Robert H Belmaker

Ben-Gurion University of the Negev | bgu · Division of Psychiatry

The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout (KO) mice of two genes (IMPA1 or Slc5a3), each encoding for a protein related to inositol metabolism, were studied in comparison with lithium-treated mice. Since we previously demonstrated that these KO mice exhibit a lithium-like neurochemic...

This article has no abstract; the first 100 words appear below. Bipolar disorder consists of depressive episodes of low mood, difficulty in concentration and work, poor sleep, and poor appetite, as well as distinct manic episodes of expansive mood, pressured speech, overactivity, sexual excesses, aggressiveness, and little need for sleep; both type...

Studies have reported that countries with high rates of fish oil consumption have low rates of depressive disorder. The authors studied a specific omega-3 fatty acid, the ethyl ester of eicosapentaenoic acid (E-EPA), as an adjunct to treatment for depressive episodes occurring in patients with recurrent unipolar depressive disorder who were receivi...

It would be appealing to attempt to categorize depression in terms of monoamine-depletion forms that are perhaps related to genes coding for enzymes involved in neurotransmission and cortisolrelated forms that are characterized by a more long-term course, hippocampal atrophy, and a history of psychosocial stress. However, the clinical data do not f...

Oxygen enriched air may increase oxygen pressure in brain tissue and have biochemical effects even in subjects without lung disease. Consistently, several studies demonstrated that normobaric oxygen treatment has clinical benefits in some neurological conditions. This study examined the efficacy of normobaric oxygen treatment in subjects with depre...

Objective To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. Method Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth...

Lithium treatment in rodents markedly enhances cholinergic agonists such as pilocarpine. This effect can be reversed in a stereospecific manner by administration of inositol, suggesting that the effect of lithium is caused by inositol monophosphatase inhibition and consequent inositol depletion. If so, inositol-deficient food would be expected to e...

BACKGROUND: The term adult neurogenesis constitutes a series of developmental steps including the birth, survival, differentiation, maturation, and even death of newborn progenitor cells within neurogenic niches. Within the hippocampus progenitors reside in the neurogenic niche of the subgranular zone in the dentate gyrus subfield. At the different...

We have previously shown that homozygote knockout (KO) of inositol-monophosphatase1 (IMPA1) results in lithium (Li)-like behavior. We now aimed to find out whether Li-treated mice and IMPA1 KO mice exhibit neurochemical similarity at the gene- and protein-expression level. Hippocampal and frontal cortex B-cell lymphoma (Bcl-2), Bcl-2-associated X p...

Reports of toxic effects on the kidney of lithium treatment emerged very soon after lithium therapy was introduced. Lithium-induced nephrogenic diabetes insipidus is usually self-limiting or not clinically dangerous. Some reports of irreversible chronic kidney disease and renal failure were difficult to attribute to lithium treatment since chronic...

BACKGROUND AND OBJECTIVES: Due to the large migrations over the past three decades, large numbers of individuals with schizophrenia are learning a second language and being seen in clinics in that second language. We conducted within-subject comparisons to clarify the contribution of clinical, linguistic and bilingual features in the first and sec...

Background: The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of f...

Objective: The underlying biology of bipolar disorder and the mechanisms by which effective medications induce their therapeutic effects are not clear. Appropriate use of animal models are essential to further understand biological mechanisms of disease and treatment, and further understanding the therapeutic mechanism of mood stabilisers requires...

Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. The database include...

According to the hypersensitive behavioral approach system (BAS) model of bipolar disorder (BP), hypersensitivity of the BAS is a trait that should be present even in the euthymic state. This would be expected to result in increased anger and reward sensitivity, both of which are related to the approach system. This study examined these predictions...

Background: Lithium has numerous biochemical effects but it is difficult to dissect which of these is responsible for its therapeutic action in bipolar disorder. In the current study we aimed to address one of the major hypotheses, the inositol depletion hypothesis. This hypothesis postulates that lithium's mood-stabilizing effect is mediated by t...

Rationale The disaccharide trehalose protects cells from hypoxic and anoxic injury and suppresses protein aggregation. In vivo studies with trehalose show cellular and behavioral beneficial effects in animal models of neurodegenerative diseases. Moreover, trehalose was shown to enhance autophagy, a process that had been recently suggested to be inv...

