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H Y Meltzer

Publications and source records attributed to H Y Meltzer.

At least 145 records · Page 8Linked to original sources
PubMed1995

Association study between the dopamine D4 receptor gene and schizophrenia.

The dopamine D4 receptor is of major interest in schizophrenia research due to its high affinity for the atypical neuroleptic clozapine and a high degree of variability in the receptor gene (DRD4). Although several genetic linkage analyses performed on schizophrenia multiplex families from different regions of the world have either excluded or failed to prove that DRD4 is a major genetic factor for the development of schizophrenia, analyses for moderate predisposing effects are still of significant interest. We performed a study examining differences in allele frequencies of 4 different DRD4 polymorphisms in schizophrenia patients and age, sex, and ethnic origin matched controls. None of these 4 polymorphisms showed evidence for genetic association with schizophrenia, although a trend towards excess of the allele with 7 repeats in the (48)n bp exon III polymorphism was observed. Complexities in the DRD4 genetic investigation and further analytic approaches are discussed.

Female↗
PubMed1995

Effects of ipsapirone on plasma cortisol and body temperature in major depression.

Major depressed patients have been reported to exhibit significantly attenuated hypothermic responses to ipsapirone, a serotonin (5-HT)-1A partial agonist, compared to normal controls. This study further investigated the cortisol and temperature responses to ipsapirone (0.5 mg/kg orally) and placebo in 20 normal volunteers and 12 major depressed patients. Both plasma cortisol and temperature were measured every 30 min before ipsapirone or placebo administration until 180 min post administration. Ipsapirone administration produced a significant increase in plasma cortisol levels as well as hypothermia. Major depressed patients showed significantly blunted ipsapirone-induced cortisol responses compared to normal controls. No significant differences in ipsapirone-induced hypothermic responses were found between major depressed patients and normal controls.

Adult↗
PubMed1995

Pindolol pretreatment blocks stimulation by meta-chlorophenylpiperazine of prolactin but not cortisol secretion in normal men.

Previous reports from this laboratory have shown that pindolol, a partial serotonin1A receptor agonist, inhibited prolactin, but not cortisol secretion induced by administration of the serotonin (5-HT) precursor L-5-hydroxytryptophan or the direct-acting 5-HT2A/5HT2C receptor agonist MK-212. The findings suggest additive or interactive effects of 5-HT1A and 5-HT2A/5-HT2C receptors in modulating 5-HT-related prolactin, but not cortisol, responsivity. To examine further the role of 5-HT1A and 5-HT2A/5-HT2C receptors in prolactin and cortisol secretion in healthy men, the effects of meta-chlorophenylpiperazine (mCPP), a potent 5-HT receptor agonist, on the above hormones were studied in eight healthy men with and without pindolol pretreatment. It has previously been demonstrated that ketanserin, a 5-HT2A antagonist, and ritanserin, a 5-HT2A/5-HT2C antagonist, block the prolactin and attenuate the hypothalamic-pituitary-adrenal axis responses to mCPP in man or rodents. Administration of mCPP induced a significant increase in plasma concentrations of prolactin and cortisol. The mCPP-induced prolactin concentrations were significantly blocked by pretreatment with pindolol, whereas mCPP-stimulated cortisol levels were not diminished by pindolol pretreatment. Thus, mCPP-induced prolactin secretion appears to require the availability of both 5-HT2C and 5-HT1A receptor activation, since blockade of either of these receptors may diminish the mCPP-induced prolactin response. Cortisol secretion stimulated by mCPP may occur following 5-HT2C receptor stimulation in the presence of 5-HT1A receptor blockade.

Adrenergic beta-Antagonists↗
PubMed1995

Effect of pindolol pretreatment on MK-212-induced plasma cortisol and prolactin responses in normal men.

