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Biomedical subjects

R H Belmaker

Publications and source records attributed to R H Belmaker.

At least 37 records · Page 2Linked to original sources
PubMed2005

Postmortem parietal cortex TPH2 expression is not altered in schizophrenic, unipolar-depressed, and bipolar patients vs control subjects.

Serotonin (5-hydroxytryptamine [5-HT]) is a neurotransmitter synthesized in the raphe nuclei of the brain stem in the central nervous system (CNS) and also in the periphery. Dysfunction of the serotonergic system has been implicated in the pathogenesis of psychiatric disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis. For more than a decade, only one gene encoding TPH was identified in vertebrates. Recently, a second TPH gene, designated TPH2, was detected, located on human chromosome 12, a susceptibility region for affective disorders. TPH2 is predominantly expressed in the brain, whereas the classical TPH gene, TPH1, is expressed in peripheral tissues. The discovery of the brain-abundant TPH2 gene justifies a new concept of the CNS serotonergic system. TPH2, rather than TPH1, has now become a candidate gene for 5-HT-related affective disorders. We compared TPH2 mRNA levels in postmortem parietal cortex of unipolar-depressed, bipolar, and schizophrenic patients vs control subjects, using real-time reverse transcription polymerase chain reaction. No significant difference in TPH2 mRNA levels was found among the four diagnostic groups. The lack of difference might suggest that this gene is not involved in the etiology of of these psychiatric disorders. Alternatively, it is possible that the parietal cortex is not the relevant brain area involved in the pathophysiology of these disorders or that posttranscriptional modifications of TPH2 mRNA occur in these patients, causing changes in protein levels and/or enzymatic activity.

Actins↗
PubMed2005

Controlled double-blind trial of phenytoin vs. fluoxetine in major depressive disorder.

BACKGROUND: Phenytoin was the first non-sedative anticonvulsant introduced and is still the anticonvulsant most widely used worldwide in neurology. Given the efficacy of the anticonvulsant lamotrigine in the depressed phase of bipolar disorder, a critical theoretical question is whether other anticonvulsants used in treating bipolar disorder might be similarly effective. We therefore undertook a controlled trial of phenytoin versus fluoxetine in major depressive disorder. METHOD: Data were collected from July 2001 to July 2003. Thirty-three subjects entered the study. All patients met DSM-IV criteria for major depressive disorder and scored a minimum of 18 on the 24-item Hamilton Rating Scale for Depression (HAM-D) at baseline. After a 3-day washout of any previous medications, patients were randomly assigned to fluoxetine or phenytoin in identical capsules. Each capsule contained phenytoin 100 mg or fluoxetine 7 mg plus cornstarch. Patients started with 1 tablet daily and increased every other day until they were taking 1 tablet 3 times daily with meals. Blood phenytoin levels were taken after 1 week, 3 weeks, and 6 weeks, and dosage was adjusted to achieve blood levels of 10 to 20 microg/mL, to a maximum dose of 4 capsules per day or a minimum dose of 2 capsules per day. Fluoxetine patients were assigned dummy blood phenytoin levels by the control psychiatrist such that the treating physician would raise the number of capsules to at least 3 per day (20 mg of fluoxetine). RESULTS: Thirty-three patients entered the study, and 28 (N = 14 in each treatment group) completed at least 3 weeks and were included in the data analysis. Patients who dropped out after week 3 (3 patients) were included in the study as last value carried forward. There was no difference between treatment groups in overall rate of response or speed of response. CONCLUSION: The absence of a placebo arm in our study allows for the possibility that neither treatment was more effective than placebo. However, the exclusion of past fluoxetine nonresponders and the minimum HAM-D score at baseline of 18 make this possibility unlikely.

Adult↗
PubMed2005

Omega-3 eicosapentaenoic acid in bipolar depression: report of a small open-label study.

INTRODUCTION: Epidemiologic studies have suggested that consumption of cold water fish oils may have some protective function against depression. This proposition is supported by a series of biochemical and pharmacologic studies that have suggested that fatty acids may modulate neurotransmitter metabolism and cell signal trans-duction in humans and that abnormalities in fatty acid and eicosanoid metabolism may play a causal role in depression. Aware of the critical need for antidepression treatments that might not carry the risk of precipitating a manic episode in bipolar patients, we decided to conduct an open-label add-on trial of eicosapentaenoic acid (EPA) in bipolar depression. METHOD: Twelve bipolar I outpatients with depressive symptoms diagnosed by DSM-IV were treated with 1.5 to 2 g/day of the omega-3 fatty acid EPA for up to 6 months. The study was conducted between September 2001 and January 2003. RESULTS: Eight of the 10 patients who completed at least 1 month of follow-up achieved a 50% or greater reduction in Hamilton Rating Scale for Depression scores within 1 month. No patients developed hypomania or manic symptoms. No significant side effects were reported. LIMITATIONS: This study is limited both by the open-label design and by the small sample size. As in all previous reported studies, patients in this study were treated in an outpatient setting, so that the most severely depressed bipolar patients (requiring hospitalization) are not represented. CONCLUSIONS: Although the ultimate utility of omega-3 fatty acids in bipolar depression is still an open question, we believe that these initial results are encouraging, especially for mild to moderate bipolar depression, and justify the continuing exploration of its use.

