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Papers by Jonathan Benjamin
Journal of Psychiatric Research, 2004
Several clinical studies showed beneficial effects of omega-3 fatty acids in major affective diso... more Several clinical studies showed beneficial effects of omega-3 fatty acids in major affective disorders, including resistant depression. Some antidepressants are also effective, albeit less so, in obsessive-compulsive disorder (OCD). We therefore undertook a preliminary placebo-controlled cross-over trial of adjunctive eicosapentaenoic acid (EPA) in OCD. Eleven patients with current obsessive-compulsive disorder, who were on a stable maximally tolerated dose of SSRI with no further improvement over at least the last two months, were recruited. Subjects were randomly allocated to begin 6 weeks of placebo (2 g liquid paraffin per day) followed by 6 weeks of 2 g of EPA or EPA followed by placebo. Patients continued their prior SSRIs at the same dose. Assessments were performed with the Yale-Brown Obsessive-Compulsive Scale (YBOCS), and the Hamilton Rating Scales for depression (HAM-D) and anxiety (HAM-A). There were no effects of order of treatment. Time had a main effect of YBOCS scores; mean scores declined from 26.0 ( AE 5) to 17.6 (AE 6) by week 6 on placebo and to 18.5 ( AE4) on EPA. There were no effects on HAM-D and HAM-A. No clinically relevant side effects were reported. The results of this study suggest that adjunctive EPA is ineffective against OCD. #
International Journal of Neuropsychopharmacology, 1999
Current serotonin reuptake inhibitor (SRI) treatments for obsessive-compulsive disorder (OCD) pro... more Current serotonin reuptake inhibitor (SRI) treatments for obsessive-compulsive disorder (OCD) provide only partial benefit. A previous study suggested that inositol alone is efficacious in OCD. Ten DSM-IV OCD patients completed a study of 18 g inositol or placebo for 6 wk each in addition to ongoing SRI treatment in a double-blind randomized cross-over design. Weekly assessments included the Yale-Brown Obsessive-Compulsive Scale (YBOCS) and Hamilton Depression and Anxiety scales. No significant difference was found between the two treatment phases.
European Neuropsychopharmacology, 2000
Acute psychological stress is the presumed immediate cause of post-traumatic stress disorder (PTS... more Acute psychological stress is the presumed immediate cause of post-traumatic stress disorder (PTSD), and may also contribute to other anxiety disorders. Abnormal activity of the hypothalamic-pituitary-adrenal (HPA) axis has been tentatively implicated in some of the features of these disorders. Ketoconazole (KTCZ), an imidazole derivative, is a potent inhibitor of gonadal and adrenal steroidogenesis. The aim of this study was to explore the effects of KTCZ blockade of adrenal steroidogenesis, and consequent elevation of adreno-corticotropic hormone (ACTH), on a model of chronic post-traumatic anxiety in rats. Amelioration of anxious behaviors after reduction of corticosterone would suggest that corticosterone (and by implication cortisol in humans) is an important mediator of anxious symptoms: exacerbation of such behaviors would suggest that corticosterone elevations are only secondary, and possibly implicate corticotropin releasing hormone (CRH) and / or ACTH in the pathogenesis of anxious symptoms. We exposed rats for 10 min to cat scent, a prima facie valid model for acute psychological stress, with and without high dose KTCZ for 14 days. Treatment with KTCZ abolished the chronic behavioral effects of acute exposure to a cat scent. Lower levels of anxious behavior in KTCZ-treated and exposed rats were accompanied by lower plasma corticosterone, ACTH and prolactin (PRL) levels compared to untreated exposed rats. Results in this model implicate corticosterone, but not ACTH, in the pathogenesis of chronic anxiety following acute psychological stress.
Neuropsychobiology, 2000
Persistence (RD2) is a subscale of the reward dependence trait, one of the three major personalit... more 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).
Molecular Psychiatry, 2000
A functional polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) h... more A functional polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) has been reported to be both associated and linked to anxietyrelated personality measures, although other studies have not replicated these findings. The current study examines both association and linkage of the gene to two major anxiety-related personality measures, the harm avoidance scale on the Tridimensional Personality Questionnaire and the neuroticism scale of the NEO-PI-R, in a sample of 148 Israeli subjects comprising 74 same-sex sibling pairs. We replicated the reported association between the short allele and higher scores on the TPQ harm avoidance scale (P = 0.03), including the subscale of shyness (P = 0.02), and also found association in the same direction between the short allele and the NEO-PI-R neuroticism subscales of anxiety (P = 0.03) and depression (P = 0.04). Sib-pair linkage analysis, using the regression method, further supported a role of the 5-HTTLPR in anxiety-related personality traits. Molecular Psychiatry (2000) 5, 216-219.
