Biomedical subjects

R H Belmaker

Publications and source records attributed to R H Belmaker.

At least 73 records · Page 4Linked to original sources

PubMed2000

Personality and polymorphisms of genes involved in aminergic neurotransmission.

Genetic factors significantly contribute to the determination of human personality traits assessed by self-report questionnaires. However, only in the past few years have common genetic polymorphisms especially the dopamine D4 receptor and the serotonin transporter promoter region been associated with specific personality traits such as novelty seeking and harm avoidance, respectively. The effects of these genes are modest and several genes are likely accounting for individual differences in personality dimensions that can be attributed to genetic factors. Molecular genetic studies of adult personality have also been extended to investigations of early human temperament and some of the genes associated with adult personality traits are also contributing to the earliest developmental expressions of human behavior. Additionally, some of these same genes have also been implicated in various types of abnormal behavior including addiction, obsessive-compulsive disorder, attention deficit, depression, aggression and psychosis. Future research directions will no doubt take advantage of the bioinformatics revolution coinciding with the completion of the first phase of the human genome project. It should soon be possible to identify many of the genes contributing to specific personality traits and to better define their role in determining normal and abnormal behavior from early development through adulthood.

Animals↗

PubMed2000

No association between the dopamine D3 receptor Bal I polymorphism and schizophrenia in a family-based study of a Palestinian Arab population.

Several recent meta-analyses appear to show a weak but significant effect of both forms of the gly/ser DRD3 polymorphism in conferring risk for schizophrenia. Since most studies have employed the artifact-prone case-control design, we thought it worthwhile to examine the role of this polymorphism using a robust family-based strategy in an ethnic group not previously systematically studied in psychiatric genetics, Palestinian Arabs. We failed to obtain any evidence in 129 Palestinian triads, using the haplotype relative risk (allele frequency: Pearson chi-square = 0.009, P > 0.1, df = 1, n = 258 alleles) or transmission disequilibrium test design (chi-square = 0.38, P > 0.1, n = 86 families) for association/linkage (or increased homozygosity) of the DRD3 Bal I polymorphism to schizophrenia in our sample. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:778-780, 2000.

Alleles↗

PubMed2000

Nordidemnin potently inhibits inositol uptake in cultured astrocytes and dose-dependently augments lithium's proconvulsant effect in vivo.

It has been suggested that inositol uptake across the cell membrane is of importance for maintenance of the inositol pool involved in lithium's therapeutic effect in bipolar disease and in the lithium-pilocarpine seizure test in freely moving rats (measuring the latency of a normally subconvulsive concentration of pilocarpine to seizure induction in the additional presence of lithium). We have tested this hypothesis by: 1) demonstrating an extremely high potency of nordidemnin as an inhibitor of myo-inositol uptake in primary cultures of mouse astrocytes; and 2) determining the dose-response correlation of a nordidemnin-induced decrease in the latency before appearance of seizures in the lithium-pilocarpine test after intracerebroventricular injection of minute samples (10 microl) of virtually isotonic saline solution.

Animals↗

PubMed2000

Chronic treatment of human astrocytoma cells with lithium, carbamazepine or valproic acid decreases inositol uptake at high inositol concentrations but increases it at low inositol concentrations.

Inositol uptake was measured at concentrations of 25, 40 and 50 microM in human astrocytoma cell cultures treated for 1-3 weeks with pharmacologically relevant concentrations of LiCl, valproic acid or carbamazepine as well as in control cultures that had not been treated with any drug. After at least 2 weeks of treatment, each of these 3 conventional anti-bipolar drugs increased the uptake significantly at 25 microM inositol, had no effect at 40 microM, and decreased it at 50 microM inositol. Reduction of the drug concentrations by 50% abolished the stimulation of uptake at 25 microM inositol by lithium and valproic acid and reduced that by carbamazepine. These findings may contribute to an understanding of the mechanisms of action for anti-bipolar medication, and explain the controversy in the literature whether or not brain inositol is reduced after chronic administration of lithium.

