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Biomedical subjects

H Y Meltzer

Publications and source records attributed to H Y Meltzer.

At least 163 records · Page 9Linked to original sources
PubMed1995

The role of serotonin in schizophrenia and the place of serotonin-dopamine antagonist antipsychotics.

After four decades of the use of antipsychotic drugs that target the dopamine D2 receptor as the initial site of action, a new strategy for antipsychotic therapy has emerged and, with it, new hope for greater efficacy and fewer side effects. This new strategy involves identifying drugs with strong serotonin (5-hydroxytryptamine) 5-HT2A receptor relative to dopamine D2 receptor blocking properties. Clozapine is now known to have these properties, but risperidone is the first drug to be designed intentionally to have these properties. Others are being developed. These drugs, the serotonin-dopamine antagonists (SDAs), may prove to have many other uses in psychiatry beyond schizophrenia because of their low propensity to cause extrapyramidal symptoms. Their pharmacologic mechanism of action may be more complex than only strong 5-HT2A and weak D2 block, e.g., 5-HT2C and D4 receptor blockade. Nevertheless, the SDAs are proving to be valuable tools in the analysis of both normal brain function and the etiology of schizophrenia.

Antipsychotic Agents↗
PubMed1995

Abnormal serotonergic stimulation of cortisol production in obstructive sleep apnea.

Because serotonin (5-HT) precursor or reuptake inhibitors improve obstructive sleep apnea (OSA), we hypothesized that brain serotonergic activity may be decreased in OSA. To test this hypothesis, we measured the cortisol response to the ingestion of L-5-hydroxytryptophan (L-5-HTP), a 5-HT precursor that is decarboxylated to 5-HT in the brain. Either L-5-HTP or an identical-looking placebo was administered at 0800, and blood was obtained over the following 4 h for serum cortisol determination. A placebo-controlled ACTH stimulation test was performed to evaluate adrenal function. We found that a group of 11 OSA patients had significantly higher cortisol production after L-5-HTP administration compared with a group of 11 control nonapneic subjects. The pretest cortisol levels and ACTH stimulation test results were not different between the two groups. We conclude that the cortisol response to L-5-HTP was elevated in the OSA patients studied, most likely as a result of increased hypophyseal 5-HT activity. We speculate that the 5-HT postsynaptic receptors that induce corticotropin releasing factor production and release are upregulated, or supersensitized, as a result of a brain 5-HT-deficient state that exists during sleep in OSA. We anticipate that medullary serotonergic neurons that affect ventilation would be altered similarly.

5-Hydroxytryptophan↗
PubMed1995

Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit assessment.

OBJECTIVE: Suicide has been reported to occur in 9%-13% of schizophrenic patients. It has been suggested that neuroleptic-resistant or neuroleptic-intolerant schizophrenic patients are at higher risk for suicide than neuroleptic-responsive patients. Clozapine is the treatment of choice for neuroleptic-resistant patients, but its use has been greatly limited because of its ability to cause potentially fatal agranulocytosis. The purpose of this study was to compare the suicidality of neuroleptic-resistant and neuroleptic-responsive patients and to determine if clozapine treatment decreased suicidality in the former group. METHOD: Prior episodes of suicidality were assessed in a total of 237 neuroleptic-responsive and 184 neuroleptic-resistant patients with schizophrenia or schizoaffective disorder. Eighty-eight of the neuroleptic-resistant patients were treated with clozapine and prospectively evaluated for suicidality for periods of 6 months to 7 years. RESULTS: There was no significant difference in prior suicidal episodes between neuroleptic-responsive and neuroleptic-resistant patients. Clozapine treatment of the neuroleptic-resistant patients during the follow-up period resulted in markedly less suicidality. The number of suicide attempts with a high-probability of success decreased from five to zero. This decrease in suicidality was associated with improvement in depression and hopelessness. CONCLUSIONS: These results suggest a basis for reevaluation of the risk-benefit assessment of clozapine, i.e., that the overall morbidity and mortality of patients with neuroleptic-resistant schizophrenia are less with clozapine treatment than with typical neuroleptic drugs because of less suicidality. This conclusion also has implications for increasing the use of clozapine with neuroleptic-responsive patients.

Adult↗
PubMed1995

Role of serotonin in the action of atypical antipsychotic drugs.

