Biomedical subjects

Bernard Lerer

Publications and source records attributed to Bernard Lerer.

At least 19 recordsLinked to original sources

PubMed2003

Cerebral blood flow in depressed patients: a methodological comparison of statistical parametric mapping and region of interest analyses.

Functional brain imaging has assumed a leading role in neuropsychiatric research. However, findings reported for mental disorders often vary. Whether this reflects diversity in pathophysiology or heterogeneity of imaging techniques and data-analytic procedures is still unknown. This study compares region of interest (ROI) and statistical parametric mapping (SPM) analyses of a Tc99m-HMPAO single photon emission computed tomography (SPECT) imaging study of 23 depressed and 21 control subjects. Reduced regional cerebral blood flow (rCBF) was demonstrated by both methods in the right parietal and occipital lobes, but additional regions were identified only on ROI analysis (left temporal) and only on SPM analysis (left parietal). To investigate the contribution of SPM spatial normalization to these discrepancies, further ROI analyses were performed, applying the original ROI templates to normalized images, and applying regions identified by SPM to the original images. This study demonstrated considerable overlap in findings of SPM and ROI analyses. Differences between these methods may be mostly related to subjective placement of ROIs in ROI analysis, and standardized warping inherent in normalization in SPM. Given the advantages and drawbacks of each procedure, the choice of methodology should be determined in accordance with the study design, and complementary use of both methods may be considered.

Adult↗

PubMed2003

Effects of chronic antidepressants and electroconvulsive shock on serotonergic neurotransmission in the rat hippocampus.

The hippocampus may play a critical role in the pathophysiology and treatment of depression. There are two main lines of evidence for this: firstly, many of its functions correspond to those altered in depression, and secondly, many hippocampal functions are regulated by the serotonergic (5-HT) system, which is a common target of antidepressant treatments. Chronic effects of antidepressants and electroconvulsive shock (ECS) have been studied by various methods using electrophysiology, in vivo microdialysis or ex vivo neurochemical measurements. The aim of the current review is to point out possible correlations between these studies based on different methods and to suggest neurochemical mechanisms that result in the observed changes in hippocampal physiology and neurogenesis. These changes in hippocampal neurochemistry are reviewed and compared with the abnormalities associated with stress, corticosterone or depression.

Animals↗

PubMed2003

Algorithm-based treatment of major depression in an outpatient clinic: clinical correlates of response to a specific serotonin reuptake inhibitor and to triiodothyronine augmentation.

Clinicians who treat major depression are faced with a bewildering choice of antidepressants. Given that all have a lag period before they are effective, choice of the right antidepressant can potentially minimize the duration of symptoms, reduce cost and enhance compliance. Unfortunately, there is very little evidence upon which to base such a decision. We developed a treatment algorithm for non-psychotic, unipolar major depression, and applied it in our clinic. It includes progression from a specific serotonin reuptake inhibitor (SSRI), usually fluoxetine, from a dose of 20 mg to a dose of 40 mg in patients who do not respond. Non-responders to this dose receive augmentation with triiodothyronine (T3, 25-50 microg). All interventions are for fixed time periods and guided by overall clinical improvement as defined by the Clinical Global Inventory. Ninety patients commenced open-label treatment with 20 mg SSRI (fluoxetine, n=81; paroxetine, n=9). Seventy-four patients completed 4 wk of treatment and 44 (48.9%) were responders (intent to treat analysis). Raising the SSRI dose to 40 mg for a further 2 wk was effective in only 5 patients (16.6%). Non-responders to SSRI were significantly more depressed at baseline as reflected by their rating scales scores. Addition of T3 was effective in 10 out of 16 women (62.5%) while none of the 9 males responded. Although values were within the normal range, patients who responded to T3 had higher serum thyroid-stimulating hormone levels than those who did not. Our experience with algorithm-based treatment of unipolar, non-psychotic major depression in outpatients suggests that more than 40% of patients will not respond to initial treatment with an SSRI even when the dose is increased to 40 mg/d; that severity of depression may be an important predictor of response and that T3 may be useful as an augmenter of response in SSRI non-responders but may be less effective in men than in women. The effect of T3 may be related to thyroid function even within the normal range.

Adult↗

PubMed2003

T2-weighted image hyperintensities in major depression: focus on the basal ganglia.