Previous reports based on studies with serotonin (5-HT) precursors or direct acting agonists have suggested that postsynaptic 5-HT1A and 5-HT2A/5-HT2C receptors may stimulate cortisol and prolactin (PRL) secretion in man. To further clarify the role of these receptors in the regulation of cortisol and PRL secretion in man, the effects of 6-chloro-2-(1-piperazinyl) pirazine (MK-212), a centrally acting direct 5-HT2A/5-HT2C agonist, on the above hormones were studied in 11 normal men with and without pretreatment with pindolol, a 5-HT1A partial agonist. MK-212 induced a significant increase in plasma concentrations of cortisol and PRL. The MK-212-induced response in plasma cortisol was not diminished by pindolol pretreatment, whereas the MK-212-induced PRL response was significantly inhibited by pindolol pretreatment. These data suggest that the MK-212-induced cortisol response may be mediated by 5-HT2A or 5-HT2C receptor activation, or both, despite 5-HT1A inhibition; however, PRL secretion by MK-212 requires 5-HT1A receptor availability as well as 5-HT2A/5-HT2C receptor activation, since blockade of the former appears to blunt the PRL responses to MK-212. These findings may be explained by postulating a cooperativity between 5-HT1A and 5-HT2A/5-HT2C receptors with regard to the 5-HT-dependent stimulation of PRL secretion.

Adrenergic beta-Antagonists↗
PubMed1995

Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression.

Recently, it was found that major depression may be accompanied by significant changes in cell-mediated and humoral immunity. The purpose of this study was to investigate the plasma concentrations of interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), sIL-2R and transferrin receptor (TfR) in patients with major depression in an acute phase of illness, in remission and during antidepressive treatment. Plasma concentrations of IL-6, sIL-6R, sIL-2R and TfR were significantly higher in major depressed subjects than in healthy controls. In major depressed subjects, but not in normal controls, there were significant positive correlations between the plasma concentrations of IL-6 and sIL-6R, IL-6 and sIL-2R, IL-6 and TfR, and between sIL-2R and TfR. Subchronic treatment with antidepressive drugs, such as fluoxetine or tricyclic antidepressants, did not significantly affect plasma IL-6, sIL-6R, sIL-2R or TfR. The latter did not significantly differ between major depressed patients in an acute phase of illness or in complete clinical remission. It is suggested that: (1) a coordinated and upregulated production of IL-6, sIL-6R, sIL-2R and TfR may constitute a trait marker of major depression; and that (2) an upregulated production of IL-6 may represent a contributing factor to the various immune disorders encountered in major depression and maybe to the pathophysiology or pathogenesis of that illness.

Adult↗
PubMed1995

Effect of antidepressants on striatal and accumbens extracellular dopamine levels.

The effect of the selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor, fluoxetine (10 mg/kg s.c.), two tricyclic antidepressants, clomipramine (10 mg/kg s.c.) and imipramine (10 mg/kg s.c.), and vehicle on extracellular dopamine levels was studied in rat nucleus accumbens and striatum by in vivo microdialysis. Fluoxetine produced significant decreases in extracellular dopamine levels in both the nucleus accumbens and striatum (mean maximum percentage decrease: 58% and 57% of pre-drug baseline, respectively). In contrast, imipramine and clomipramine significantly increased extracellular dopamine in the striatum (148% and 150%, respectively) compared to the effect of vehicle alone (118%). These results suggest that the selective serotonin reuptake inhibitor, fluoxetine, and the tricyclic antidepressants, clomipramine and imipramine, affect dopaminergic activity in diverse ways and in a region-specific manner. Thus, the antidepressant effect of these drugs is unlikely to be related to their acute effects on dopaminergic neurotransmission. The differential effects of the selective serotonin reuptake inhibitor and tricyclic antidepressants on extracellular dopamine could account for other differences in their clinical and side effect profiles. Further studies of the chronic effects of the selective serotonin reuptake inhibitor and the tricyclic antidepressants on dopaminergic activity are required to elucidate the role of dopamine in the antidepressant effect.

Animals↗
PubMed1995

Dopamine D4 receptors and effects of guanine nucleotides on [3H]raclopride binding in postmortem caudate nucleus of subjects with schizophrenia or major depression.