Clozapine is the first of a new generation of antipsychotic drugs which constitutes a major advance in the treatment of schizophrenia. Numerous theories have been proposed to explain the advantages of clozapine over typical neuroleptics. Most of these focus on its effects on dopaminergic and serotonergic neurotransmission. This article reviews the effects of clozapine and related antipsychotic drugs on dopamine (DA) D1, D2, and D4, and serotonin (5-HT) 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, as well as its ability to modulate DA and 5-HT release. Clozapine and other atypical antipsychotic drugs share the ability to cause fewer extrapyramidal symptoms at clinically effective doses. This may be related to their potent 5-HT2A and weak D2 receptor blocking properties, a profile shared by risperidone, melperone, olanzapine, amperozide, HP-873, seroquel, sertindole, and ziprasidone. The basis for the superior ability of clozapine to treat negative symptoms and enhance cognitive function compared to typical neuroleptic drugs in schizophrenic patients has not yet been ascertained, but there is evidence that its effect on 5-HT2A, D2, or D4 receptors may be important. Other aspects of the pharmacology of clozapine which may contribute to its actions include potent alpha 1-adrenergic, M1, M2, M3, and M5 receptor blocking properties, as well as M4 agonist effects.

Antipsychotic Agents↗
PubMed1994

Lower serum prolyl endopeptidase enzyme activity in major depression: further evidence that peptidases play a role in the pathophysiology of depression.

Prolyl endopeptidase (PEP) is a serine proteinase, which may cleave peptides that are involved in the pathophysiology of major depression, such as arginine vasopressin, beta-endorphin, luteinizing hormone-releasing hormone, thyrotropin-releasing hormone, and maybe corticotropin-releasing hormone. PEP may be involved in activation of cell-mediated immunity, autoimmune and inflammatory responses, which repeatedly occur in severe depression. The present study investigates serum PEP activity in 33 normal controls, 16 minor, 14 simple major, and 18 melancholic depressed subjects. Pre-dexamethasone and post-dexamethasone (DST) intact adrenocorticotropic hormone (ACTH) and cortisol values were determined in 33 depressed subjects. Serum PEP activity was significantly lower in depressed subjects compared to normal controls and in melancholic depressed subjects compared to minor and simple major depressed subjects. Up to 61.1% of the melancholic patients had serum PEP activities below the mean PEP values of normal controls minus two SDs. In the depressed study group, significant negative correlations between serum PEP activity and severity of illness, post-DST cortisol, and ACTH values were observed. There was a trend toward higher serum PEP activity with increasing age. It is hypothesized that lower serum PEP activity, and lower serum activity of other peptidases, may play a role in the neuroendocrine and immune pathophysiology of major depression.

Adrenocorticotropic Hormone↗
PubMed1994

Effects of buspirone on plasma prolactin and cortisol levels in major depressed and normal subjects.

The cortisol response to ipsapirone (a 5-HT1A-partial agonist that produces a dose-dependent increase in plasma cortisol secretion in man) is blunted in major depression. Buspirone is another 5-HT1A agonist that increases cortisol secretion in man. This study investigated cortisol and prolactin (PRL) responses to buspirone (30 mg orally) in 45 major depressed subjects and 28 normal controls. Buspirone administration yielded a significant increase in cortisol and PRL levels in both normal controls and depressed subjects. No differences in buspirone-induced hormone responses were found either between major depressives and normal controls or between melancholic and nonmelancholic depressives. There were no significant relationships between severity of depression and any of the hormonal responses to buspirone. PRL responses to buspirone were significantly higher in women than in men.

Adult↗
PubMed1994

Effect of pindolol on the L-5-HTP-induced increase in plasma prolactin and cortisol concentrations in man.

Previous studies with direct-acting serotonin (5-HT) agonists and antagonists have demonstrated that stimulation of 5-HT1A, 5-HT1C and 5-HT2 receptors may promote cortisol and prolactin (PRL) secretion in man. There is also evidence that 5-HT1C/2 receptor stimulation contributes to the cortisol and PRL responses following administration of the 5-HT precursor, L-5-hydroxytryptophan (L-5-HTP), in man. To clarify the possible contribution of 5-HT1A receptor stimulation to the ability of L-5-HTP to stimulate cortisol and PRL secretion in man, the effect of pindolol, a beta adrenoceptor antagonist that is also a 5-HT1A partial agonist, on the L-5-HTP-induced increases in cortisol and PRL secretion, was examined in 12 normal male volunteers. Pretreatment with pindolol, 30 mg orally, significantly inhibited the PRL but not the cortisol response to L-5-HTP, 200 mg PO. Pindolol alone decreased basal plasma PRL levels and increased basal plasma cortisol levels, possibly due to 5-HT1A antagonist and agonists effects, respectively. These data, coupled with observations from other studies, suggest that the L-5-HTP-induced increase in PRL but not cortisol secretion requires 5-HT1A receptor activation. PRL secretion due to 5-HT formed from exogenous L-5-HTP may require the availability of both intact 5-HT1A and 5-HT2/5-HT1C receptors, since blockade of either receptor type inhibited the PRL response to L-5-HTP. The implication of this synergistic effect for interpretation of neuroendocrine studies involving the serotonergic system in man is discussed.