A major focus of attention in structural brain-imaging research in major depression is the increased prevalence of T2-weighted image 'hyperintensities' (T2-WIH). Our aims in this study were to characterize the distribution and magnetic resonance imaging (MRI) presentation of brain hyperintensities in major depression patients compared to healthy control subjects and to explore the association between the presence of T2-WIH and measures of clinical and cognitive state. Thirty-seven patients suffering from major depression and 27 age- and sex-matched healthy controls underwent brain MRI and were evaluated by the Hamilton Rating Scale for Depression, the Mini Mental State Examination and the Haschinsky Ischaemia Index. T2-WIH (at least one) were found in 26 out of 37 major depression patients and 7 out of 27 controls (p=0.0001). The number of brain T2-WIH was significantly and positively correlated with age in depressed (p=0.001) but not in healthy subjects. Mean volume of T2-WIH was significantly greater (p=0.004) in depressed subjects. In the control group T2-WIH were exclusively located in the supratentorial hemispheral white matter while in the depressed group T2-WIH were also found in basal ganglia, temporal lobe, cerebellum and brainstem. More (52 vs. 20%; p=0.018) T2-WIH were demonstrable on T1 in depressed subjects. Depressed patients with T2-WIH in basal ganglia were clearly the most severely depressed and cognitively impaired subjects, and may constitute a clinically distinct subgroup within major depression.

Adult↗

PubMed2002

Effects of triiodothyronine and imipramine on basal 5-HT levels and 5-HT(1) autoreceptor activity in rat cortex.

Clinical studies have shown that triiodothyronine (T3) both augments and accelerates the therapeutic response to antidepressant drugs, particularly tricyclics. There is evidence that this effect is mediated by the serotonergic system. We show here that T3 administered daily for 7 days over the range 0.02-0.5 mg/kg increases basal serotonin (5-hydroxytryptamine, 5-HT) levels, as measured by in vivo microdialysis in rat cortex, in a dose-dependent fashion. All the doses of T3 examined reduced 5-HT(1A) autoreceptor activity, as measured by the effect of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.05 mg/kg s.c.) to decrease 5-HT levels in frontal cortex. T3 administered daily for 14 days at 0.02 mg/kg also reduced 5-HT(1B) autoreceptor activity, as measured by the effect of locally administered 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93129, 10 microM) to decrease 5-HT levels. In animals administered imipramine (10 mg/kg/day by osmotic minipump) concurrently with T3 injections, no further changes in either 5-HT(1A) or 5-HT(1B) autoreceptor activity were seen. We suggest that the effect of T3 to accelerate the therapeutic actions of antidepressant drugs may be due to a combination of the actions of T3 at autoreceptors and the actions of the drugs at postsynaptic 5-HT(1A) receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2002

Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families.

Genetic variants in a gene on 6p22.3, dysbindin, have been shown recently to be associated with schizophrenia (Straub et al. 2002a). There is no doubt that replication in other independent samples would enhance the significance of this finding considerably. Since the gene is located in the center of the linkage peak on chromosome 6p that we reported earlier, we decided to test six of the most positive DNA polymorphisms in a sib-pair sample and in an independently ascertained sample of triads comprising 203 families, including the families for which we detected linkage on chromosome 6p. Evidence for association was observed in the two samples separately as well as in the combined sample (P=.00068 for SNP rs760761). Multilocus haplotype analysis increased the significance further to .00002 for a two-locus haplotype and to .00001 for a three-locus haplotype. Estimation of frequencies for six-locus haplotypes revealed one common haplotype with a frequency of 73.4% in transmitted, and only 57.6% in nontransmitted, parental haplotypes. All other six-locus haplotypes occurring at a frequency of >1% were less often transmitted than nontransmitted. Our results represent a first successful replication of linkage disequilibrium in psychiatric genetics detected in a region with previous evidence of linkage and will encourage the search for causes of schizophrenia by the genetic approach.

Carrier Proteins↗

PubMed2002

Functional effects of chronic electroconvulsive shock on serotonergic 5-HT(1A) and 5-HT(1B) receptor activity in rat hippocampus and hypothalamus.