Prefrontal mechanisms are implicated in obsessive-compulsive disorder. The authors investigated w... more Prefrontal mechanisms are implicated in obsessive-compulsive disorder. The authors investigated whether prefrontal repetitive transcranial magnetic stimulation influenced obsessive-compulsive disorder symptoms. Twelve patients with obsessive-compulsive disorder were given repetitive transcranial magnetic stimulation (80% motor threshold, 20 Hz/2 seconds per minute for 20 minutes) to a right lateral prefrontal, a left lateral prefrontal, and a midoccipital (control) site on separate days, randomized. The patients' symptoms and mood were rated for 8 hours afterward. Compulsive urges decreased significantly for 8 hours after right lateral prefrontal repetitive transcranial magnetic stimulation, but there were nonsignificant increases in compulsive urges after repetitive transcranial magnetic stimulation of the midoccipital site. A shorter-lasting (30 minutes), modest, and nonsignificant reduction in compulsive urges occurred after left lateral prefrontal repetitive transcranial magnetic stimulation. Mood improved during and 30 minutes after right lateral prefrontal stimulation. These preliminary results suggest that right prefrontal repetitive transcranial magnetic stimulation might affect prefrontal mechanisms involved in obsessive-compulsive disorder.
Personality and Individual Differences, 1997
American Journal of Medical Genetics, 2000
Investigations into serotonin transporter and anxiety and depression have shown an association be... more Investigations into serotonin transporter and anxiety and depression have shown an association between stress, depression onset and genotype. We investigated the relationship between 5-HTTLPR genotype and depression and anxiety in a population with diabetes mellitus, a condition associated with high rates of stress and depression. Participants were classified according to 'S' and 'L' alleles as well as the modification of the single nucleotide polymorphism (SNP) rs25531. The 5-HTTLPR lowexpression genotype group (S or L G allele carriers) had significantly higher psychological distress (K10) scores (N ¼ 234, P ¼0.047). Subsequent analysis revealed that the effect of genotype was related to anxiety symptoms rather than depression symptoms. Furthermore, the main effect of genotype was not observed when the modification of the SNP polymorphism was not taken into account. Findings suggest that 5-HTTLPR/rs25531 genotype is associated with psychological distress in a sample of subjects with diabetes.
American Journal of Psychiatry, 2003
Studies have shown that genetic factors are significant in predisposing individuals to shyness an... more Studies have shown that genetic factors are significant in predisposing individuals to shyness and social phobia. Toward further elucidating the genetic structure of shyness, the authors examined four functional polymorphisms that make biological sense for contributing to the development of this phenotype: serotonin transporter promoter region 44 base pair insertion/deletion (5-HTTLPR), dopamine D(4) receptor exon III repeat (DRD4), catechol O-methyltransferase (COMT), and monoamine oxidase A promoter region repeat (MAO(A)). The authors assessed shyness after recruitment of a nonclinical sample (N=118, unscreened second-grade children) using a composite scale derived from questionnaires administered to the children, parents, and teachers. DNA from buccal smears successfully obtained from 98 children was genotyped by polymerase chain reaction methods for the 5-HTTLPR, DRD4, COMT, and MAO(A) polymorphisms. Significant correlations were observed for parents', teachers', and children's ratings of shyness, and Cronbach's alpha reliability was high for all three scales. A significant association was observed between the long 5-HTTLPR polymorphism and shyness, both by the functional classification of Lesch as well as by consideration of all three genotypes. No significant association was observed for the DRD4, COMT, or MAO(A) polymorphisms. This study provisionally identifies a common genetic polymorphism, 5-HTTLPR, that modestly (effect size=7%) contributed to greater shyness scores in a nonclinical group of second-grade students. These first findings may be relevant to previous reports that have shown an association between the 5-HTTLPR long form and obsessive-compulsive disorder and autism.
Psychopharmacology, 1998
Enhanced serotonergic transmission may underlie therapeutic effects of serotonin reuptake inhibit... more Enhanced serotonergic transmission may underlie therapeutic effects of serotonin reuptake inhibitors in obsessive-compulsive disorder. However, such treatment may decrease serotonin receptor responsivity. We investigated whether the serotonin antagonist metergoline would exacerbate or further improve systems in fluoxetine-responsive patients. Pilot results suggested open metergoline produced delayed symptom worsening in fluoxetine-treated patients. Fourteen patients continuing fluoxetine received metergoline and placebo (double-blind, randomized). Symptom ratings continued for 1 week afterwards. Ten unmedicated patients underwent the same procedures. Symptoms improved 4 h after both metergoline and placebo. The day after metergoline but not placebo, fluoxetine-treated patients had significantly increased anxiety, obsessions and compulsions, abating over several days. Depression was unchanged. Metergoline had no similar delayed effects in unmedicated patients. Metergoline levels were higher in fluoxetine-treated patients. These results, consistent with less conclusive earlier findings, suggest that prolonged changes in brain serotonin function underlie symptom re-emergence following administration of metergoline to fluoxetine-treated patients with obsessive-compulsive disorder.