Antimanic Agents↗

PubMed2000

Animal models of the mechanisms of action of repetitive transcranial magnetic stimulation (RTMS): comparisons with electroconvulsive shock (ECS).

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive means of brain stimulation with a broad range of basic neuroscience and potential future clinical applications. Recent animal studies have shed some light on the mechanisms of action of rTMS, and broadened our understanding of how this intervention affects brain functioning acutely and chronically. Differences in the physical properties of magnetic and electrical stimulation result in marked disparities in the amount and distribution of electrical current induced in the brain; nevertheless, rTMS shares many of the behavioral and biochemical actions of electroconvulsive shock (ECS) and other antidepressant treatments. rTMS reduces immobility in the Porsolt swim task and enhances apomorphine-induced stereotypy, as does ECS. Although rTMS can induce a seizure when given at high enough doses, most studies have found subconvulsive levels of rTMS to be anticonvulsant. rTMS acutely modulates dopamine and serotonin content and turnover rates. Chronic rTMS modulates cortical beta-adrenergic receptors, reduces frontal cortex 5-HT2 receptors, increases 5-hydroxytryptamine1A receptors in frontal cortex and cingulate, and increases N-methyl-D-aspartate receptors in the ventromedial hypothalamus, basolateral amygdala, and parietal cortex. More work will be needed to clarify and explore the mechanism behind the early suggestions that rTMS may exert long-term-potentiation-like or long-term-depression-like action on hippocampal activity. Finally, rTMS is emerging as yet another intervention, like ECS and other antidepressants, that can regulate gene expression and may have an impact on neuronal viability and synaptic plasticity.

Animals↗

PubMed2000

Scyllo-inositol in post-mortem brain of bipolar, unipolar and schizophrenic patients.

Inositol levels measured in postmortem brain of unipolar, bipolar and schizophrenic patients, suicide victims and normal controls showed no difference in scyllo-inositol levels in frontal or occipital cortex between any of the groups. We could not replicate previous reports of low myo-inositol levels in the frontal cortex of unipolar, bipolar and schizophrenic patients and suicide victims. There was no correlation between myo-inositol levels and estimated chlorpromazine equivalents in neuroleptic-treated subjects, and no effect of chronic haloperidol treatment on rat brain myo-inositol levels.

Adolescent↗

PubMed2000

The effectiveness of olanzapine in treatment-refractory schizophrenia when patients are nonresponsive to or unable to tolerate clozapine.

OBJECTIVE: This multicenter, open-label study was designed to assess the efficacy and tolerability of olanzapine in patients with chronic schizophrenia who are resistant to therapy with classic neuroleptic agents and are either not responsive to or unable to tolerate clozapine. METHODS: Patients received olanzapine orally once daily for 18 weeks at doses ranging from 5 to 25 mg. The primary efficacy measure was change in the total score on the Positive and Negative Syndrome Scale (PANSS) from baseline to end point. Secondary efficacy measures were the total score on the Brief Psychiatric Rating Scale (BPRS); the PANSS positive, negative, general psychopathology, and mood subscores; and the Clinical Global Impression improvement score. Also recorded were spontaneously reported adverse events; extrapyramidal symptoms (assessed by the Abnormal Involuntary Movement Scale, Simpson-Angus Scale, and Barnes Akathisia Scale); vital signs; and clinical laboratory test results. RESULTS: Forty-eight patients were treated with olanzapine; of these, 45 were assessable over the full 18-week study period. Total scores on the PANSS and BPRS were reduced from baseline by an average of 17.7 (14.2%) and 9.8 points (20.2%), respectively. Eighteen patients (40.0%) experienced a treatment response, defined as a reduction in PANSS total score of > or = 20%. A total of 25 patients (55.6%) achieved a similar reduction in BPRS total score. Significant reductions were seen in both the positive and negative symptom scores on the PANSS (P < 0.001). Olanzapine was well tolerated, with minimal treatment-emergent adverse events or clinically relevant changes in vital signs or clinical laboratory test results. No clinically significant blood dyscrasias were observed in olanzapine-treated patients, including those who had discontinued clozapine because of treatment-associated leukopenia or neutropenia. CONCLUSION: The results of this study suggest that olanzapine may be of benefit in patients who are refractory to or unable to tolerate clozapine.