The aims of this work were to determine the influence of chronic electroconvulsive shock (ECS) on presynaptic 5-HT(1A) receptor function, postsynaptic 5-HT(1A) receptor function in hippocampus and hypothalamus, and presynaptic 5-HT(1B) receptor function in hippocampus and hypothalamus. This represents part of an on-going study of the effects of ECS on serotonergic receptor activity in selected brain areas which may be relevant to the effects of electroconvulsive therapy (ECT) in humans. Chronic ECS reduced the ability of the 5-HT(1A) receptor agonist 8-hydroxy-2(di-n-propylamino)tetraline (8-OH-DPAT) (0.2 mg/kg s.c.) to decrease 5-HT levels in hypothalamus as shown by in vivo microdialysis, indicative of a reduction in sensitivity of presynaptic 5-HT(1A) autoreceptors. The ability of the 5-HT(1B) receptor antagonist GR 127935 (5 mg/kg s.c.) to increase 5-HT levels in both hippocampus and hypothalamus was unaffected by chronic ECS. 8-OH-DPAT (0.2 mg/kg s.c.) increased cyclic AMP levels in hippocampus measured by in vivo microdialysis approximately 2-fold. The degree of stimulation of cyclic AMP formation was not altered by chronic ECS. However the cyclic AMP response to forskolin (50 micro M) administered via the microdialysis probe, which was approximately 4-fold of basal in sham-treated rats, was almost completely abolished in ECS-treated rats. Since this indicates that either adenylate cyclase catalytic unit activity or Gs protein activity is reduced in the hippocampus after chronic ECS, the lack of change in 8-OH-DPAT-induced cyclic AMP formation may be taken as possible evidence of an increase in sensitivity of postsynaptic 5-HT(1A) receptors in the hippocampus by chronic ECS. Chronic ECS increased basal plasma levels of corticosterone, ACTH and oxytocin. The ACTH response to s.c. injections of 0.2 mg/kg or 0.5 mg/kg 8-OH-DPAT was reduced by chronic ECS. Postsynaptic 5-HT(1A) receptor activity in the hypothalamus, in contrast to the hippocampus, thus appears to be desensitized after chronic ECS. We conclude that chronic ECS has regionally specific effects on both pre- and post-synaptic 5-HT(1A) receptors, but, in contrast to some antidepressant drugs, does not affect presynaptic 5-HT(1B) receptor activity.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2002

No major schizophrenia locus detected on chromosome 1q in a large multicenter sample.

Reports of substantial evidence for genetic linkage of schizophrenia to chromosome 1q were evaluated by genotyping 16 DNA markers across 107 centimorgans of this chromosome in a multicenter sample of 779 informative schizophrenia pedigrees. No significant evidence was observed for such linkage, nor for heterogeneity in allele sharing among the eight individual samples. Separate analyses of European-origin families, recessive models of inheritance, and families with larger numbers of affected cases also failed to produce significant evidence for linkage. If schizophrenia susceptibility genes are present on chromosome 1q, their population-wide genetic effects are likely to be small.

Africa↗

PubMed2002

Angiotensin converting enzyme gene insertion/deletion polymorphism: case-control association studies in schizophrenia, major affective disorder, and tardive dyskinesia and a family-based association study in schizophrenia.

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) compared to healthy control subjects (n = 87). There was no evidence for allelic or genotypic association of the polymorphism with any of the disorders or with tardive dyskinesia (TD) in patients with schizophrenia. In a sample of nuclear families (n = 61) made up of one or more patients with schizophrenia recruited with their parents, there was no evidence for biased transmission of ACE I/D alleles. Particularly in the case of schizophrenia, these findings do not support an association of the ACE I/D polymorphism with the phenotypes examined.

Alleles↗

PubMed2002

Investigation of linkage and association/linkage disequilibrium of HLA A-, DQA1-, DQB1-, and DRB1-alleles in 69 sib-pair- and 89 trio-families with schizophrenia.

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 linkage disequilibrium with the HLA antigen DQB1. Spurious evidence for negative association as calculated by the transmission disequilibrium test was found for HLA- DRB1*11 (chi-square = 11.72, corrected P value = 0.03) and for the haplotype DQB1*301-DQA1*501-DRB1*11 (chi-square = 11.3, corrected P value = 0.043). No evidence of association with these alleles was obtained in a sample of 89 trios with schizophrenic offspring and parents. Our results are not in favor of a direct involvement of the HLA system in development of schizophrenia, but are compatible with the possible existence of a susceptibility gene in the MHC region at chromosome 6p 21.31.

Alleles↗

PubMed2002

Positive association of dopamine D2 receptor polymorphism with bipolar affective disorder in a European Multicenter Association Study of affective disorders.

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 Mendelian but most likely oligogenic (or polygenic) and that the contribution of genes could be moderate or weak. The purpose of the present European multicenter study (13 centers) was to test the potential role in BPAD and UPAD of two candidate dopaminergic markers, DRD2 and DRD3, using a case-control association design. The following samples were analyzed for DRD2: 358 BPAD/358 control (C) and 133 UPAD/ 133 C subjects, and for DRD3: 325 BPAD/ 325 C and 136 UPAD/136 C subjects. Patients and controls were individually matched for sex, age ( plus minus five years) and geographical origin. Evidence for significant association between BPAD and DRD2 emerged, with an over-representation of genotype 5-5 (P=0.004) and allele 5 (P=0.002) in BPAD cases compared to controls. No association was found for DRD2 in UPAD, and for DRD3 neither in BPAD or UPAD. Our results suggest that the DRD2 microsatellite may be in linkage disequilibrium with a nearby genetic variant involved in the susceptibility to BPAD. Our large European sample allowed for replicating of some previous reported positive findings obtained in other study populations.