Rationale Lithium has been a standard pharmacological treatment for bipolar disorder over the last 60 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. Attenuation of the phosphatidylinositol signal transduction pathway as a consequence of inhibition of inositol monophosphatase (IMPase...

Several open studies and a small number of small clinical trials have been performed with omega 3 fatty acids in autism. These trials were based both on the reported etiological abnormalities of fatty acid metabolism in autism and also on the reported efficacy of omega 3 fatty acids in other syndromes such as obsessive compulsive disorder and depre...

BACKGROUND: Bipolar disorder may be associated with a hypersensitive behavioral approach system and therefore to increased reward sensitivity. The objective of this study is to explore the interrelationships between bipolar disorder, behavioral addictions, and personality/temperament traits in a group of euthymic outpatients with bipolar I disorde...

Individual differences in response to pharmacologic treatment limits the usefulness of mean data obtained from randomized controlled trials. These individual differences exist even in genetically uniform inbred mouse strains. While stratification can be of value in large studies, the individual patient history is the most effective currently availa...

Several studies of normobaric hyperoxia in neurological conditions have found positive results. The impaired energy metabolism due to mitochondrial dysfunction and frontal lobe hypofunction in schizophrenia might be improved by increasing O2 supply to the brain. Normobaric hyperoxia may be a potential treatment for schizophrenia. Participants in th...

Lithium salts are among the drugs of choice for the treatment of bipolar disorder. Despite six decades of intensive research and an accumulating number of known cellular targets, lithium's mechanism of action still needs to be unraveled. The evolution of large-scale gene-expression analysis methodologies has provided a promising tool to understand...

Lithium is the gold-standard treatment for bipolar disorder, a severe mental illness. A large body of evidence suggests that inflammation plays a role in the pathogenesis of bipolar disorder and that mood stabilizers exhibit anti-inflammatory properties. However, contradicting findings have also been reported. In this study, we examined the effects...

Female genital mutilation (FGM) is practiced in many areas of the world, including the Middle East, Africa and Australia. Although it is most common in Muslim populations it is not a dictate of Islam. In the 1980s this practice was reported among Bedouin tribes, originally nomadic, in the southern area of Israel. Almost all of the women interviewed...

Bipolar-disorder, characterized by switches between depressive and manic mood, is treated by mood-stabilizers, lithium being one of them. Among hypotheses suggested, the inositol-depletion hypothesis proposes that lithium attenuates hyperactivation of phosphatidylinositol signaling linked to neurotransmission-related receptors.Available for us are...

Emerging evidence suggests impaired one-carbon metabolism in schizophrenia. Homocysteine is one of the key components of one-carbon metabolism. Elevated plasma homocysteine levels were reported in schizophrenia. A linkage study found that nicotinamide-N-methyltransferase (NNMT), an enzyme involved in one-carbon metabolism, is a determinant of plasm...

Glycogen synthase kinase (GSK-3) is a key enzyme in multiple cell processes. Since many pharmacological compounds that have effects on common metabolic pathways may have uses in many different diseases, we review here the possible involvement of glycogen synthase kinase 3 in diabetes, cancer and CNS diseases. Moreover, diabetes has recently been st...

DNA methylation is coupled with one-carbon metabolism involving homocysteine/methionine interconversion. Correlation between plasma homocysteine levels and leukocyte global DNA methylation was reported but not always replicated. Nicotinamide N-methyltransferase (NNMT) is a determinant of plasma homocysteine levels. Findings suggest alteration of on...

While neuropsychological impairment in bipolar disorder is well documented, the effect size of this impairment is rarely compared directly to that in other clinically familiar cognitive disorders. This study compares neuropsychological functioning of euthymic bipolar patients to those with mild cognitive impairment (MCI) as well as healthy controls...

In early March 2011 the European College of Neuropsy-chopharmacology (ECNP) hosted a summit to consider the implications and consequences of the abrupt withdrawal of a number of major pharmaceutical companies from key areas of neuroscience research and development in brain disorders and psychopharmacology in particular. This paper presents the reco...

One of the first discovered effects of lithium was inhibition of adenylyl cyclase (AC). AC is linked to many brain receptors and transmits their message into the cell by catalyzing the formation of cyclic AMP from adenosine triphosphate. Since the original report found lithium inhibition at 2 mM we attempted to see whether this effect actually occu...