Antipsychotic Agents↗

PubMed2000

Rorschach markers in offspring of manic-depressive patients.

BACKGROUND: Previously published data show large differences between euthymic Israeli adult bipolar patients and US normative data on several measures of psychological functioning as assessed with a sensitive projective measure (Rorschach Inkblot Test). The current study examines the Rorschach performance of healthy offspring of bipolar parents and compares them to matched normal controls. METHODS: 14 asymptomatic offspring of Israeli manic-depressive parents were matched for age, gender, and other demographic variables with 14 children of normal parents. All subjects were individually administered the Rorschach Inkblot Test, and protocols were scored blindly according to the Exner Comprehensive System. RESULTS: Offspring of bipolar parents, like bipolar patients themselves, show significantly increased incidence and severity of thought disorder (as defined by Exner), lower numbers of cognitively mediated affective responses, and fewer responses indicating conventional perceptions. LIMITATIONS AND CONCLUSIONS: Although the sample size is small, this study strengthens the possibility that these measures of psychological functioning may serve as markers for manic-depressive illness.

Adolescent↗

PubMed2000

The high affinity inositol transport system--implications for the pathophysiology and treatment of bipolar disorder.

The 'inositol-depletion hypothesis' postulates that the therapeutic effects of lithium are due to inhibition of inositol monophosphatase, which leads to depletion of brain cells of myo-inositol and consequently to dampening of phosphoinositide (PI) signaling. This article examines the potential relevance of an alternative mechanism for inositol depletion: inhibition of myo-inositol uptake that proceeds via the sodium/myo-inositol cotransport (SMIT). We discuss recent in vitro experiments that show a pronounced downregulation of SMIT after chronic treatment with lithium, carbamazepine, and valproate at therapeutically relevant concentrations. It is concluded that downregulation of SMIT could represent a common mechanism of action of mood stabilizers.

Antimanic Agents↗

PubMed2000

Association between tridimensional personality questionnaire (TPQ) traits and three functional polymorphisms: dopamine receptor D4 (DRD4), serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT).

Dopamine D4 receptor (DRD4), serotonin transporter promoter regulatory region (5-HTTLPR) and catechol O-methyltransferase (COMT) polymorphisms were examined for association with TPQ personality factors in 455 subjects. Significant interactions were observed by multivariate analysis, (COMT x 5-HTTLPR: Hotelling's Trace = 2.3, P = 0.02) and by subsequent univariate 3-way ANOVA when Novelty Seeking (NS) was the dependent variable: 5-HTTLPR x D4DR (F = 6.18, P = 0.03) and COMT x 5-HTTLPR (F = 4.42, P = 0.03). In the absence of the short 5-HTTLPR allele and in the presence of the high enzyme activity COMT val/val genotype, NS scores are higher in the presence of the DRD4 seven-repeat allele. The effect of these three polymorphisms on NS was also examined using a within-families design. Siblings who shared identical genotype groups for all three polymorphisms (COMT, DRD4 and 5-HTTLPR) had significantly correlated NS scores (intraclass coefficient = 0.39, F = 2.26, P = 0.008, n = 49) whereas sibs with dissimilar genotypes in at least one polymorphism showed no significant correlation for NS scores (intraclass coefficient = 0.177, F = 1.43, P = 0.09, n = 110). Similar interactions were also observed between these three polymorphisms and Novelty Seeking when the 150 independently recruited and non-related subjects were analyzed. The current results are consistent with two earlier reports in which we demonstrated an interaction between the 5-HTTLPR and DRD4 polymorphisms in 2-week-old neonates, in the same children assessed again at 2 months of age and in adults. Molecular Psychiatry (2000) 5, 96-100.

