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Publications (84)
Major depressive disorder (MDD) is a heterogeneous, highly prevalent, and moderately heritable disorder. A complex and diverse genetic-environmental interplay converges to set apart a significant minority that is susceptible to MDD, from among those who experience shorter lived and less recurrent intensive and incapacitating forms of sadness. The m...
In sorrow thou shalt bring forth children (Genesis 3:16) seems as relevant today, with one of seven mothers afflicted by a depressive episode, constituting the most common medical complication after delivery. Why mothers are variably affected by mood symptoms postpartum remains unclear, and the pathogenesis and early molecular indicators of this di...
Schizophrenic patients who are treated with antipsychotics, especially second generation antipsychotics, such as clozapine and olanzapine, manifest an increase in cholesterol and triglycerides as well as other changes associated with diabetes or the metabolic syndrome. Previous studies have shown that polymorphisms in several genes that regulate li...
The aim of the study was to prospectively evaluate the association between the occurrence of post-traumatic stress disorder (PTSD) and the adrenergic response to the traumatic event, and additionally, to explore the link between PTSD and the initial norepinephrine:cortisol ratio. Plasma levels and urinary excretion of norepinephrine (NE) were measu...
The aim of the study was to evaluate the association between post-traumatic disorder (PTSD) and hypothalamic-pituitary-adrenal (HPA) axis responses to the triggering trauma. A companion paper evaluates the adrenergic response and interactions between the two. We measured plasma and saliva cortisol, hourly urinary excretion of cortisol, plasma level...
Summarizing the contributions in this section of the book, this chapter addresses questions regarding the complex etiology of PTSD, and the relative strength of discernable biological indicators of the disorder. It outlines two major approaches to exploring the biology of the disorder and discusses the reason for the many non-replications of findin...
Cigarette smoking is a complex behavior to which environmental, psychological, and genetic factors contribute. Applying a multifactorial model, we examined the role of genetic variation in the dopamine transporter (DAT1) in smoking initiation (SI) and nicotine dependence. The participants were female college students who had never smoked (n = 148)...
Schizophrenia, a severe neuropsychiatric disorder, is believed to involve multiple genetic factors. A significant body of evidence supports a pivotal role for abnormalities of brain development in the disorder. Linkage signals for schizophrenia map to human chromosome 6q. To obtain a finer localization, we genotyped 180 single nucleotide polymorphi...
The thyroid hormone triiodothyronine (T3) has been used both to augment and accelerate the clinical effects of antidepressants, particularly the tricyclics. More recent work indicates that it may have similar actions with regard to the SSRIs. Two main mechanisms have been put forward to explain its antidepressant actions, (a) an action at the nucle...
The core hypothesis underlying pharmacogenetics is that genetic factors play a significant role in the well-recognized differences between individuals in response to medication and susceptibility to adverse effects. If these genetic factors can be identified and understood, they may serve as predictors to guide clinicians in tailoring medication to...
Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A)...
We previously reported an autosomal scan for schizophrenia susceptibility loci in a systematically recruited sample of Arab Israeli families. The scan detected significant evidence for linkage at chromosome 6q23 with a nonparametric LOD score (NPL) of 4.60 (P=0.000004) and a multipoint parametric LOD score of 4.16. In order to refine this finding w...
Trauma survivors show marked differences in the severity and persistence of post-traumatic stress disorder (PTSD) symptoms. Early symptoms subside in most, but persist as acute and chronic PTSD in a significant minority. The underlying molecular mechanisms or outcome predictors determining these differences are not known. Molecular markers for iden...
SIR—The dopamine transporter gene (DAT1 SCL6A3) is an important candidate for mediating susceptibility to attention-deficit hyperactivity disorder (ADHD), given its relevance for related behaviors, and its blockade by effective stimulant drugs. To date, most studies examined a 40 bp variable number tandem repeat (VNTR) in the 3'-untranslated region...
Correction to: Molecular Psychiatry 10, 500–513. doi:10.1038/sj.mp.4001636 Following the 1 February 2005 advance online publication of this article, the authors noted the following error: In the Supplementary Notes of this article, the password and username of the GEO deposit were included by mistake.
Schizophrenia is characterized by thought disorders, hallucinations and delusions. Genetic studies have shown a high linkage at chromosome 6q16-21. Among the genes located in this region is the glutamate receptor ionotropic kainate 2 gene (GRIK2 or GLUR6), a functional candidate for susceptibility to schizophrenia. In this study, transmission of GR...