The densities of dopamine-D4 receptors were determined in postmortem samples of caudate nucleus from patients with schizophrenia (n = 9) and age-matched controls (n = 10). D4 receptor binding was defined as the difference between binding sites labeled by [3H]YM-09151-2 (D2 + D3 + D4 receptors) and those by [3H]raclopride, in the presence of 5'-guanylylimidodiphosphate (Gpp(NH)p) (D2 + D3 receptors). D4 receptor binding was measurable in all the subjects with schizophrenia (mean = 3.8 pmol/g tissue) but only in 3/10 controls. To determine the specificity of these findings for schizophrenia, D4 receptor binding was also measured in the caudate nucleus of suicide victims with major depression (n = 6) and age-matched controls (n = 6). A small amount of D4 binding was noted in some of the controls + depressed subjects and there was no significant difference between controls and patients with major depression. The addition of 200 microM Gpp(NH)p to the assay significantly increased the amount of specific binding of [3H]raclopride in control tissues, but not in tissues from subjects with schizophrenia, suggesting an abnormality in the G-protein component coupled to the D2 receptor. [3H]Raclopride binding was also significantly increased by Gpp(NH)p in subjects with major depression. These results confirm a previous report of Seeman et al. (1993) and suggest that measurable D4 receptor binding in the caudate nucleus is more frequent in patients with schizophrenia as compared with normal controls and subjects with major depression and that guanine nucleotides do not enhance [3H]raclopride binding in schizophrenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Relationship between smooth pursuit eye-tracking and cognitive performance in schizophrenia.

The relationship between measures of smooth pursuit and neuropsychological performance was assessed in 20 unmedicated schizophrenics. Eye-tracking measures included gain, catch-up saccade parameters, and rate of saccadic intrusions. Neuropsychological measures included tests generally considered as "frontal": Wisconsin Card Sorting Test (WCST), Consonant Trigram Test (CTT), and Controlled Oral Word Association Test (COWAT). The Digit Symbol Test (DST), which is generally considered to be a measure of global functioning, was also included. Gain and other pursuit measures were significantly correlated with the DST and the COWAT, but were not correlated with the WCST or the CTT.

Adult↗
PubMed1995

Meta-analyses of studies of ventricular enlargement and cortical sulcal prominence in mood disorders. Comparisons with controls or patients with schizophrenia.

BACKGROUND: The findings of ventricular enlargement and increased sulcal prominence are well documented in schizophrenia, but the consistency of similar findings in mood disorders is less well appreciated. Reliable documentation of the presence of these structural abnormalities in mood disorders would require a reassessment of their significance for both schizophrenia and mood disorders. In this article, we meta-analytically review the literature on ventricular enlargement and cortical sulcal prominence in patients with mood disorders compared with controls and patients with schizophrenia. METHODS: Four meta-analytic reviews were conducted, two comparing patients with mood disorders with normal controls on ventricular enlargement (meta-analysis 1) or sulcal prominence (meta-analysis 2) and two comparing patients with mood disorders with schizophrenic patients on these same measures (meta-analyses 3 and 4). RESULTS: Meta-analyses 1 and 2 revealed statistically significant (P < .001) moderate composite effect sizes (d) for the comparisons of patients with mood disorders with controls on both ventricular enlargement (d = 0.44) and sulcal prominence (d = 0.42). Meta-analysis 3 further revealed that patients with schizophrenia have significantly greater ventricular enlargement than patients with mood disorders (P = .002), but the effect size was small (d = -0.20). There were too few studies comparing these patient groups on sulcal prominence to support a quantitative meta-analysis. CONCLUSIONS: This review documents the presence of ventricular enlargement and increased sulcal prominence in mood disorders. Patients with mood disorders have less ventricular enlargement than patients with schizophrenia, but this effect is small. These results reinforce previous suggestions of the nonspecificity of structural brain changes in schizophrenia and mood disorders.

Adult↗
PubMed1995

Plasma-soluble interleukin-2 and transferrin receptor in schizophrenia and major depression.

This study was carried out to examine some components of in vivo immune function in major depression and schizophrenia. Toward this end, plasma concentrations of interleukin-1 beta (IL-1 beta) and IL-6, soluble IL-2 receptor (sIL-2R), and transferrin receptor (TfR) were measured in 28 normal controls, 11 schizophrenics and 13 major-depressed patients. Schizophrenic and major-depressed patients showed significantly higher plasma sIL-2R and TfR than normal controls. There was a trend toward higher plasma IL-6 in the psychiatric patients, and particularly in schizophrenic patients, than in normal volunteers. In normal controls and in the total study group, there were highly significant and positive correlations between plasma TfR and sIL-2R concentrations. It is suggested that schizophrenia and major depression are characterized by immune disorders that may indicate activation of cell-mediated immunity such as T-cell activation.