Adolescent↗

PubMed2000

An interaction between the catechol O-methyltransferase and serotonin transporter promoter region polymorphisms contributes to tridimensional personality questionnaire persistence scores in normal subjects.

Persistence (RD2) is a subscale of the reward dependence trait, one of the three major personality factors assessed by the Tridimensional Personality Questionnaire (TPQ). Subjects with high RD2 scores are characterized as industrious, hard-working, ambitious, perfectionistic. TPQ scores were examined in 577 normal subjects inventoried for two common genetic polymorphisms, the catechol O-methyltransferase (COMT) valine to methionine (val to met) amino acid substitution that determines high and low enzyme activity, and the serotonin transporter promoter region 44 bp deletion (5-HTTLPR) linked in some studies to harm avoidance or neuroticism. When TPQ RD2 scores are grouped by COMT and 5-HTTLPR polymorphisms and analyzed by two-way ANOVA, significant main effects for COMT (F = 2. 98, p = 0.05) and 5-HTTLPR (F = 4.27, p = 0.04) and a significant interaction COMT x 5-HTTLPR (F = 6.18, p = 0.002) are observed. In the presence of COMT homozygosity (val/val or met/met genotypes), the presence of the short 5-HTTLPR allele raises RD2 scores. The effect of these two polymorphisms on RD2 was also examined using a within-families design. Siblings in our data set who shared identical genotypes had significantly correlated RD2 scores (intraclass coefficient = 0.34, F = 2.03, p = 0.002, n = 67), whereas sibs with dissimilar genotypes in at least one polymorphism showed no significant correlation for RD2 scores (intraclass coefficient = 0.105, F = 1.23, p = 0.16, n = 92).

Adolescent↗

PubMed2000

Phenytoin as an antimanic anticonvulsant: a controlled study.

OBJECTIVE: Phenytoin, a classical anticonvulsant, shares with antimanic anticonvulsants the property of blockade of voltage-activated sodium channels. The authors therefore planned a trial of phenytoin for mania. METHOD: Patients with either bipolar I disorder, manic type, or schizoaffective disorder, manic type, entered a 5-week, double-blind controlled trial of haloperidol plus phenytoin versus haloperidol plus placebo. Of 39 patients, 30 completed at least 3 weeks and 25 completed 5 weeks. RESULTS: Significantly more improvement was observed in the patients receiving phenytoin. Added improvement with phenytoin in scores on the Brief Psychiatric Rating Scale and Clinical Global Impression was seen in the patients with bipolar mania but not those with schizoaffective mania. CONCLUSIONS: Blockade of voltage-activated sodium channels may be a common therapeutic mechanism of many anticonvulsants given for mania, and phenytoin may be a therapeutic option for some manic patients.

Anticonvulsants↗

PubMed2000

Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients.

OBJECTIVE: Glycogen synthase kinase-3 (GSK-3) is a protein kinase that is highly abundant in the brain. It is involved in signal transduction cascades of multiple cellular processes, particularly neurodevelopment. In an attempt to explore possible involvement of GSK-3beta in psychiatric disorders, the authors examined its levels in postmortem brain tissue. METHOD: Western blot analysis was performed to measure GSK-3beta in the frontal cortex of 14 schizophrenic patients, 15 patients with bipolar disorder, 15 patients with unipolar depression, and 14 normal comparison subjects. RESULTS: GSK-3beta levels were 41% lower in the schizophrenic patients than in the comparison subjects. Other diagnostic groups did not differ from the comparison subjects. CONCLUSIONS: These results are consistent with the notion that schizophrenia involves neurodevelopmental pathology. It remains to be investigated whether the active fraction of GSK-3beta, or its activity, is also low in frontal cortex of schizophrenic patients and if this is also reflected in other brain regions.

Adult↗

PubMed2000

Predominant polarity of bipolar patients in Israel.