Adult↗
PubMed2004

Bipolar disorder.

Explore the source record for details and available documents.

Antidepressive Agents↗
PubMed2004

Trafficked female sex workers awaiting deportation: comparison with brothel workers.

In 2002, we researched the psychosocial characteristics of 55 women working in the commercial brothel-based sex industry in three Israeli cities. This previous social epidemiological study focused exclusively on women working in brothels and the brothel owners consented to their interviews, suggesting that this might be a sample of the most organized brothels with the best social conditions. We therefore decided to study a second sample obtained by different referral methods. The sample consisted of 49 women in a detention center who are awaiting judicial hearings for deportation. This prison sample of sex workers is strikingly similar to the previously studied sample of sex workers working in brothels in terms of demographic features and working conditions. A higher percentage of the prison sample reported depression and somatic symptoms. However, this finding is consistent with a reaction to being arrested and awaiting deportation. Guided by a life course perspective, in the combined sample, we examined whether early exposure to trauma, motherhood and early entry into sex work affected current health and mental health. Those who were mothers were likely to have entered sex work at a later age but no other aspect of their working conditions differed from the non-mothers suggesting that motherhood per se did not appreciably change the experience of these mostly trafficked women sex workers. Early exposure to trauma increased the likelihood for work-related trauma, poor health and mental health outcomes.

Adolescent↗
PubMed2004

Reduced GSK-3beta mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients.

Glycogen Synthase Kinase (GSK)-3 is a ubiquitous serine/threonine protein kinase highly abundant in brain which plays a key role in neural development and neuron survival. We have previously reported that GSK-3beta protein levels and GSK-3 activity are reduced by over 40% in postmortem prefrontal cortex of schizophrenic patients compared to patients with bipolar illness, unipolar depression and to normal controls, and Emamian et al. have recently presented convergent evidence for impaired AKT1-GSK-3beta signaling in schizophrenia. Using specimens of dorsolateral prefrontal cortex tissue obtained from The Stanley Medical Research Institute's Brain Collection, from the same subjects used previously, we now show that GSK-3beta, but not GSK-3alpha, mRNA levels are 36% lower in the patients with schizophrenia compared to all other comparison groups. The present study lends further support to the finding of low GSK-3beta levels in schizophrenia and extends this observation by suggesting that the decrease in GSK-3beta may be due to reduced protein synthesis possibly due to altered transcriptional drive of the GSK-3beta gene.

Adult↗
PubMed2004

GSK-3beta in cerebrospinal fluid of schizophrenia patients.

Cerebrospinal fluid contains proteins and metabolites of brain origin and was extensively studied in psychiatry in the 1970's with few definitive results. We have recently found 40% reduced protein levels of GSK-3beta in schizophrenia in postmortem prefrontal cortex, but our attempt to develop a diagnostic marker using peripheral lymphocyte GSK-3beta was not successful. In this study we aimed to find whether the reduction in brain GSK-3beta is reflected in CSF of schizophrenia patients. We report a significant reduction in CSF GSK-3beta protein levels in six schizophrenia patients compared to seventeen healthy subjects. Our results corroborate other studies in which CSF protein levels reflect the alteration found in these proteins in schizophrenia patients' postmortem brain.

Adult↗
PubMed2004

Genetic correlational analysis of glycogen synthase kinase-3 beta and prepulse inhibition in inbred mice.

In humans, GSK-3 beta activity is diminished in schizophrenic patients as is prepulse inhibition of the startle response (PPI). We performed a genetic correlational analysis between published PPI values and frontal cortex GSK-3 activity analyzed in our laboratory in 10 inbred mouse strains. This methodology could indicate relevant parameters for study in an animal model. Indeed, we obtained significant correlations between the enzyme's activity and PPI measured by two different methods. This may indicate that investigation of the genetics of GSK-3 beta regulation holds promise for understanding some of the biochemical underpinnings of schizophrenia.

Animals↗
PubMed2004

Single-dose intravenous valproate in acute mania.