Personality and Individual Differences, 2001
The Hebrew Tridimensional Personality Questionnaire was administered to over a thousand individua... more The Hebrew Tridimensional Personality Questionnaire was administered to over a thousand individuals in the community, 16–78 years of age. Factor analysis was run first on individual items, and then on the 12 sub-scales described by [Cloninger, CR, Pryzbeck, TR, & Svrakic, DM (1991). The TPQ: US normative data. Psychological Reports, 69, 1047–1051)]. The factor analyses were restricted to four orthogonal factors in order to attempt confirmation of the corrected four-factor solution [Stallings, MC, Hewitt, JK, Cloninger, RC, Heath, AC, & ...
Autonomic Neuroscience-basic & Clinical, 2006
Spectral analysis of heart rate variability (HRV) and related measures has been shown to be a rel... more Spectral analysis of heart rate variability (HRV) and related measures has been shown to be a reliable noninvasive technique enabling quantitative assessment of cardiovascular autonomic regulatory responses to autonomic regulatory mechanisms; it provides a dynamic probe of sympathetic and parasympathetic tone, reflecting the interactions between the two. Over 20 studies reported abnormalities of HRV in anxiety, and patients with heart disease and anxiety are at increased risk for morbidity and mortality. Psychiatric drugs partly correct abnormalities of HRV and, recently, autonomic drugs (h-blockers) have been studied in anxiety disorders. The authors call for further studies, especially in patients with co-existing anxiety disorders and heart disease, incorporating assessment of HRV. D 2006 Published by Elsevier B.V.
American Journal of Medical Genetics, 1997
We recently reported an association between the long repeat allele of the dopamine D4 exon III re... more 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 polymorphism (D4DR) accounts for only a small percent of the variance for this trait, suggesting that additional genes influence both novelty seeking as well as the other temperaments that are inventoried by the Cloninger TPQ. In the current investigation, we examined, in the original cohort of 120 normal volunteers, two additional coding region polymorphisms, a glycine to serine substitution in the dopamine D3 receptor (D3DR) and a cysteine to serine substitution in the 5-HT2C serotonin receptor (HTR2C). Three-way analysis of variance (TPQ score grouped by D4DR, D3DR and 5-HT2C) demonstrated that reward dependence and persistence scores were significantly reduced by the presence of the less common 5-HT2Cser polymorphism. The effect of the serine substitution in this X-linked serotonin receptor polymorphism on reward dependence was also observed when male and female subject groups were separately analyzed. There was also a significant interaction between the two dopamine receptor polymorphisms and the serotonin polymorphism on reward dependence. In particular, the effect of the 5-HT2C polymorphism on reward dependence was markedly accentuated in individuals who had the long version of the D4DR exon III repeat polymorphism. When present in the same individual, the 5-HT2C and dopamine receptor polymorphisms account for 30% of the observed variance for persistence (RD2) and 13% of the variance for reward dependence scores (RD134). However, the number of subjects with both less common D4DR and 5-HT2C polymorphisms is small, underscoring the importance of verifying this interaction in a larger cohort.
Psychiatry Research, 2000
. Ž . Power spectral analysis PSA of heart rate variability HRV offers reliable assessment of car... more . Ž . Power spectral analysis PSA of heart rate variability HRV offers reliable assessment of cardiovascular autonomic responses, providing a 'window' onto the interaction of peripheral sympathetic and parasympathetic tone. Alterations in HRV are associated with various physiological and pathophysiological processes, and may contribute Ž . to morbidity and mortality. Previous studies of posttraumatic stress disorder PTSD found lower resting HRV in patients compared to controls, suggesting increased sympathetic and decreased parasympathetic tone. This article Ž . describes the analysis of HRV at rest and after psychological stress in panic disorder PD patients, in an enlarged Ž . sample of PTSD patients, and in healthy control subjects. Standardized heart rate HR analysis was carried out in 14 PTSD patients, 11 PD patients and 25 matched controls. ECG recordings were made while subjects were resting Ž . 'rest 1' , while recalling the trauma implicated in PTSD, or the circumstances of a severe panic attack, as Ž . Ž . appropriate 'recall' , and again while resting 'rest 2' . Controls were asked to recall a stressful life event during Ž . recall. While both patient groups had elevated HR and low frequency LF components of HRV at baseline Ž . suggesting increased sympathetic activity , PTSD patients, unlike PD patients and controls, failed to respond to the recall stress with increases in HR and LF. HRV analysis demonstrates significant differences in autonomic regulation of PTSD and PD patients compared to each other and to control subjects. HRV analysis may augment biochemical studies of peripheral measures in these disorders. ᮊ
Psychopharmacology, 1996