Studies in European and American populations have suggested that the course of bipolar illness is most often characterised by a predominance of depressions over manias. The current chart review study suggests that among manic-depressive patients in Southern Israel, a predominately manic course of illness is more common. Unlike some previous studies, no sex differences were noted in type of illness course. Possible explanations for the main finding, including climate-related factors, are discussed.

Adult↗

PubMed1999

Combination of inositol and serotonin reuptake inhibitors in the treatment of depression.

BACKGROUND: Inositol has been reported to be an effective treatment in depression, and we hypothesized that inositol addition might enhance or speed up response to serotonin selective reuptake inhibitors (SSRI). METHODS: Twenty-seven depressed patients completed a double-blind controlled 4-week trial of SSRI plus placebo or SSRI plus inositol. Hamilton Depression Rating Scale was used as an assessment tool at baseline, and 1, 2, 3, and 4 weeks. RESULTS: No significant difference was found between the two treatment groups. CONCLUSIONS: Previous studies combining different effective antidepressant therapies similarly found no evidence for additive effects [e.g., monoamine oxidase inhibitors (MAOI) plus tricyclic antidepressants (TCA), TCA plus lithium]. By contrast, augmentation by lithium or MAOI after a failed course of antidepressant treatment is effective and should be studied with inositol.

Adult↗

PubMed1999

Inositol reduces depressive-like behaviors in two different animal models of depression.

RATIONALE: Myo-inositol is an isomer of glucose that is a precursor in the phosphatidylinositol (PIP) cycle, a source of two second messengers: diacylglycerol (DAG) and inositol triphosphate (IP3). Clinical studies have reported that inositol is effective in relieving symptoms of depression. OBJECTIVE: The present study examined the effects of inositol on two animal models of depression: the Porsolt forced swim test, a behaviorally based model; and the reserpine-induced immobility model, a pharmacologically based model. METHODS AND RESULTS: Chronic inositol injections (daily for 14 days) of 1.2 g/kg (but not at lower doses) reduced immobility time and increased struggle time in the Porsolt test compared with control animals. The same dose and treatment schedule also reduced complete immobility time but did not affect ambulatory activity in the reserpine test compared with controls. Chronic oral treatment with inositol (10% in food for 14 days) had effects similar to IP inositol in the Porsolt test. CONCLUSIONS: The effect of inositol in animal models of depression supports its possible importance as a new treatment for the disorder, and permits research on its mechanisms of action.

Animals↗

PubMed1999

Inositol addition does not improve depression in SSRI treatment failures.

Some antidepressants, such as Lithium, can augment the antidepressant effect of serotonin selective uptake inhibitors (SSRI) in patients who have failed to respond to SSRI. Inositol has demonstrated antidepressant effects but in a controlled double blind augmentation trial did not improve depression in SSRI treatment failures.

Adult↗

PubMed1999

Epi-inositol and inositol depletion: two new treatment approaches in affective disorder.

Inositol is a simple polyol precursor in a second messenger system important in brain myo-insitol, the natural isomer, which has been found to be therapeutically effective in depression, panic disorder, and obsessive-compulsive disorder in double-blind controlled trials. Recently, epi-inositol, an unnatural stereoisomer of myo-inositol, was found to have effects similar to those of myo-inositol to reverse lithium-pilocarpine seizures. We measured the behavior of rats in an elevated plus maze model of anxiety after chronic treatment of 11 daily intraperitoneal injections of epi-inositol, myo-inositol, or control solution. Epi-inositol reduced anxiety levels of rats compared with controls, and its effect was stronger than that of myo- inositol. Lithium has been hypothesized to alleviate mania by reducing brain inositol levels. Inositol in brain derives from the second messenger cycle, from new synthesis, or from diet via transport across the blood brain barrier. Because the first two are inhibited by lithium, we propose that an inositol-free diet will augment lithium action in mania by enhancing restriction of inositol.

Animals↗