Antipsychotic drugs are widely used for the treatment of psychosis, especially schizophrenia. Their long-term use can result at times in serious side-effects such as Tardive Dyskinesia (TD). Since over 80% of schizophrenia sufferers (lifetime prevalence 1%) receive long-term antipsychotic drug treatment, the extent of the problem is potentially lar...
The available data from preclinical and pharmacological studies on the role of the serotonin transporter (5-HTT) support the hypothesis that a dysfunction in brain serotonergic system activity contributes to the vulnerability to affective disorders (AD). 5-HTT is the major site of serotonin reuptake into the presynaptic neuron, and it has been show...
Posttraumatic stress disorder (PTSD) is a prevalent anxiety disorder marked by behavioral, physiologic, and hormonal alterations. PTSD is disabling and commonly follows a chronic course. The etiology of PTSD is unknown, although exposure to a traumatic event constitutes a necessary, but not sufficient, factor. A twin study of Vietnam veterans has s...
Increased distress in medical students has been previously documented. However, causal relationship between putative, nh stress factors and emotional state has not yet been determined. Moreover, most data concerning mental health of medical students has been acquired in the USA.
A list of conceivable stress factors and the Brief Symptom Inventory w...
Posttraumatic stress disorder (PTSD) is a prevalent anxiety disorder marked by behavioral, physiologic, and hormonal alterations. PTSD is disabling and commonly follows a chronic course. The etiology of PTSD is unknown, although exposure to a traumatic event constitutes a necessary, but not sufficient, factor. A twin study of Vietnam veterans has s...
Hypothalamic pituitary adrenal axis abnormalities have been described in posttraumatic stress disorder (PTSD), and among the recently traumatized. Plasma cortisol and continuous measures of PTSD symptoms were obtained from 21 survivors, at 1 week and 6 months after traumatic events. Eight survivors met Clinician Administered PTSD Scale criteria for...
Schizophrenia is a complex neuropsychiatric disorder to which an as-yet-unknown number of genes contribute, interacting with each other and the environment. Linkage analyses have implicated several chromosomal regions as harboring schizophrenia susceptibility loci although rarely at levels commensurate with proposed thresholds for genome-wide signi...
Attention Deficit and Hyperactivity Disorder (ADHD) is a common idiopathic childhood neurodevelopmental disorder, exacting a significant clinical and public health toll. It impairs schooling and social adaptation, resulting in high rates of depression, conduct disorder, school dropouts, and substance abuse, and necessitating exposure of many childr...
Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal side effect profile of atypical antipsychotic drugs. We evaluated candidate dopamine and serotonin genes for association wit...
Posttraumatic stress disorder (PTSD) is a chronic anxiety disorder that follows exposure to extreme events. A large twin study of Vietnam veterans had demonstrated a significant genetic contribution to chronic PTSD upon exposure to combat.(1,2) The underlying genes, however, have not been described. Given previous findings of abnormal dopamine (DA)...
Variability among individuals in their therapeutic response to psychotropic drugs and in susceptibility to adverse effects is considerable. Pharmacogenetics addresses the contribution of genetic factors to this variability. An important focus of interest in pharmacogenetics has been on candidate genes that play a role in susceptibility to the antip...
Angiotensin converting enzyme (ACE) is a candidate gene for psychiatric disorders. We examined the frequency of a functional insertion/deletion (I/D) polymorphism in the 16th intron of the ACE gene (located on chromosome 17q23) in groups of patients with schizophrenia (n = 104 and 113), major depression (n = 55), and bipolar disorder (n = 87) compa...
The hypothesis that HLA antigens confer susceptibility to schizophrenic disorders has been tested by studying linkage and association in a family sample with 69 sib-pair families. Suggestive evidence for linkage was obtained by nonparametric multipoint LOD score analysis with a maximum around DQB CAR (P = 0.0004), a microsatellite marker that is in...
Convincing evidence for a genetic component in the etiology of affective disorders (AD), including bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD), is supported by traditional and molecular genetic studies. Most arguments lead to the complex inheritance hypothesis, suggesting that the mode of inheritance is probably not Men...
