Biomedical subjects

Bernard Lerer

Publications and source records attributed to Bernard Lerer.

At least 55 records · Page 3Linked to original sources

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↗

PubMed1998

An association between clozapine-induced agranulocytosis in schizophrenics and HLA-DQB1*0201.

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 blood cell count <3000/mm(3) and absolute polymorphonuclear count <500/mm(3)) and 3 developed granulocytopenia (total white blood cell count <3500/mm(3) and absolute polymorphonuclear count <1000/mm(3)). HLA-DQB1*0201 was present in all five patients who developed agranulocytosis or granulocytopenia (5/5; 100%), but in only 54% (7/13) of the patients who did not develop those complications. These findings indicate that DQB1*0201 or a gene located nearby could be involved in clozapine-induced agranulocytosis.

Journal Article↗

PubMed1998

Evaluation of central serotonergic function in affective and related disorders by the fenfluramine challenge test: a critical review.

Plasma prolactin levels following oral administration of the serotonin (5-HT) releasing agent, fenfluramine hydrochloride, have been extensively used to evaluate central serotonergic function in affective and related disorders. Cortisol responses to fenfluramine have generally been a less informative measure. In healthy subjects, prolactin release by fenfluramine is dose-dependent, blocked by antagonists of serotonin receptors of the 5-HT-2a/2c type, negatively correlated with age and increased in young females. In major depression, a preponderance of studies have found blunted prolactin responses compared to matched normal controls. Although a significant minority of studies have not found blunting, increased prolactin release has not been observed. The blunted prolactin release is not due to a deficient secretory capacity of pituitary lactotrophs and is congruent with other evidence for reduced central serotonergic function in major depression. Blunting of the prolactin response may be associated with severity of depression and with elevated baseline cortisol levels. Treatment with antidepressant drugs and electroconvulsive therapy has been reported to increase the prolactin response but this has not been replicated in all studies. Blunted prolactin responses to fenfluramine have been fairly consistently associated with impulsive aggression in different personality disorders and with severity of suicide attempts in depressed patients. A number of studies employing the fenfluramine challenge test (FCT) have been conducted in obsessive compulsive disorder but their results have been variable. Prolactin responses to fenfluramine may be enhanced in panic disorder and chronic fatigue syndrome but the number of studies in these conditions is small as is the case for seasonal affective disorder. Since the therapeutic administration of fenfluramine as an appetite suppressant has been suspended because of reports of cardiac complications, further use of this compound as a challenge agent is not anticipated. Future studies are likely to employ agents acting on specific serotonin receptors and should apply methodological insights from the use of the FCT, which are considered in this review. Use of concomitant brain imaging to evaluate the central effects of challenge agents directly is likely to become more prevalent and may supplant neuroendocrine challenge paradigms such as the FCT which have been remarkably heuristic but are limited in scope and methodologically complex.

Journal Article↗

PubMed1998

The International Journal of Neuropsychopharmacology.

Almost half a century ago, a series of remarkable therapeutic developments occurred and were soon recognised as milestones in the history of medicine. The introduction of lithium, chlorpromazine, imipramine and the monoamine oxidase inhibitors, within a few years of each other, radically altered the prospects for treating serious psychiatric disorders. Until then, electroconvulsive therapy had been the only definitive treatment available. Research on pharmacological agents that alleviate disturbances of mood, cognition and behaviour, was given an impetus that led to quantum expansion in the ensuing years. It has become customary to recount the history of neuropsychopharmacology from that time. Although this is an understandable bias, it ignores much fundamental research in neurophysiology, neurochemistry and pharmacology and clinical experimentation with psychoactive agents that laid the foundations for what was to follow. Nevertheless, neuropsychopharmacology is still a very young discipline. This manifests not only in chronology but in the ferment, rapid shifts in priorities and fluidity of fundamental concepts that are hallmarks of youth. The critical observer cannot but concede the likelihood that tenets held basic to contemporary neuropsychopharmacology could turn out to be substantially overemphasised, unacceptably simplistic or even incorrect, in the relatively near future. Perusal of major papers in the field, published no more than one or two decades ago, confirms this impression. Rather than detracting from the discipline, these attributes are what give neuropsychopharmacology its remarkable allure. There is the distinct feeling that much of what can be known has yet to be discovered. Steps equal to or greater in impact than those of half a century ago, wait to be taken.

Journal Article↗

PubMed1993

Age-Dependent Effects of Electroconvulsive Therapy on Memory.

We examined the relation between age and recovery of memory functions after electroconvulsive therapy (ECT). In a group of patients 20-65 years of age, older depressed patients treated with ECT experienced more severe and longer lasting memory deficits than did younger patients. Testing conducted 24-72 h after a course of ECT showed more severe deficits in older patients for verbal and visuospatial anterograde memory, and for retrograde memory. The difference between younger and older subjects was marginal at 1 month follow-up, seen only in differences in verbal anterograde memory. At 6 months follow-up, no difference in memory test scores between older and younger patients was observed. Older patients are more vulnerable to cognitive effects of ECT, and these effects last longer.

Journal Article↗

PubMed1992

Electroconvulsive Therapy in a Depressed Heart Transplant Patient.