The serotonergic agent meta-chlorophenylpiperazine (m-CPP) increases temperature and plasma ACTH ... more The serotonergic agent meta-chlorophenylpiperazine (m-CPP) increases temperature and plasma ACTH and other hormones and decreases soical interaction, locomotor activity and food intake in rats, most likely via stimulation of 5-HT2c receptors. Repeated daily administration ofm-CPP to rats induces rapid tolerance to these effects ofm-CPP. Asm-CPP has been used in challenge tests and in preliminary treatment trials in humans, we evaluated the possible development of tolerance tom-CPP in ten healthy human volunteers using a double-blind, random assignment crossover study of placebo versus dailym-CPP infusions. Psychological and physical symptoms of anxiety, temperature, pupil size, diastolic blood pressure, and plasma ACTH, cortisol, and prolactin concentrations were increased by the first administration ofm-CPP (0.08 mg/kg) compared to placebo. All of these responses were attenuated onm-CPP days 2 and 3. Plasmam-CPP levels did not differ across the 3m-CPP days. Repeatedm-CPP administration thus appears to induce rapid, tolerance to its behavioral and physiological effects in humans Further investigations of the mechanisms involved in the development of subsensitivity tom-CPP may contribute to increased understanding tom-CPP may contirbute to increased understanding of the regulation of serotonin-mediated functions and of anxiety, disorders.
Molecular Psychiatry, 2000
Keywords: personality; polymorphism; tridimensional personality questionnaire; catechol O-methylt... more Keywords: personality; polymorphism; tridimensional personality questionnaire; catechol O-methyltransferase; dopamine D4 receptor; serotonin transporter promoter Dopamine D4 receptor (DRD4), serotonin transporter promoter regulatory region (5-HTTLPR) and catechol Omethyltransferase (COMT) polymorphisms were examined for association with TPQ personality factors in 455 subjects. Significant interactions were observed by multivariate analysis, (COMT × 5-HTTLPR: Hotelling's Trace = 2.3, P = 0.02) and by subsequent univariate 3way ANOVA when Novelty Seeking (NS) was the dependent variable: 5-HTTLPR × D4DR (F = 6.18, P = 0.03) and COMT × 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 2week-old neonates, in the same children assessed again at 2 months of age and in adults. Molecular Psychiatry (2000) 5, 96-100.
American Journal of Medical Genetics, 2003
Human personality traits are moderately heritable but only recently have specific polymorphisms b... more Human personality traits are moderately heritable but only recently have specific polymorphisms been associated with particular personality dimensions especially anxiety-related and novelty-seeking traits. The first genome-wide scan for personality traits was recently carried out by Cloninger et al. [1998: Am J Med Genet 81:313–317] and his colleagues and they reported that a region on 8p21 showed linkage to TPQ Harm Avoidance, an anxiety-related personality trait. Towards replicating and extending these results, we examined both 8p21 and two additional chromosomal regions (1q21–24 and 22q12–13) for linkage to TPQ personality traits by genotyping at least three microsatellite markers in each region in a group of 384 sibling pairs. We found evidence for linkage to TPQ HA at 8p21–23 (Lod score = 2.907) confirming in an independent sample the initial findings by Cloninger and his colleagues. © 2003 Wiley-Liss, Inc.
International Journal of Neuropsychopharmacology, 1998
Although 30-60% of the variance in many personality traits is inherited, until recently, little w... more Although 30-60% of the variance in many personality traits is inherited, until recently, little was known about the genes responsible. Preliminary studies of family history in bipolar disorder and of X-linkage of personality traits in colour-blindness suggested a 'quantitative trait locus' (QTL) approach to the genetics of normal personality. In methodically similar but independent studies of 124 Israeli and 315 American normal volunteers, an association was found between the dopamine D4 receptor gene (D4DR) and the personality trait of novelty-seeking. In the Israeli sample there was preliminary evidence for an interaction between the D4DR gene and the serotonin 2C receptor gene (5-HT-2C), with a marked effect on the trait of reward dependence. In addition to receptors, monoamine uptake mechanisms, such as the serotonin transporter (5-HTT), are candidate genes for personality traits. 5-HTT gene transcription is modulated by a frequent polymorphism in its promoter region, with resulting effects on 5-HTT expression and 5-HT uptake. In an extended American sample totalling 505 subjects, the 5-HTT polymorphism was associated with anxiety- and depression-related personality traits. The allelic variation in functional expression of the 5-HTT may also be a susceptibility factor for disorders of the affective spectrum. Further investigation of genes for personality traits may provide additional links between normal personality and psychiatric illness.
European Journal of Pharmacology, 2000
Genetic factors significantly contribute to the determination of human personality traits assesse... more 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.