OBJECTIVE: High-dose loading with oral and intravenous valproate has been reported to be therapeutic in mania over 48 to 72 hours. We hypothesized that very high dose intravenous (IV) valproate might have even more rapid effects equivalent to effects in status epilepticus that occur within 20 minutes. METHOD: Seven patients with mania (Young Mania Rating Scale score > 20) and minimal prior drug treatment were given valproate 20 mg/kg IV over 30 minutes. RESULTS: No antimanic effects were observed during 120 minutes of observation. There were no side effects. CONCLUSION: Slowly evolving biochemical changes, perhaps at the gene level, may be required for the antimanic effect of anticonvulsants.

Acute Disease↗
PubMed2003

The effect of lithium on expression of genes for inositol biosynthetic enzymes in mouse hippocampus; a comparison with the yeast model.

In the de novo synthesis of inositol, the conversion of D-glucose-6-phosphate to L-myo-inositol-1-phosphate (MIP) is catalyzed by MIP synthase. Little is known about mammalian MIP synthase and nothing is known about its regulation. The second step in inositol biosynthesis is the conversion of MIP to inositol by inositol-monophosphatase (IMPase), a common step to inositol production via the de novo pathway and its recycling from inositol phosphates. Because lithium inhibits IMPase both in yeast and in mammals, and the drug upregulates yeast MIP synthase (INO1) and downregulates IMPase (INM1), the present study was undertaken to determine whether chronic in vivo therapeutic lithium concentrations affect MIP synthase and IMPase expression in mouse frontal cortex and hippocampus. Mice were treated with food containing LiCl (2.5 g/kg) for 10 days. RNA was purified from the brain areas and mRNA amplified using RT-PCR. Expression of MIP synthase and IMPA1 (one of the genes coding for IMPase) but not IMPA2 was upregulated in mouse hippocampus. None of the genes were affected in the frontal cortex. In yeast, when inositol is limiting, the heterodimeric transcriptional activator Ino2p/Ino4p derepresses expression of INO1 by binding to the upstream activation sequence UAS(INO). Using the TFSEARCH program, we found that the promoter of the virtual human MIP synthase gene contains upstream stimulating factor (USF) elements with a similar core binding sequence. The fact that lithium treatment upregulates both MIP synthase and IMPA1 mRNA levels in mouse hippocampus may reflect a compensatory response of both genes to inositol depletion.

Animals↗
PubMed2003

Family-based and case-control study of catechol-O-methyltransferase in schizophrenia among Palestinian Arabs.

COMT is a ubiquitous enzyme crucial to catechol metabolism. The molecular basis of COMT thermolability, that leads to three to fourfold differences in enzyme activity, is due to a substitution of valine with methionine in the Val158/108Met polymorphism. Of special interest is the role of this gene in major psychoses especially since a microdeletion (22q11) containing the COMT gene (velo-cardio-facial syndrome) also carries with it several types of behavioral disorders, including an increased prevalence of schizophrenia. Almost 20 genetic studies have examined the role of COMT in schizophrenia with ambiguous results. Towards clarifying the role of this polymorphism in conferring risk for psychosis, we examined a large group of culturally and ethnically akin Palestinian Arab schizophrenic triads (N = 276) using both a case-control and family-based study. In 194 informative triads with at least one heterozygote parent, no preferential transmission of either COMT allele was observed in this sample (TDT statistic chi-square = 0.14 NS; 131 COMT valine alleles were transmitted and 125 alleles not transmitted). However, using a case-control design a significant increase (Likelihood ratio = 3.935, P = 0.047) in the valine allele was observed in the group of schizophrenic patients (N = 276) compared to an ethnically matched control group (N = 77). The association was stronger in female patients (P = 0.012) similar to other studies showing that some COMT behavioral effects are gender sensitive. In summary, by case-control design but not by a family-based study, there is a weak effect in female patients of the high activity COMT allele in conferring risk for schizophrenia.

Amino Acid Substitution↗
PubMed2003

Right prefrontal TMS versus sham treatment of mania: a controlled study.

OBJECTIVE: Left prefrontal transcranial magnetic stimulation (TMS) has been reported to have ECT-like effects in depression and we therefore planned a study of TMS in mania. Sixteen patients completed trial of right versus left prefrontal TMS at 20 Hz, 2-sec duration per train, 20 trains per day for 10 treatment days. Mania was evaluated using the Mania Scale, the Brief Psychiatric Rating Scale and the Clinical Global Impression. Significantly more improvement was observed in patients treated with right prefrontal TMS than with left prefrontal. We now report a follow-up study of right active TMS versus right sham TMS with the same indications and parameters. METHODS: Twenty-five patients entered and 19 completed right TMS versus sham right TMS. RESULTS: Right TMS was no more effective than sham TMS. CONCLUSIONS: It is possible that the previous results were due to an effect of left TMS to worsen mania. Alternatively, it is noted that the present patient group had much more psychosis than the previous study of TMS in mania, and depression studies have reported that psychosis is a poor prognostic sign for TMS response.