Tardive dyskinesia is a chronic adverse effect of anti psychotic drugs, where association with a polymorphic site in the dopamine D3 receptor gene has been previously reported. Cytochrome P 450 17alpha-hydroxylase activity has been implicated with modulation of central dopamine release as well as neuroprotection. We investigated the association of...
Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, where family data support substantial heritability.(1) To date, association studies focussed mainly on genes regulating dopaminergic neurotransmission.(2)Interleukin-1 (IL-1) activity in the brain has been implicated with differentiation of dopaminergic neurons...
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, where family data support substantial heritability. To date, association studies focussed mainly on genes regulating dopaminergic neurotransmission. Interleukin-1 (IL-1) activity in the brain has been implicated with differentiation of dopaminergic neurons and...
Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar.(1) Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs(2) and also in the action of m...
Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers.(1) Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal effects profile of atypical antipsychotic drugs.(2) We examined the association of three polymorphisms in the 5-HT2A rece...
Tardive dyskinesia (TD) is a longterm adverse effect of dopamine receptor blockers. The dopamine D3 receptor gene (DRD3) ser9gly polymorphism has been previously associated with susceptibility to TD. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extra-pyramidal effects profile of atypical antipsychoti...
Evidence from epidemiological studies and segregation analysis suggests oligo- or polygenic inheritance in schizophrenia. Since model independent methods are thought to be most appropriate for linkage analysis in complex disorders, we performed a genome-wide autosomal screen in 71 families from Germany and Israel containing 86 independent affected...
Rationale: Tardive dyskinesia (TD) is a long-term adverse effect of dopamine receptor blockers. The dopamine D3 receptor gene (DRD3)
ser9gly polymorphism has been previously associated with susceptibility to TD. Serotonin receptor antagonism has been proposed
as a common mechanism contributing to the low extrapyramidal effects profile of atypical a...
As for other complex traits, there is considerable interest in identifying candidate genes that may predispose individuals to cigarette smoking addiction, influence intensity of smoking, and produce difficulties with smoking cessation. Preliminary reports have implicated a number of candidate genes. We are studying a large sample of individuals phe...
Three polymorphisms in the 5-HT2A receptor gene, one intronic (T102C), one in the coding region (His452Tyr) and one in the promoter (-1438A/G), were examined for association with tardive dyskinesia (TD). The sample included 57 chronic schizophrenia patients with TD who were matched to 63 schizophrenia patients without TD. For the T102C polymorphism...
We previously reported an excess of the dopamine D3 receptor glycine allele (DRD3gly) and of DRD3ser-gly and DRD3gly-gly genotypes in 53 chronic schizophrenia patients with tardive dyskinesia (TD) who were on a stable antipsychotic dose and were matched to 63 schizophrenia patients without TD (Segman et al., Mol Psychiatry, 4:247-253, 1999). We gen...
Dopamine receptor antagonism is a common mechanism underlying the therapeutic efficacy of all classical antipsychotic drugs. It is also thought to underlie the propensity of these agents to induce the movement disorder, tardive dyskinesia (TD), in one fifth of chronically exposed schizophrenia patients. We examined the polymorphic serine to glycine...
A possible association between the small conductance calcium-regulated potassium channel gene, hSKCa3, and schizophrenia has recently been described by Chandy et al using a case-control design with patients with schizophrenia (n=141) and matched controls (n = 158). The gene may be considered as an excellent candidate gene for psychiatric disorders,...
In spite of substantial advances in the treatment of major depression by pharmacotherapy and other means, a significant number of depressed patients require hospitalization. In the context of the Jerusalem Collaborative Depression Project, possible precipitants of psychiatric hospitalization were sought in a cohort of patients (n = 107) who were ad...
Severe disturbances of sleep architecture and circadian rhythms are common in traumatic brain injured patients; however, complete absence of the rapid eye movement sleep stage is very rare. We describe a brain injured patient with cognitive disturbances who developed severe alterations of sleep architecture, accompanied by paranoid and jealousy del...
Potential linkage to a susceptibility locus for schizophrenia has been recently reported by the NIMH Genetics Initiative Millenium Schizophrenia Consortium [Faraone et al., Am J Med Genet, in press] and by Straub and colleagues from the Medical College of Virginia [Am J Med Genet, in press]. We have scanned initially chromosome 10 with 20 markers i...