Journal of Psychiatric Research, 2004
Several clinical studies showed beneficial effects of omega-3 fatty acids in major affective diso... more Several clinical studies showed beneficial effects of omega-3 fatty acids in major affective disorders, including resistant depression. Some antidepressants are also effective, albeit less so, in obsessive-compulsive disorder (OCD). We therefore undertook a preliminary placebo-controlled cross-over trial of adjunctive eicosapentaenoic acid (EPA) in OCD. Eleven patients with current obsessive-compulsive disorder, who were on a stable maximally tolerated dose of SSRI with no further improvement over at least the last two months, were recruited. Subjects were randomly allocated to begin 6 weeks of placebo (2 g liquid paraffin per day) followed by 6 weeks of 2 g of EPA or EPA followed by placebo. Patients continued their prior SSRIs at the same dose. Assessments were performed with the Yale-Brown Obsessive-Compulsive Scale (YBOCS), and the Hamilton Rating Scales for depression (HAM-D) and anxiety (HAM-A). There were no effects of order of treatment. Time had a main effect of YBOCS scores; mean scores declined from 26.0 ( AE 5) to 17.6 (AE 6) by week 6 on placebo and to 18.5 ( AE4) on EPA. There were no effects on HAM-D and HAM-A. No clinically relevant side effects were reported. The results of this study suggest that adjunctive EPA is ineffective against OCD. #
International Journal of Neuropsychopharmacology, 1999
Current serotonin reuptake inhibitor (SRI) treatments for obsessive-compulsive disorder (OCD) pro... more Current serotonin reuptake inhibitor (SRI) treatments for obsessive-compulsive disorder (OCD) provide only partial benefit. A previous study suggested that inositol alone is efficacious in OCD. Ten DSM-IV OCD patients completed a study of 18 g inositol or placebo for 6 wk each in addition to ongoing SRI treatment in a double-blind randomized cross-over design. Weekly assessments included the Yale-Brown Obsessive-Compulsive Scale (YBOCS) and Hamilton Depression and Anxiety scales. No significant difference was found between the two treatment phases.
European Neuropsychopharmacology, 2000
Acute psychological stress is the presumed immediate cause of post-traumatic stress disorder (PTS... more Acute psychological stress is the presumed immediate cause of post-traumatic stress disorder (PTSD), and may also contribute to other anxiety disorders. Abnormal activity of the hypothalamic-pituitary-adrenal (HPA) axis has been tentatively implicated in some of the features of these disorders. Ketoconazole (KTCZ), an imidazole derivative, is a potent inhibitor of gonadal and adrenal steroidogenesis. The aim of this study was to explore the effects of KTCZ blockade of adrenal steroidogenesis, and consequent elevation of adreno-corticotropic hormone (ACTH), on a model of chronic post-traumatic anxiety in rats. Amelioration of anxious behaviors after reduction of corticosterone would suggest that corticosterone (and by implication cortisol in humans) is an important mediator of anxious symptoms: exacerbation of such behaviors would suggest that corticosterone elevations are only secondary, and possibly implicate corticotropin releasing hormone (CRH) and / or ACTH in the pathogenesis of anxious symptoms. We exposed rats for 10 min to cat scent, a prima facie valid model for acute psychological stress, with and without high dose KTCZ for 14 days. Treatment with KTCZ abolished the chronic behavioral effects of acute exposure to a cat scent. Lower levels of anxious behavior in KTCZ-treated and exposed rats were accompanied by lower plasma corticosterone, ACTH and prolactin (PRL) levels compared to untreated exposed rats. Results in this model implicate corticosterone, but not ACTH, in the pathogenesis of chronic anxiety following acute psychological stress.
Neuropsychobiology, 2000
Persistence (RD2) is a subscale of the reward dependence trait, one of the three major personalit... more 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).
Molecular Psychiatry, 2000
A functional polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) h... more A functional polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) has been reported to be both associated and linked to anxietyrelated personality measures, although other studies have not replicated these findings. The current study examines both association and linkage of the gene to two major anxiety-related personality measures, the harm avoidance scale on the Tridimensional Personality Questionnaire and the neuroticism scale of the NEO-PI-R, in a sample of 148 Israeli subjects comprising 74 same-sex sibling pairs. We replicated the reported association between the short allele and higher scores on the TPQ harm avoidance scale (P = 0.03), including the subscale of shyness (P = 0.02), and also found association in the same direction between the short allele and the NEO-PI-R neuroticism subscales of anxiety (P = 0.03) and depression (P = 0.04). Sib-pair linkage analysis, using the regression method, further supported a role of the 5-HTTLPR in anxiety-related personality traits. Molecular Psychiatry (2000) 5, 216-219.