5-Hydroxytryptophan↗
PubMed1994

Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response.

There is now some evidence that major depression may be accompanied by an immune response. The latter condition is suggested by elevated secretion of neopterin and interferon-gamma (IFN gamma) and by lower L-tryptophan (L-TRP) plasma levels. This study investigated the plasma levels of neopterin, L-TRP, and the L-TRP/competing amino acids (CAA) ratio in 30 normal control subjects and 47 depressed subjects (16 minor depressed, 13 simple major depressed, and 18 melancholic subjects), and IFN gamma secretion by mitogen-stimulated peripheral blood mononuclear cells in 7 normal control subjects and 13 major depressed subjects. Plasma neopterin levels were significantly higher in depressed subjects than in normal controls; 61% of melancholic patients had increased neopterin levels (> or = 7 nmol/l) with a specificity of 90%. Patients with major depression had significantly lower L-TRP and L-TRP/CAA values compared with normal control subjects. The amino acid values were significantly and negatively correlated with plasma neopterin levels. Major depressed subjects exhibited significantly higher IFN gamma secretion than did normal control subjects. The results further support the hypothesis that major depression is accompanied by an immune response and that the lower L-TRP availability in that illness may be an epiphenomenon of immune activation.

Adult↗
PubMed1994

Motor mechanisms in schizophrenic patients with tardive dyskinesia.

A specific aspect of the motor output of patients with tardive dyskinesia was investigated with an experimental procedure referenced in force control function (i.e., the maintenance of sustained force output). We hypothesized that response output (button press) at a given level would be significantly altered when preceded by an output of a higher force than when preceded by an output of a lower force. The difference could be interpreted as a behavioral measure of fatigability and/or threshold change, and its quantitative aspects could serve as a marker of motor impairment. Three groups of subjects participated in the study: schizophrenic patients with tardive dyskinesia (TD), schizophrenic patients without tardive dyskinesia, and normal control subjects. The test used was a target-matching task with force output ranging from 5 to 560 cN. Three dependent measures were used: output force, steadiness of force maintenance, and latency of target capture. Results indicated that precedent output at the previous trial significantly altered force, but even better group separation was attained with the measure of steadiness. The TD schizophrenic group's performance was least efficient, the control group's was most efficient, and the non-TD schizophrenic group's performance was intermediate. The principal conclusions reached were that the target-matching response reflects mechanisms related to both fatigability and recruitment of motor units involved in output control.

Adult↗
PubMed1994

Effect of the placebo control condition in neuroendocrine challenge studies.

Neuroendocrine challenge studies are frequently used to make inferences about the pathophysiology of psychiatric illness or about the effects of chronic psychotropic drug treatment on brain monoamine function. The outcome of these exploratory neuroendocrine tests, however, may be influenced by the effects of confounding variables, such as specific stress effects and variations in basal hormone levels. The inclusion of a placebo control condition minimizes the variability due to these variables. A number of recent neuroendocrine studies have omitted the placebo control condition. Based on experimental data, it can be shown that failure to include a placebo control condition may result in both Type I and Type II errors of inference. These results suggest a placebo control condition should be included in exploratory neuroendocrine challenge studies.

5-Hydroxytryptophan↗
PubMed1994

The relevance of the in- versus outpatient status for studies on HPA-axis in depression: spontaneous hypercortisolism is a feature of major depressed inpatients and not of major depression per se.

Increased spontaneous activity of the hypothalamic-pituitary-adrenal (HPA)-axis is frequently reported in major depressed inpatients. The aim of the present study was to determine whether there are differences in spontaneous HPA-axis activity between major depressed inpatients and outpatients. Toward this end, the authors measured basal 9:00 a.m. plasma cortisol and the integrated assessment of plasma morning cortisol secretion over 2 (AUC 120) hours in 48 major depressed inpatients, 17 major depressed outpatients and 73 normal volunteers. Major depressed inpatients exhibit significantly higher plasma cortisol values than healthy controls and major depressed outpatients. The cortisol data from the latter are not significantly different from these of the healthy controls. The cortisol differences between in and outpatients were still present after considering the influences of age, sex, body mass index, severity or endogeneity of illness, unipolar/bipolar subclassification, or specific symptoms such as suicidal thoughts, insomnia, psychomotor disorders, psychoticism, weight loss or anxiety. The results indicate that hypercortisolism as measured by basal morning plasma levels is not a feature of major depression per se, but rather of an interaction between the illness and hospitalization.