The German/Israeli sample consists of 72 families (470 individuals) ascertained through a schizophrenic or chronic schizoaffective (RDC) index patient, each family having at least 2 affected siblings and parental information (67 families with both parents, 5 families with one parent, but additional nonaffected siblings). Thirteen families were from...
Tardive dyskinesia (TD) is a debilitating, adverse drug reaction characterized by involuntary, choreoathetotic movements in approximately 20% of patients chronically exposed to dopamine receptor antagonist drugs. Functional variability resulting from polymorphic sites in genes encoding key proteins of neurotransmitter and drug metabolizing systems...
Angiotensin converting enzyme (ACE) produces the active octapeptide angiotensin II from the decapeptide angiotensin I, as part of the renin-angiotensin cascade. A prevalent insertion/deletion polymorphism of a 287 nucleotide fragment in the 16th intron of the ACE gene has been found to correlate with plasma ACE activity. Numerous studies have repor...
In complex genetic disorders, the interval containing a potential susceptibility gene usually is large and cannot be narrowed by searching for linked families with recombinations close to the locus. If linkage disequilibrium can be detected, the interval can be narrowed to 1 cM or less. We had previously obtained evidence for association/linkage di...
The action of antipsychotic drugs on dopamine receptors suggests that dopaminergic signal transmission may play a role in the development of schizophrenia. We tested eight candidate genes (coding for dopamine receptors, the dopamine transporter, and G-proteins) in 59 families from Germany and Israel, for association. A P value of .00055 (.0044 when...
Recent reports on potential linkage by Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557], and by Straub et al. [1997: Am J Med Genet 74:558], prompted us to study chromosome 10 in a sample of 72 families containing 2 or more affected sibs with schizophrenia for additional evidence of linkage....
Recent reports on potential linkage by Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557], and by Straub et al. [1997: Am J Med Genet 74:558], prompted us to study chromosome 10 in a sample of 72 families containing 2 or more affected sibs with schizophrenia for additional evidence of linkage....
A group of 18 Israeli, clozapine-treated, schizophrenia patients underwent molecular and serological HLA typing in order to determine whether the major histocompatibility complex is associated with the development of clozapine-induced agranulocytosis. While under treatment with clozapine, 2 of the 18 patients developed agranulocytosis (total white...
Only in the past decade has a role of heredity in substance abuse been established as a result of extensive twin and family studies. More recently, several candidate genes have been investigated for their possible role in alcoholism and cocaine abuse. Specific genetic factors in opioid substance abuse have not been investigated in man, although ani...
Frequency of a polymorphism in the coding region of the 5-hydroxytryptamine(2C) (5-HT2C) receptor gene (HTR2C Xq24) was not significantly different in 122 unrelated Israeli schizophrenia patients compared with 180 control subjects matched for gender and ethnicity. However, proportion of time spent in hospital since the first admission was significa...
We recently reported an association between the long repeat allele of the dopamine D4 exon III receptor polymorphism and a human personality dimension, novelty seeking, as measured by the tridimensional personality questionnaire (TPQ), a personality instrument designed by Cloninger to reflect heritable facets of human temperament. The D4 receptor p...
Frequency of a polymorphism in the coding region of the 5-hydroxytryptamine2C (5-HT2C) receptor gene (HTR2C Xq24) was not significantly different in 122 unrelated Israeli schizophrenia patients compared with 180 control subjects matched for gender and ethnicity. However, proportion of time spent in hospital since the first admission was significant...
Onset and time course of antidepressant effect were examined in 47 patients with major depressive disorder who had been randomly assigned to twice weekly bilateral, brief pulse electroconvulsive therapy plus one simulated treatment per week (ECTx2) or to a three times weekly schedule of administration (ECTx3). Rapid improvement was observed in the...
Despite the demonstrated anti-depressant efficacy of the selective serotonin reuptake inhibitors (SSRIs), increased suicidal ideation and/or agitation have been reported in a small proportion of individuals receiving fluoxetine or other SSRIs. Part II of this review examines fluoxetine's acute effects on serotonergic functioning. Although acute flu...
The general enhancement of central serotonin (5-HT) neurotransmission following long-term administration of serotonin-selective reuptake inhibitors (SSRIs) appears to play an important role in these drugs' anti-depressant efficacy. Because suicide and/or aggression appear linked to diminished levels of brain 5-HT and its metabolites, it has been su...