Schizophrenia is associated with rare copy-number (CN) mutations. Screening for such alleles genome-wide, though comprehensive, cannot study in-depth the causality of particular loci, therefore cannot provide the functional interpretation for the disease etiology. We hypothesized that CN mutations in the SELENBP1 locus could associate with the diso...

Homocysteine is reported to be a risk factor for schizophrenia. The methionine loading test evaluates the summation of a multitude of enzymatic pathways associated with homocysteine metabolism. Using a challenge paradigm, we measured homocysteine levels in 10 chronic schizophrenia patients and five controls at baseline and 3h after 100mg/kg oral me...

Valproic acid's well-known teratogenicity limits its use in women of childbearing age. Valnoctamide is an analog of valproate that does not undergo biotransformation to the corresponding free acid. In mice, valnoctamide has been shown to be distinctly less teratogenic than valproate. Valnoctamide is an anticonvulsant, and we hypothesized that valno...

Until the early 1950s, no effective pharmacological treatment existed for bipolar affective disorder. By the early 1960s, specialty clinics were being set up to dispense lithium carbonate to bipolar patients. By the late 1980s, a new body of knowledge was influencing the perception of bipolar disorder and how the disease should be treated. The auth...

Preliminary clinical trials have recently shown that phenytoin, an antiepileptic drug, may also be beneficial for treatment of bipolar disorder. To examine molecular mechanisms of action of phenytoin as a potential mood stabilizer, DNA microarrays were used to study the effect of phenytoin on gene expression in the hippocampus and frontal cortex of...

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Psychiatrists' MindsetChaos Theory: Relevancy to PsychiatryOutlook: Science and Religion Seven Days a WeekReferences

Inhibition of glycogen synthase kinase-3 (GSK-3) is thought to be a major consequence of the biological and clinical activity of the mood stabilizer lithium, however, lithium and GSK-3 may activate distinct cellular pathways. We employed a proteomic method to uncover new downstream targets of lithium, and then examined how these proteins are relate...

Lithium, valproate, and carbamazepine decrease stimulated brain cyclic-AMP (cAMP) levels. Adenylyl cyclase (AC), of which there are nine membrane-bound isoforms (AC1-AC9), catalyzes the formation of cAMP. We have recently demonstrated preferential inhibition of AC5 by lithium. We now sought to determine whether carbamazepine and valproate also pref...

Lithium, which is approved for treating patients with bipolar disorder, is reported to inhibit 3′(2′)-phosphoadenosine-5′-phosphate (PAP) phosphatase activity. In yeast, deletion of PAP phosphatase results in elevated PAP levels and in inhibition of sulfation and of growth. The effect of lithium on PAP phosphatase is remarkable for the low Ki (~0.2...

Lithium inhibits IMPase (inositol monophosphatase) activity, as well as inositol transporter function. To determine whether one or more of these mechanisms might underlie lithium's behavioural effects, we studied Impa1 (encoding IMPase) and Smit1 (sodium-myo-inositol transporter 1)-knockout mice. In brains of adult homozygous Impa1-knockout mice, I...

The purpose of this study was to determine the efficacy and safety of omega-3 fatty acids for children with autistic spectrum disorder (ASD). This was an open-label pilot study. Ten children aged 4-7 years old with ASD according to the Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV), were given 1 gram daily of omega-3...

We review three studies of omega-3 fatty acids in the treatment of depression that were carried out by our research group at the Beer Sheva Mental Health Center. The first study examined eicosapentaenoic acid (EPA) versus placebo as an adjunct to antidepressant treatment in 20 unipolar patients with recurrent major depression. The second study used...

Fountoulakis and Vieta's comprehensive literature search on bipolar disorder (Fountoulakis & Vieta, 2008) seems to have missed the three controlled trials of phenytoin by our group (Bersudsky, 2006; Mishory et al. 2000, 2003; Nemets et al. 2005) even though other somewhat experimental treatments such as tamoxifen were covered. While phenytoin is no...

Recently, clinicians in Southern Israel perceived that the practice of female genital mutilation had disappeared entirely in the Bedouin population. We previously studied the prevalence of this practice in 1995. We decided to survey again the Bedouin population focusing on those tribes previously reported to perform this practice. Eighty percent of...

Gottesman and Gould's 2003 paper on endopheno-types 1 as a research strategy for psychiatry has almost 800 citations and the present volume is an impressive summary of how far this fi eld has come. Recently, whole genome wide scans for schizophrenia and bipo-lar disorder with excellent methodology and large, well diagnosed samples have yielded few...