Medication-resistant major depression was diagnosed in a 67-year-old man 1 1/2 years after heart transplantation. Electroconvulsive therapy was administered, resulting in remarkable improvement in depressive symptoms without complications related to the cardiac condition.

Journal Article↗

PubMed1991

Atropine and Cognitive Performance After Electroconvulsive Therapy.

Two groups of patients receiving bilateral, moderately suprathreshold electroconvulsive therapy (ECT) were compared in their cognitive functions after receiving either 0.5 mg atropine i.v. or no atropine before ECT. The patients were tested for cognitive functions after four treatments using various measures, including orientation; retrograde (verbal and visuospatial) memory for information acquired about 15 minutes pretreatment and tested for about 1 hour posttreatment; anterograde (verbal and visuospatial) memory for information acquired about 1 hour, 30 minutes posttreatment and tested for both immediately after learning and 20 minutes later; and retrieval from semantic memory as assessed by word fluency. We found no effect of 0.5 mg atropine on cognitive performance, even though anticholinergic drugs that cross the blood brain barrier might be expected to affect cognition after ECT.

Journal Article↗

PubMed1991

Disorientation and Bilateral Moderately Suprathreshold Titrated ECT.

Thirty-seven inpatients with major depression were assessed for postictal and interictal disorientation after they received 8 of 12 ECTs. In 20 patients, four of the eight assessments were after simulated ECT only. Only real, but not simulated, ECT produced postictal disorientation. Postictal disorientation was greatest after the first treatment, less after the second, and did not change in later assessments. It was shortest for person, longer for place, and longest for time, and showed a temporal time gradient. Interictal disorientation increased with the number of treatments. Two electrical stimulus variables (seizure duration and electrical stimulus intensity) correlated with the length of postictal disorientation. The influence of seizure duration and stimulus variables were independent of each other. The influence of the electrical stimulus variables was independent of the influence of demographic variables. These, however, did affect the length of postictal disorientation.

Journal Article↗

PubMed1991

Change in Attitude Toward Electroconvulsive Therapy: Effects of Treatment, Time Since Treatment, and Severity of Depression.

Attitudes toward electroconvulsive therapy (ECT) of patients with major depressive episodes who are treated with ECT were evaluated before the beginning of treatment, 1 to 2 days after completion of the 12th treatment, and 6 months after the termination of the series using a questionnaire (adapted from Freeman and Kendall, 1980). Attitudes toward ECT become more positive after treatment, and remain so at the 6-month follow-up. Attitude changes correlate with changes in depressive symptoms and with subjective side effects during treatment. Patients who had a prior course of ECT had more knowledge of ECT but not a more positive attitude.

Journal Article↗

PubMed1991

Factors Influencing Response to Bilateral Electroconvulsive Therapy in Major Depression.

The records of 52 patients with major depression who were treated with bilateral electroconvulsive therapy (ECT) were reviewed. Responders and nonresponders were compared on demographic, clinical, and treatment parameters. ECT nonresponders had a longer duration of current depressive episode as well as a greater initial severity of depression. The groups did not differ in age, sex, polarity, presence of psychosis, pre-ECT pharmacotherapy, and treatment parameters other than total electrical charge administered. Patients with long episode duration and greater severity of illness may represent a subgroup of major depressives relatively refractory to ECT and warranting novel therapeutic approaches.

Journal Article↗

PubMed1989

Implications of Clinical Spectrum for Mechanisms of Action: ECT and Antidepressants Reconsidered.

The similarities and differences between electroconvulsive therapy (ECT) and antidepressant medications are reviewed with respect to their clinical indications. The implications of the overlap and divergence in their spectra of clinical efficacy are discussed in reference to mechanisms of action. The hypothesis is offered that ECT has multiple mechanisms of action, which differ depending on the clinical syndrome being treated. From this perspective, ECT may share similar mechanisms of action with other agents that are also effective in treating the specific syndrome. Thus, although ECT may result in a plethora of neurobiological effects, depending on the clinical syndrome, specific and differing subsets of neurobiological changes are relevant to therapeutic action.

Journal Article↗

PubMed1989

In Reply.

Explore the source record for details and available documents.

Letter↗

PubMed1988

Medication Outcome in ECT-Resistant Depression.

The outcome of antidepressant treatment in 12 cases of electroconvulsive therapy (ECT)-resistant depression is presented. Eight patients had been refractory to a clinically adequate course of ECT (Hamilton Depression Scale improvement <20%) and four were partial responders (improvement 20-49%). All remitted completely on antidepressant medication within 2.2 +/- 1.1 (mean +/- SD) months of the ECT course. Remission was associated with clomipramine treatment (139 +/- 49.7 mg/day) in seven cases and maprotiline (125 mg/day) in one case. Four patients who did not respond to a tricyclic antidepressant alone remitted following supplementation (of clomipramine in 2 cases, clomipramine + haloperidol in 1 case, and imipramine in 1 case) with lithium carbonate. Although a delayed therapeutic response to ECT cannot be excluded, the results suggest that ECT may alter the sensitivity of refractory patients to antidepressant medication.

Journal Article↗