECS. A single TMS treatment markedly reduces the percentage of rats seizing in response to a ECS-like electrical stimulus to the brain 10 s later, as does an ECS treatment itself but not a sub-convulsive electrical stimulus to the brain. Long-term administration of ECS as well as other antidepressant treatments downregulates β-adrenergic receptors. We found that TMS significantly reduced the density of [3H]CGP-12177 (a radioligand with β-adrenergic affinity) binding sites in cortical (p < 0.05) but not hippocampal membranes. The role of monoamines in the mechanism of action of antidepressant treatments was investigated in numerous studies. Region-specific changes in the brain steady-state levels, and turnover rates of monoamines were detected 10 s after administration of a single repetitive TMS (rTMS) session. In the striatum and hippocampus, dopamine levels were increased by 25 ± 1.5% and 18 ± 0.8%, respectively, but were reduced in frontal cortex and decreased in the striatum and hippocampus in the TMS-treated rats with no change to the midbrain. TMS caused an increase in serotonin and 5-HIAA levels in the hippocampus but not in other brain regions examined in this study. The ability of TMS to induce behavioral and biochemical alterations similar to those of ECS may further support the potential role of TMS as an antidepressant treatment and bring us closer to the understanding of the mechanism of action of TMS.

Repetitive transcranial magnetic stimulation in the treatment of depression in adolescents: an open-label study.

Objective: This open-label pilot study examined repetitive transcranial magnetic stimulation as a possible treatment of adolescent resistant depression. Method: Nine adolescents (aged 16-18 years) with severe resistant depression (determined by SCID) were recruited, and their depression, suicidality, and cognitive functions were evaluated before, during, and after a course of twenty 10-Hz, 2-second trains (intertrain intervals of 58 seconds) given over 20 min/d over 14 working days. Results: Lower levels of depression with progression in therapy were recorded by both the Beck Depression Inventory and Child Depression Rating Scale measures (F1.7,14.01 = 4.52, P < 0.05; F4,32 = 6.645, P < 0.01, respectively). Three patients reached the primary outcome measure of less than 30% reduction in their Child Depression Rating Scale. The effect on suicidality was not significant. Side effects were considered mild. Conclusions: Repetitive transcranial magnetic stimulation might be a possible therapy for adolescent depression. Our preliminary findings warrant double-blind, controlled studies.

Effect on the Emotions of Healthy Individuals of Slow Repetitive Transcranial Magnetic Stimulation Applied to the Prefrontal Cortex

Summary Recent studies indicate that both slow and fast repetitive transcranial magnetic stimulation (rTMS) have a mood-elevating effect in major depressive episodes. The effect of slow rTMS on the emotions of healthy individuals has not been examined. Methods We studied the effects of slow rTMS applied to the left and right prefrontal cortex (PFC) of 18 healthy individuals. Active and sham stimulation was applied to both sides of all individuals. Stimulation was with a 9-cm figure-of-eight coil at the following parameters: 110% of motor threshold, 1 Hz, single train of 500 stimuli. Depression, happiness, irritability, and anxiety were measured before and 5, 30, and 240 min after stimulation using visual analogue scales. A sleep questionnaire was completed the morning after each stimulation session. A new method of providing sham was used. Results Slow rTMS applied to the PFC did not produce significant changes in the emotions of healthy individuals; nor was sleep influenced. Discussion In conclusion, slow rTMS at these parameters applied to the PFC does not produce significant changes in the emotions of healthy individuals.

Beneficial effects of caloric vestibular stimulation on denial of illness and manic delusions in schizoaffective disorder: a case report.

INTRODUCTION Preliminary data suggests that caloric vestibular nerve stimulation (CVS) single session application of cold water to the left ear induces a clinically significant, short-lived beneficial effect on specific types of illness denial (i.e., anosognosia) and delusions (i.e., somatic type). METHODS We recently studied the effect of left versus right ear ice water (4°C) CVS on delusions and insight of illness in a patient with manic episode due to schizoaffective disorder. The patient was evaluated at baseline, immediately after the CVS, and then at 20 minutes, 60 minutes, and 24 hours. The method was first applied to one ear and 4 days later to the other. To assess whether the effect is specific to mania we employed the same procedure in two other patients with schizophrenia who also demonstrated delusions and impaired insight. RESULTS All three patients showed a difference favoring left versus right ear CVS that was maintained for 20 minutes, and diminished over a 60 minute period. EEG analyses showed a numerically non-significant increase in bilateral frontal and central alpha EEG band activation (more pronounced in the right hemisphere) with left but not right ear CVS 5 minutes after the CVS, and that diminished after 20 minutes. DISCUSSION The results suggest that left versus right CVS may have a short lived beneficial effect on manic delusions and insight of illness that seem to appear in other types of psychoses (i.e., schizophrenia). CONCLUSION These preliminary results suggest that single session CVS may have short lived beneficial effects in mania and perhaps in other types of psychoses. Further research is mandatory.

Ritual Female Genital Surgery Among Ethiopian Jews

Ritual female genital surgery is usually associated with Muslim countries although it is normative also among Ethiopian Coptic Christians. Ethiopian Jewish women immigrants to Israel report that ritual female genital surgery was normative in their culture in Ethiopia, but expressed no desire to continue the custom in Israel. This contrasts with Israeli Bedouin Muslims, who were reported to regard ritual female genital surgery as an important part of their identity. Physical examination of 113 Ethiopian Jewish immigrant women in Israel found a variety of lesions in about a third of women, with 27% showing total or partial clitoral amputation. The heterogeneity of the physical findings contrasts with uniform verbal reports in interviews of having undergone a ritual of female genital surgery.

Possession by the ‘Zar’ among Ethiopian Immigrants to Israel: Psychopathology or Culture-Bound Syndrome?

The article describes a cultural pattern related to altered states of consciousness, observed amongst new immigrants from Ethiopia to Israel. The belief in possession by Zar spirits is one of the most common possession phenomena in Africa and in other continents. Possession by Zar is expressed by a wide range of behaviors, such as involuntary movements, mutism and incomprehensible language. Such behavior can be misinterpreted as representing symptoms of neuralgic or psychiatric disorders. We demonstrate the Zar phenomenon by a description of a detailed case. The article discusses the cultural and anthropological aspects of the Zar and its clinical implications and suggests that the Zar phenomenon should be understood as a culture-bound syndrome.