Consanguinity may contribute to the incidence of schizophrenia in offspring despite the usually accepted polygenic model of schizophrenia inheritance. Bedouin Arab families in southern Israel have a high rate of cousin marriages as do families throughout most Arab societies. We studied consanguinity in the parents of schizophrenic patients admitted...

Along with the development of selective serotonin reuptake inhibitors there has been a tremendous widening of the definition of depression and an impressive decrease in the placebo-drug difference in controlled studies. In the early 1960s, about one third of depressed patients improved with placebo and two thirds with active compounds. Current cont...

Lithium ions' inhibition of adenylyl cyclase (AC) has not been previously studied for the newly discovered AC isoforms. COS7 cells were transfected with each of the nine membrane-bound AC isoforms cDNAs with or without D 1-or D 2-dopamine receptor cDNA. AC activity was measured as [ 3 H]cAMP accumulation in cells pre-incubated with [ 3 H]adenine fo...

Medication is a necessary part of treatment for severe psychiatric illnesses such as schizophrenia and nonadherence to prescribed medication is one of the most important public health issues in psychiatry today. The devastating consequences of nonadherence have motivated the development of novel therapeutic strategies, including a new long-term imp...

Lithium inhibits inositol monophosphatase and also reduces inositol transporter function. To determine if one or more of these mechanisms might underlie the behavioral effects of lithium, we studied inositol transporter knockout mice. We previously reported that heterozygous knockout mice with reduction of 15-37% in brain inositol had no abnormalit...

The report of the CINP Task Force ‘Antidepressant medications and other treatments of depressive disorders’ (CINP Task Force, 2007) represents a scholarly and comprehensive review on the huge literature on antidepressants. As such, it is within the burgeoning modern tradition of evidence-based medicine. However, as a CINP report several points ment...

In mice glycogen synthase kinase (GSK)-3beta heterozygote knockout status was reported to cause reduced immobility in the Porsolt forced swim test and reduced amphetamine-induced hyperactivity, behaviors that mimic the effects of lithium. GSK-3beta protein and mRNA level and activity have been reported to be reduced in the postmortem brain of schiz...

We were interested to read the article by Beaulieu et al. (1), suggesting that GSK3β haploinsufficiency counteracts depressive-like behavior in mice expressing a functional TPH2 mutant with a marked decrease in serotonin production. In the figures of the current article, it is clear that GSK3β haploinsufficiency had no antidepressant effect in the...

Meta-analysis recently suggested that a 5 muM increase in homocysteine is associated with a 70% higher risk for schizophrenia. Elevated homocysteine is reported to alter macromolecule methylation. We studied whether elevated plasma homocysteine levels in schizophrenia are associated with altered leukocyte global DNA methylation. DNA was extracted f...

Par-4 has been suggested to mediate dopamine neurotransmission. Dopamine D2 receptor (DRD2) activation induces a signalling complex of AKT1, PP2A and beta-arrestin2 which dephosphorylates/inactivates AKT1 thereby activating GSK-3beta, transducing dopamine-dependent behaviour. DRD2 activation also results in down-regulation of PKA activity. Among ot...

Data from two major government-funded studies of comparative antipsychotic effectiveness in schizophrenia contradict the widely prevalent belief that the newer second-generation medications are vastly superior to the older first-generation drugs. This has caused uncertainty among patients, clinicians and policy-makers about the relative utility of...

Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1-/-) to study the in vivo physiological functions of IMPA1, in ge...

Lithium and valproate are the prototypic mood stabilizers and have diverse structures and targets. Both drugs influence inositol metabolism. Lithium inhibits IMPase and valproate inhibits MIP synthase. This study shows that MIP synthase inhibition does not replicate or augment the effects of lithium in the inositol sensitive pilocarpine-induced sei...

We have previously reported that homocysteine levels are elevated in euthymic bipolar patients with functional deterioration. The current study was designed to extend this finding by examining the relationship between neuropsychological functioning and homocysteine levels in euthymic bipolar patients. Fifty-seven euthymic bipolar outpatients were a...

This article reviews the existing animal and human literature on the clinical potential of transcranial magnetic stimulation (TMS) in mania and bipolar depression, and discusses potential future directions for this work. Studies of TMS in depression and normal volunteers suggested lateral specificity of TMS-induced mood effects. Clinical trials to...