Prefrontal mechanisms are implicated in obsessive-compulsive disorder. The authors investigated w... more Prefrontal mechanisms are implicated in obsessive-compulsive disorder. The authors investigated whether prefrontal repetitive transcranial magnetic stimulation influenced obsessive-compulsive disorder symptoms. Twelve patients with obsessive-compulsive disorder were given repetitive transcranial magnetic stimulation (80% motor threshold, 20 Hz/2 seconds per minute for 20 minutes) to a right lateral prefrontal, a left lateral prefrontal, and a midoccipital (control) site on separate days, randomized. The patients' symptoms and mood were rated for 8 hours afterward. Compulsive urges decreased significantly for 8 hours after right lateral prefrontal repetitive transcranial magnetic stimulation, but there were nonsignificant increases in compulsive urges after repetitive transcranial magnetic stimulation of the midoccipital site. A shorter-lasting (30 minutes), modest, and nonsignificant reduction in compulsive urges occurred after left lateral prefrontal repetitive transcranial magnetic stimulation. Mood improved during and 30 minutes after right lateral prefrontal stimulation. These preliminary results suggest that right prefrontal repetitive transcranial magnetic stimulation might affect prefrontal mechanisms involved in obsessive-compulsive disorder.
Personality and Individual Differences, 1997
American Journal of Medical Genetics, 2000
Investigations into serotonin transporter and anxiety and depression have shown an association be... more Investigations into serotonin transporter and anxiety and depression have shown an association between stress, depression onset and genotype. We investigated the relationship between 5-HTTLPR genotype and depression and anxiety in a population with diabetes mellitus, a condition associated with high rates of stress and depression. Participants were classified according to 'S' and 'L' alleles as well as the modification of the single nucleotide polymorphism (SNP) rs25531. The 5-HTTLPR lowexpression genotype group (S or L G allele carriers) had significantly higher psychological distress (K10) scores (N ¼ 234, P ¼0.047). Subsequent analysis revealed that the effect of genotype was related to anxiety symptoms rather than depression symptoms. Furthermore, the main effect of genotype was not observed when the modification of the SNP polymorphism was not taken into account. Findings suggest that 5-HTTLPR/rs25531 genotype is associated with psychological distress in a sample of subjects with diabetes.
American Journal of Psychiatry, 2003
Studies have shown that genetic factors are significant in predisposing individuals to shyness an... more Studies have shown that genetic factors are significant in predisposing individuals to shyness and social phobia. Toward further elucidating the genetic structure of shyness, the authors examined four functional polymorphisms that make biological sense for contributing to the development of this phenotype: serotonin transporter promoter region 44 base pair insertion/deletion (5-HTTLPR), dopamine D(4) receptor exon III repeat (DRD4), catechol O-methyltransferase (COMT), and monoamine oxidase A promoter region repeat (MAO(A)). The authors assessed shyness after recruitment of a nonclinical sample (N=118, unscreened second-grade children) using a composite scale derived from questionnaires administered to the children, parents, and teachers. DNA from buccal smears successfully obtained from 98 children was genotyped by polymerase chain reaction methods for the 5-HTTLPR, DRD4, COMT, and MAO(A) polymorphisms. Significant correlations were observed for parents', teachers', and children's ratings of shyness, and Cronbach's alpha reliability was high for all three scales. A significant association was observed between the long 5-HTTLPR polymorphism and shyness, both by the functional classification of Lesch as well as by consideration of all three genotypes. No significant association was observed for the DRD4, COMT, or MAO(A) polymorphisms. This study provisionally identifies a common genetic polymorphism, 5-HTTLPR, that modestly (effect size=7%) contributed to greater shyness scores in a nonclinical group of second-grade students. These first findings may be relevant to previous reports that have shown an association between the 5-HTTLPR long form and obsessive-compulsive disorder and autism.
Psychopharmacology, 1998
Enhanced serotonergic transmission may underlie therapeutic effects of serotonin reuptake inhibit... more Enhanced serotonergic transmission may underlie therapeutic effects of serotonin reuptake inhibitors in obsessive-compulsive disorder. However, such treatment may decrease serotonin receptor responsivity. We investigated whether the serotonin antagonist metergoline would exacerbate or further improve systems in fluoxetine-responsive patients. Pilot results suggested open metergoline produced delayed symptom worsening in fluoxetine-treated patients. Fourteen patients continuing fluoxetine received metergoline and placebo (double-blind, randomized). Symptom ratings continued for 1 week afterwards. Ten unmedicated patients underwent the same procedures. Symptoms improved 4 h after both metergoline and placebo. The day after metergoline but not placebo, fluoxetine-treated patients had significantly increased anxiety, obsessions and compulsions, abating over several days. Depression was unchanged. Metergoline had no similar delayed effects in unmedicated patients. Metergoline levels were higher in fluoxetine-treated patients. These results, consistent with less conclusive earlier findings, suggest that prolonged changes in brain serotonin function underlie symptom re-emergence following administration of metergoline to fluoxetine-treated patients with obsessive-compulsive disorder.