Adult↗
PubMed2003

Intravenous fosphenytoin in acute mania.

OBJECTIVES: Since several anticonvulsants are therapeutic in mania and since acute mania requires rapid and intensive treatment, we hypothesized that intravenous high-dose phenytoin might be acutely antimanic. A new prodrug of phenytoin, fosphenytoin, which has few cardiac or local vein side effects, was used to test this hypothesis. METHOD: Seven patients with a DSM-IV manic episode and minimal prior drug treatment were given intravenous fosphenytoin and were assessed at baseline and after 15, 30, 45, and 60 minutes with the Young Mania Rating Scale, the Clinical Global Impressions scale, and the Mini-Mental State Examination. Data were gathered in 2002. RESULTS: No antimanic effects were observed. No subject had any clear improvement in manic symptoms on the YMRS at any timepoint assessed. CONCLUSION: Intravenous fosphenytoin at doses that are effective in status epilepticus appears to be ineffective in acute mania.

Acute Disease↗
PubMed2002

Preliminary evaluation of oral anticonvulsant treatment in the quinpirole model of bipolar disorder.

A potential model for bipolar disorder, quinpirole-induced biphasic locomotion, was used for a preliminary evaluation of behavioral effects of oral anticonvulsant treatment. Quinpirole, a D2/D3 agonist, induces a biphasic locomotor response starting with inhibition and followed by excitation, resembling the oscillating nature of bipolar disorder. The present study developed a paradigm for oral administration of anticonvulsants that resulted in therapeutic blood levels and tested the effects of treatment on the quinpirole-induced response. Eleven days treatment with valproate (12 g/liter water), phenytoin (6 g/kg food), and carbamazepine (8 g/kg food) resulted in therapeutic blood levels and in a borderline significant reduction in quinpirole-induced hyperactivity without effects on the hypoactive phase. Valproate effects became more significant at the height of the hyperactivity response. Eleven days treatment with topiramate (30 mg/kg) resulted in a significant attenuation of quinpirole-induced hyperactivity, qualitatively similar to the effects of the other anticonvulsants. The results suggest that mood-stabilizing anticonvulsant drugs including topiramate may attenuate quinpirole-induced hyperactivity.

Administration, Oral↗
PubMed2002

GSK-3 and the neurodevelopmental hypothesis of schizophrenia.

The Neurodevelopmental Hypothesis of schizophrenia suggests that interaction between genetic and environmental events occurring during critical early periods in neuronal growth may negatively influence the way by which nerve cells are laid down, differentiated and selectively culled by apoptosis. Recent advances offer insights into the regulation of brain development. The Wnt family of genes plays a central role in normal brain development. Activation of the Wnt cascade leads to inactivation of glycogen synthase kinase-3beta (GSK-3beta), accumulation and activation of beta-catenin and expression of genes involved in neuronal development. Alteration in the Wnt transduction cascade, which may represent an aberrant neurodevelopment in schizophrenia, is discussed. Programmed cell death is also an essential component of normal brain development. Abnormal neuronal distribution found in schizophrenic patients' brains may imply aberrant programmed cell death. GSK-3 participates in the signal transduction cascade of apoptosis. The possible role of aberrant GSK-3 in the etiology of schizophrenia is discussed.

Animals↗
PubMed2002

Reduced inositol content in lymphocyte-derived cell lines from bipolar patients.

OBJECTIVES: The study aimed to determine whether low inositol content and uptake previously reported in brain and peripheral tissue of bipolar patients are also reflected in lymphocyte-derived cell lines from these patients. METHODS: Inositol content and uptake were studied in lymphocyte-derived cell lines grown in vitro for at least five generations to eliminate influences of drug treatment. Inositol content was studied gas chromatographically and inositol uptake by following 3H-inositol incorporation at various concentrations. RESULTS: Inositol levels of cell lines derived from bipolar patients were significantly lower than those of cell lines from controls. CONCLUSIONS: Low inositol content in lymphocyte-derived cell lines from bipolar patients corroborates previous findings in frontal cortex and in lymphoblastoid cell lines and are consistent with the notion that the phosphatidylinositol signaling system is involved in the pathophysiology of this disorder.

Bipolar Disorder↗