Acute-Phase Reaction↗
PubMed1995

Immunoendocrine aspects of major depression. Relationships between plasma interleukin-6 and soluble interleukin-2 receptor, prolactin and cortisol.

Recently, a complete bidirectional circuit between the immune and neuroendocrine systems has been documented. Previous reports from this laboratory have shown that there are complex reciprocal relationships between immune and hypothalamic-pituitary-adrenal (HPA)-axis function in major depression. To further examine the immune-endocrine relationships, this study investigates plasma baseline cortisol and prolactin secretion in relation to plasma interleukin-6 (IL-6) and soluble IL-2 receptor (sIL-2R) levels in 34 healthy controls and 56 major depressed patients. There were significant positive correlations between IL-6 or sIL-2R and plasma cortisol in major depressed subjects and in the combined group of major depressed and healthy subjects. There were also significant positive correlations between plasma prolactin and sIL-2R concentrations in major depressed subjects and in the combined groups of normal and major depressed subjects.

Adult↗
PubMed1995

D4 dopamine receptor binding affinity does not distinguish between typical and atypical antipsychotic drugs.

The affinities of 13 atypical and 12 typical antipsychotic drugs for the cloned rat D4 dopamine receptor and the D4/D2 ratios were examined. Of the atypical antipsychotic drugs tested, only clozapine, risperidone, olanzapine, zotepine and tiospirone had affinities less than 20 nM. In fact, many atypical antipsychotic drugs had relatively low affinities for the cloned rat D4 receptor, with Ki values greater than 100 nM (Seroquel, fluperlapine, tenilapine, FG5803 and melperone). Additionally, several typical antipsychotic drugs had high affinities for the cloned rat D4 receptor, with Kis less than 20 nM (loxapine, chlorpromazine, fluphenazine, mesoridazine, thioridazine and trifluoroperazine). The ratios of D2/D4 affinities did not differentiate between these two types of antipsychotic drugs. Thus, D4 dopamine receptor affinity, used as a single measure, does not distinguish between the group of typical and atypical antipsychotic drugs analyzed.

Animals↗
PubMed1995

Effects of serotonin precursors on the negative feedback effects of glucocorticoids on hypothalamic-pituitary-adrenal axis function in depression.

In order to investigate the relationships between brain serotonergic turnover and hypothalamic-pituitary-adrenal (HPA) axis function in unipolar depression, the authors measured intact adrenocorticotropic hormone (ACTH) and cortisol levels in baseline conditions and after combined dexamethasone (1 mg PO) and L-5-hydroxytryptophan (L-5-HTP, 200 mg PO) administration in 13 minor, 17 simple major, and 17 melancholic subjects. L-5-HTP significantly enhanced post-DST ACTH and cortisol secretion in major--but not in minor--depressed subjects. Major depressed subjects with or without melancholia exhibited significantly higher post-DST ACTH and cortisol responses to L-5-HTP than minor depressed subjects. L-5-HTP administration converted some major depressed ACTH or cortisol suppressors into nonsuppressors. L-5-HTP stimulated ACTH or cortisol secretion to the same extent in major depressed HPA-axis suppressors and nonsuppressors. It is concluded that L-5-HTP loading may augment ACTH and, consequently, cortisol escape from suppression by dexamethasone in major but not in minor depressed subjects. The findings show that serotonergic mechanisms modulate the negative feedback of glucocorticoids on central HPA-axis regulation. It is hypothesized that the higher L-5-HTP-induced post-DST HPA-axis hormone responses in major depression reflect upregulated 5-HT2 receptor-driven breakthrough secretion of pituitary ACTH from suppression by dexamethasone.

Adrenocorticotropic Hormone↗
PubMed1995

Plasma clozapine levels and the treatment of L-DOPA-induced psychosis in Parkinson's disease. A high potency effect of clozapine.