Personality and Individual Differences, 2001
The Hebrew Tridimensional Personality Questionnaire was administered to over a thousand individua... more The Hebrew Tridimensional Personality Questionnaire was administered to over a thousand individuals in the community, 16–78 years of age. Factor analysis was run first on individual items, and then on the 12 sub-scales described by [Cloninger, CR, Pryzbeck, TR, & Svrakic, DM (1991). The TPQ: US normative data. Psychological Reports, 69, 1047–1051)]. The factor analyses were restricted to four orthogonal factors in order to attempt confirmation of the corrected four-factor solution [Stallings, MC, Hewitt, JK, Cloninger, RC, Heath, AC, & ...
Autonomic Neuroscience-basic & Clinical, 2006
Spectral analysis of heart rate variability (HRV) and related measures has been shown to be a rel... more Spectral analysis of heart rate variability (HRV) and related measures has been shown to be a reliable noninvasive technique enabling quantitative assessment of cardiovascular autonomic regulatory responses to autonomic regulatory mechanisms; it provides a dynamic probe of sympathetic and parasympathetic tone, reflecting the interactions between the two. Over 20 studies reported abnormalities of HRV in anxiety, and patients with heart disease and anxiety are at increased risk for morbidity and mortality. Psychiatric drugs partly correct abnormalities of HRV and, recently, autonomic drugs (h-blockers) have been studied in anxiety disorders. The authors call for further studies, especially in patients with co-existing anxiety disorders and heart disease, incorporating assessment of HRV. D 2006 Published by Elsevier B.V.
American Journal of Medical Genetics, 1997
We recently reported an association between the long repeat allele of the dopamine D4 exon III re... more 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 polymorphism (D4DR) accounts for only a small percent of the variance for this trait, suggesting that additional genes influence both novelty seeking as well as the other temperaments that are inventoried by the Cloninger TPQ. In the current investigation, we examined, in the original cohort of 120 normal volunteers, two additional coding region polymorphisms, a glycine to serine substitution in the dopamine D3 receptor (D3DR) and a cysteine to serine substitution in the 5-HT2C serotonin receptor (HTR2C). Three-way analysis of variance (TPQ score grouped by D4DR, D3DR and 5-HT2C) demonstrated that reward dependence and persistence scores were significantly reduced by the presence of the less common 5-HT2Cser polymorphism. The effect of the serine substitution in this X-linked serotonin receptor polymorphism on reward dependence was also observed when male and female subject groups were separately analyzed. There was also a significant interaction between the two dopamine receptor polymorphisms and the serotonin polymorphism on reward dependence. In particular, the effect of the 5-HT2C polymorphism on reward dependence was markedly accentuated in individuals who had the long version of the D4DR exon III repeat polymorphism. When present in the same individual, the 5-HT2C and dopamine receptor polymorphisms account for 30% of the observed variance for persistence (RD2) and 13% of the variance for reward dependence scores (RD134). However, the number of subjects with both less common D4DR and 5-HT2C polymorphisms is small, underscoring the importance of verifying this interaction in a larger cohort.
Psychiatry Research, 2000
. Ž . Power spectral analysis PSA of heart rate variability HRV offers reliable assessment of car... more . Ž . Power spectral analysis PSA of heart rate variability HRV offers reliable assessment of cardiovascular autonomic responses, providing a 'window' onto the interaction of peripheral sympathetic and parasympathetic tone. Alterations in HRV are associated with various physiological and pathophysiological processes, and may contribute Ž . to morbidity and mortality. Previous studies of posttraumatic stress disorder PTSD found lower resting HRV in patients compared to controls, suggesting increased sympathetic and decreased parasympathetic tone. This article Ž . describes the analysis of HRV at rest and after psychological stress in panic disorder PD patients, in an enlarged Ž . sample of PTSD patients, and in healthy control subjects. Standardized heart rate HR analysis was carried out in 14 PTSD patients, 11 PD patients and 25 matched controls. ECG recordings were made while subjects were resting Ž . 'rest 1' , while recalling the trauma implicated in PTSD, or the circumstances of a severe panic attack, as Ž . Ž . appropriate 'recall' , and again while resting 'rest 2' . Controls were asked to recall a stressful life event during Ž . recall. While both patient groups had elevated HR and low frequency LF components of HRV at baseline Ž . suggesting increased sympathetic activity , PTSD patients, unlike PD patients and controls, failed to respond to the recall stress with increases in HR and LF. HRV analysis demonstrates significant differences in autonomic regulation of PTSD and PD patients compared to each other and to control subjects. HRV analysis may augment biochemical studies of peripheral measures in these disorders. ᮊ
Psychopharmacology, 1996