Alleles↗

PubMed2002

Interactive effect of cytochrome P450 17alpha-hydroxylase and dopamine D3 receptor gene polymorphisms on abnormal involuntary movements in chronic schizophrenia.

BACKGROUND: 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 a T -->C variation in the cytochrome P 450 17alpha-hydroxylase gene with tardive dyskinesia in patients with chronic schizophrenia. METHODS: Cytochrome P 450 17 allele and genotype frequencies were compared between matched schizophrenia patients with (n = 55) or without tardive dyskinesia (n = 58). Interactive effects of cytochrome P 450 17alpha-hydroxylase with the dopamine D3 Ser9Gly polymorphism on abnormal involuntary movements were examined. RESULTS: There was no difference in cytochrome P 450 17alpha-hydroxylase genotype distribution between patients with and without tardive dyskinesia; however, patients carrying the cytochrome P 450 17alpha-hydroxylase A2-A2 genotype and the dopamine D3gly allele had the highest orofacial (p <.04), distal (p <.05), and incapacitation (p <.04) scores on the Abnormal Involuntary Movements Scale. CONCLUSIONS: Schizophrenia patients who carry the dopamine D3gly allele and the cytochrome P 450 17alpha-hydroxylase A2-A2 genotype may be more likely to develop abnormal orofoacial and distal involuntary movements and to be incapacitated by these movements when chronically exposed to classical antipsychotic drugs.

Adult↗

PubMed2002

Effects of chronically administered venlafaxine on 5-HT receptor activity in rat hippocampus and hypothalamus.

The effects of chronic administration of the mixed serotonin [5-hydroxytryptamine (5-HT)]/norepinephrine re-uptake inhibitor venlafaxine (5 mg/kg daily by osmotic minipump for 28 days) on the sensitivity of somatodendritic 5-HT(1A) autoreceptors on serotonergic neurons innervating the hypothalamus, and on 5-HT(1B) autoreceptors in both hypothalamus and hippocampus, were determined using in vivo microdialysis in freely moving rats. Venlafaxine induced a reduction in sensitivity of 5-HT(1B) autoreceptors in hypothalamus, but did not affect the sensitivity of 5-HT(1A) autoreceptors, or of 5-HT(1B) autoreceptors in hippocampus. The corticosterone and oxytocin responses to the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.05 or 0.2 mg/kg), a measure of postsynaptic 5-HT(1A) receptor activity in the hypothalamus, were reduced in animals administered 5 or 10 mg/kg venlafaxine daily by intraperitoneal injection for 21 days. This desensitization of post-synaptic 5- HT(1A) receptors in the hypothalamus may be a consequence of increased 5-HT levels induced by desensitization of the presynaptic 5-HT(1B) receptors. These results taken together with those of previous studies suggest that the hypothalamus might be an important site of drug action, and that venlafaxine has an overall mechanism similar to that of selective serotonin re-uptake inhibitors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2002

Effects of chronic antidepressants and electroconvulsive shock on serotonergic neurotransmission in the rat hypothalamus.

The hypothalamus may play a critical role in the pathophysiology and treatment of depression. There are two main lines of evidence for this: firstly, many of its functions correspond to those altered in depression; and secondly, many hypothalamic functions are regulated by the serotonergic system, which is a common target of antidepressant treatments. In keeping with observations from other laboratories, we have found that chronic antidepressants and electroconvulsive shock increase serotonergic neurotransmission in the rat hypothalamus by inducing desensitization of presynaptic autoreceptors. We have also found that chronic hypercorticosolemia, which constitutes a model of depression, has an opposite effect. We postulate that presynaptic autoregulation of serotonergic neurotransmission in the hypothalamus may play a critical role in the pathophysiology and treatment of depression.

Animals↗

PubMed2002

Pharmacogenetics of tardive dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism.