The purpose of this study was to determine the plasma level of clozapine and its metabolite, N-desmethylclozapine, in Parkinson's disease patients with L-DOPA-induced psychosis responsive to clozapine. The psychotic symptoms of the three patients studied responded to low doses of clozapine with plasma levels of clozapine between 4.5 and 16.1 ng/ml and N-desmethylclozapine between 2.6 and 6.1 ng/ml, much below the plasma clozapine levels usually found in clozapine-treated refractory schizophrenia or affective disorders (range 100 to 687 ng/ml). Possible mechanisms that may account for clozapine's antipsychotic action in dopaminomimetic-induced psychosis in Parkinson's disease, including serotonin2A (5-HT2A) and dopamine D4 receptor blockade, at plasma levels that would be ineffective in refractory schizophrenia, are discussed. It is suggested that 5-HT2A receptor blockade is the most likely basis for the effectiveness of clozapine in L-DOPA psychosis.

Aged↗
PubMed1995

Plasma concentrations of excitatory amino acids, serine, glycine, taurine and histidine in major depression.

This study was carried out to investigate plasma levels of excitatory amino acids, such as glutamate and aspartate, and glutamine, serine, glycine, taurine and histidine in major depression. The plasma amino acids were determined by means of HPLC in 22 normal controls and 25 unmedicated patients with major depression. Major depression was characterized by higher plasma taurine levels than normal controls. Significantly lower plasma glycine values and a higher serine/glycine ratio were observed in the depressed group. No significant differences in glutamine, histidine, serine or aspartate levels could be detected between the study groups. By means of linear discriminant analysis, a highly significant separation between major depressed subjects and normal volunteers was found using glycine, glutamate and taurine as discriminatory variables. No significant relationships between any of the amino acids and severity of depression could be found. The results suggest that major depression is accompanied by perturbations in the serine/glycine ratio, excitatory amino acids, such as glutamate, and inhibitory amino acids, such as taurine.

Adult↗
PubMed1995

Smooth pursuit performance in patients with affective disorders or schizophrenia and normal controls: analysis with specific oculomotor measures, RMS error and qualitative ratings.

Smooth pursuit performance in schizophrenia and affective disorders has generally been found to be abnormal using a variety of measures. The purpose of this study was to assess patients with these disorders and normal controls in order to compare the different measures across diagnoses. Smooth pursuit was assessed using quantitative specific measures (gain, catch-up saccade rate and amplitude, square-wave jerk rate, number of anticipatory saccades and total time scored), as well as two global measures: root mean-square error (RMS) and qualitative rating. As previously reported, patients with schizophrenia had low gain, increased catch-up saccade rate and spent less time engaged in scoreable smooth pursuit than normal controls. Patients with affective disorders were not statistically different from controls on any of these measures, and had significantly higher gain than patients with schizophrenia. RMS error and qualitative rating measures were highly correlated (r = 0.87). In linear regression analyses, the quantitative specific measures were highly significant predictors of both RMS error and qualitative ratings (P < 0.0001). Linear regression analyses and a modelling study indicated that one quantitative specific measure, the percent of time engaged in scoreable smooth pursuit (total time scored), was most related to global ratings. However, RMS error and qualitative ratings were less sensitive than total time scored to the difference between controls and patients with schizophrenia. These data indicate two smooth pursuit performance deficits in schizophrenia: patients spend less time engaged in scoreable smooth pursuit and have low gain (accompanied by increased compensatory saccades) when the smooth pursuit is engaged.

Adult↗
PubMed1995

Neuropeptide Y in frontal cortex is not altered in major depression.

Previously, we reported a modest but significant reduction in the concentration of neuropeptide Y in frontal cortices from victims of suicide relative to age-matched natural or accidental death control subjects. The reduction in neuropeptide Y appeared to be greatest in a subgroup of victims of suicide for which there was indirect evidence of histories of depression. We pursued these initial findings in the present study by measuring neuropeptide Y concentrations in frontal cortices from natural or accidental death control subjects and from suicide victims in whom a firm diagnosis of major depression was established by psychiatric autopsy. Because several subjects with major depression had a comorbid diagnosis of alcoholism, a group of victims of suicide that had an Axis I diagnosis of alcohol dependence was also studied. No significant differences in neuropeptide Y concentrations were observed between control subjects and victims of suicide with major depression or victims of suicide with alcohol dependence. These findings do not support a role for neuropeptide Y in major depression.

Adult↗