The serotonergic agent meta-chlorophenylpiperazine (m-CPP) increases temperature and plasma ACTH ... more The serotonergic agent meta-chlorophenylpiperazine (m-CPP) increases temperature and plasma ACTH and other hormones and decreases soical interaction, locomotor activity and food intake in rats, most likely via stimulation of 5-HT2c receptors. Repeated daily administration ofm-CPP to rats induces rapid tolerance to these effects ofm-CPP. Asm-CPP has been used in challenge tests and in preliminary treatment trials in humans, we evaluated the possible development of tolerance tom-CPP in ten healthy human volunteers using a double-blind, random assignment crossover study of placebo versus dailym-CPP infusions. Psychological and physical symptoms of anxiety, temperature, pupil size, diastolic blood pressure, and plasma ACTH, cortisol, and prolactin concentrations were increased by the first administration ofm-CPP (0.08 mg/kg) compared to placebo. All of these responses were attenuated onm-CPP days 2 and 3. Plasmam-CPP levels did not differ across the 3m-CPP days. Repeatedm-CPP administration thus appears to induce rapid, tolerance to its behavioral and physiological effects in humans Further investigations of the mechanisms involved in the development of subsensitivity tom-CPP may contribute to increased understanding tom-CPP may contirbute to increased understanding of the regulation of serotonin-mediated functions and of anxiety, disorders.
Molecular Psychiatry, 2000
Keywords: personality; polymorphism; tridimensional personality questionnaire; catechol O-methylt... more Keywords: personality; polymorphism; tridimensional personality questionnaire; catechol O-methyltransferase; dopamine D4 receptor; serotonin transporter promoter Dopamine D4 receptor (DRD4), serotonin transporter promoter regulatory region (5-HTTLPR) and catechol Omethyltransferase (COMT) polymorphisms were examined for association with TPQ personality factors in 455 subjects. Significant interactions were observed by multivariate analysis, (COMT × 5-HTTLPR: Hotelling's Trace = 2.3, P = 0.02) and by subsequent univariate 3way ANOVA when Novelty Seeking (NS) was the dependent variable: 5-HTTLPR × D4DR (F = 6.18, P = 0.03) and COMT × 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 2week-old neonates, in the same children assessed again at 2 months of age and in adults. Molecular Psychiatry (2000) 5, 96-100.
American Journal of Medical Genetics, 2003
Human personality traits are moderately heritable but only recently have specific polymorphisms b... more Human personality traits are moderately heritable but only recently have specific polymorphisms been associated with particular personality dimensions especially anxiety-related and novelty-seeking traits. The first genome-wide scan for personality traits was recently carried out by Cloninger et al. [1998: Am J Med Genet 81:313–317] and his colleagues and they reported that a region on 8p21 showed linkage to TPQ Harm Avoidance, an anxiety-related personality trait. Towards replicating and extending these results, we examined both 8p21 and two additional chromosomal regions (1q21–24 and 22q12–13) for linkage to TPQ personality traits by genotyping at least three microsatellite markers in each region in a group of 384 sibling pairs. We found evidence for linkage to TPQ HA at 8p21–23 (Lod score = 2.907) confirming in an independent sample the initial findings by Cloninger and his colleagues. © 2003 Wiley-Liss, Inc.
International Journal of Neuropsychopharmacology, 1998
Although 30-60% of the variance in many personality traits is inherited, until recently, little w... more Although 30-60% of the variance in many personality traits is inherited, until recently, little was known about the genes responsible. Preliminary studies of family history in bipolar disorder and of X-linkage of personality traits in colour-blindness suggested a 'quantitative trait locus' (QTL) approach to the genetics of normal personality. In methodically similar but independent studies of 124 Israeli and 315 American normal volunteers, an association was found between the dopamine D4 receptor gene (D4DR) and the personality trait of novelty-seeking. In the Israeli sample there was preliminary evidence for an interaction between the D4DR gene and the serotonin 2C receptor gene (5-HT-2C), with a marked effect on the trait of reward dependence. In addition to receptors, monoamine uptake mechanisms, such as the serotonin transporter (5-HTT), are candidate genes for personality traits. 5-HTT gene transcription is modulated by a frequent polymorphism in its promoter region, with resulting effects on 5-HTT expression and 5-HT uptake. In an extended American sample totalling 505 subjects, the 5-HTT polymorphism was associated with anxiety- and depression-related personality traits. The allelic variation in functional expression of the 5-HTT may also be a susceptibility factor for disorders of the affective spectrum. Further investigation of genes for personality traits may provide additional links between normal personality and psychiatric illness.
European Journal of Pharmacology, 2000
Genetic factors significantly contribute to the determination of human personality traits assesse... more 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.