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 antipsychotic drug-induced adverse effect, tardive dyskinesia (TD). Four published studies have reported an association between a serine (ser) to glycine (gly) polymorphism in exon 1 of the dopamine D3 receptor gene (DRD3) and TD; three failed to replicate this finding and one found an insignificant trend. We examined the association in a pooled sample of 780 patients (317 with TD and 463 without TD) drawn from 6 research centers, who were divided into 8 groups based on their population origin. The analysis employed stepwise logistic regression so as to allow confounding effects of group, age, and gender to be taken into account. TD was significantly associated with DRD3 gly allele carrier status (x(2)=4.46, df 1, p =.04) and with DRD3 genotype (x(2)=6.62, df 2, p =.04) over and above the effect of group. Similar positive effects were observed when controlling for age and gender (x(2)=5.02, df 1, p =.02 for gly allele carrier status; x(2) = 7.51, df 2, p =.002 for genotype). Examining abnormal involuntary movement scores as a continuous variable, we found that patients homozygous for the gly allele had significantly higher scores than ser-gly heterozygotes (p =.006) or ser-ser homozygotes (p <.0001). We also performed a meta-analysis that included, besides the groups in the combined analysis, three other published studies on DRD3 and TD. The Mantel-Haenszel pooled odds ratio for DRD3 gly allele carrier status increasing susceptibility to TD was 1.33 (95% CI 1.04-1.70, p =.02); the cumulative pooled estimate showed an odds ratio of 1.52 (95% CI 1.08-1.68, p <.0001). These findings support a small but significant contribution of the DRD3 ser9gly polymorphism to TD susceptibility that is demonstrable over and above population effects and the effect of age and gender on the phenotype.

Adult↗

PubMed2002

Pharmacogenetics of antidepressant and mood-stabilizing drugs: a review of candidate-gene studies and future research directions.

Heterogeneity of clinical response to antidepressant and mood-stabilizing drugs and susceptibility to adverse effects are major clinical problems. It is reasonable to suggest a genetic contribution to these inter-individual differences. Thus, pharmacogenetic approaches could provide the clinician with tools to individualize pharmacotherapy. In this paper, published reports that address the genetic basis of response to antidepressant drugs and mood-stabilizing drugs are selectively reviewed. There is substantial support for the assumption that genetic factors play a role in response to lithium and a degree of support for a role of such factors in response to antidepressants. Based on a Medline search and access to papers accepted but not yet published, studies on the role of specific candidate genes are comprehensively evaluated. A number of studies from different groups point to a role for polymorphism of the serotonin transporter gene in the therapeutic response to specific serotonin reuptake inhibitors. There are reports of other candidate genes, particularly in the serotonergic system, but these have still to be replicated. There is little evidence thus far that points to a role for specific candidate genes in response to mood-stabilizing drugs. Future research directions including the selection of relevant candidate genes, pivotal issues in the design of studies and high throughput methods of analysis are discussed in the light of the findings. Although pharmacogenetic approaches have great potential in the treatment of major depression and bipolar disorder, substantial further research is needed. Careful attention needs to be paid to research design issues and potential confounding factors such as population stratification. High throughput, genome-wide approaches could greatly accelerate the acquisition of relevant data but their success is dependent on the availability of appropriate clinical samples.

Affect↗

PubMed2002

Genetics of schizophrenia: a review of linkage findings.

BACKGROUND: Family, twin and adoption studies have demonstrated the genetic basis of schizophrenia. Several genes, acting synergistically with each other and with the environment probably underlie the disorder. Different genes for schizophrenia are surely present in different populations. Parametric and nonparametric linkage analyses are the main methods employed in the search for schizophrenia genes. Only one study, published recently, has aspired to report the cloning of such a gene, and its significance is debated. METHOD: This review covers the significant and suggestive evidence found in linkage studies for localization of schizophrenia genes. Support for these results from other sources is also described. RESULTS: Significant and suggestive linkage results were reported for at least 18 different chromosomal regions. The more convincing evidence is for loci on 1q, 5q, 6p, 6q, 8p, 10p, 13q, 22q and Xp. CONCLUSIONS: Current methods of genetic analysis are limited in their power to detect genes for complex disorders such as schizophrenia. Technological advances and the use of special populations such as genetic isolates could overcome these limitations.

Genetic Linkage↗

PubMed2000

Pharmacological mechanisms of T3 augmentation of antidepressant action.

Pharmacological mechanisms which have been proposed to account for the potentiating effect of T3 on antidepressant action include actions via nuclear receptors on gene expression, effects on membrane-bound receptors, and actions at the second-messenger level. Interactions of T3 with mechanisms involved in noradrenergic and serotonergic neurotransmission are of particular interest in that these systems have been implicated in the neurobiology of depression and in the actions of antidepressant drugs. Several examples of such interactions are discussed.

Journal Article↗