Adolescent↗
PubMed1994

Natural killer cell activity in major depression: relation to circulating natural killer cells, cellular indices of the immune response, and depressive phenomenology.

1. Recently, blunted natural killer cell activity (NKCA) has been found in major depression. The present study investigates the relationships between ex vivo blunted NKCA in major depression, number or percentage of NKC, in vivo indices of systemic immune activation and depressive phenomenology. 2. Toward this end, NKCA, absolute number of leukocytes and number or percentage of lymphocytes, monocytes, neutrophils, activated T lymphocytes (HLA-DR+, CD25+) and NKC (CD3-CD56+) were determined in 13 normal controls and 36 depressed inpatients. 3. NKCA was significantly and positively related to number and percentage of NKC in the peripheral blood. The major depression-related reduction in NKCA was not related to alterations in peripheral NKC. There were significant negative correlations between NKCA and number or percentage of leukocytes, monocytes, neutrophils and HLA-DR+ T cells. Up to 50% of the variance in NKCA could be explained by the regression on the number of monocytes, percentage of HLA-DR+ T and NKC cells, and diagnostic classification. Up to 43% of the variance in NKCA was explained by depressed mood, somatic anxiety and less diurnal variation. 4. The results show that blunted NKCA in major depression is not related to alterations in peripheral NKC, but reflects in part the systemic immune activation in that illness.

Adult↗
PubMed1994

Effects of age on spontaneous cortisolaemia of normal volunteers and depressed patients.

The aim of this study was to characterize the relationships between age and endogenous cortisol secretion in healthy controls and in major depressed patients between 18 and 58 years of age. Toward this end, the authors measured morning basal plasma cortisol secretion every 30 min from 0900 h until 1100 h and computed the integrated morning cortisol secretion in 80 normal controls and 118 major depressed patients. A significant negative correlation between age and plasma morning cortisol was found in normal volunteers but not in major depressives. The observed decrease in cortisol secretion with age in normal controls older than 35 years does not occur in major depressives. The middle age (+/- 35 years) appears to be an important turning point in hypothalamo-pituitary-adrenal (HPA)-axis function of normal persons vs. major depressives.

Adolescent↗
PubMed1994

Blunted oral body temperature response to MK-212 in cocaine addicts.

Previous studies have suggested that chronic cocaine administration may affect serotonergic function and that serotonin (5-HT) may be of importance in cocaine craving. Ten male cocaine addicts and 28 male normal controls were challenged with MK-212 (6-chlor-2-[1-piperazinyl]-pyrazine) (20 mg), a direct acting 5-HT receptor agonist which has affinity for a variety of 5-HT receptor subtypes, and placebo, on separate days. The plasma cortisol and prolactin (PRL) concentrations and oral body temperature responses to MK-212 and placebo were compared between groups. The temperature response to MK-212 was significantly blunted in cocaine addicts compared to normal controls. However, the plasma cortisol and PRL responses to MK-212 did not differ between the two groups. These results suggest selective alteration of presynaptic 5-HT1A or postsynaptic 5-HT2A/2C function in cocaine addicts.

Adult↗
PubMed1994

Multiple reciprocal relationships between in vivo cellular immunity and hypothalamic-pituitary-adrenal axis in depression.

Major depression is reportedly characterized by increased activity of the hypothalamic-pituitary-adrenal (HPA) axis and by in vivo immune activation. The present study was carried out in order to investigate the relationships between HPA-axis activity and in vivo immune function in depression. Towards this end the following parameters were measured: 24 h urinary cortisol (UC) excretion; basal and post-dexamethasone (DST) plasma cortisol, beta-endorphin/beta-lipotropin (beta END/beta LPH) and dexamethasone concentrations; and leucocyte subsets (i.e. lymphocytes, neutrophils, monocytes, CD4+, CD4+CD45RA+, CD4+CD45RO+, CD8+, CD8+CD57+, CD8+CD57-, HLA-DR+, CD25+ T cells, HLA-DR+, CD19+, CD20+, and CD21+ B cells) both pre- and post-DST. Dexamethasone administration (1 mg orally) induced leucocytosis, lymphocytopaenia, monocytopaenia and neutrophilia. HPA-axis non-suppressors exhibited a relative resistance to the enhancing (e.g. neutrophils) or depressant (e.g. lymphocytes, CD4+ T cells) effects of dexamethasone. There were significant correlations between UC excretion and the number of percentage of lymphocytes, monocytes, CD4+CD45RA+ and CD8+CD57- T cells (negatively) and neutrophils (positively). It is concluded that multiple and complex intertwined relationships between HPA-axis hyperactivity and systemic immune stimulation participate in the pathophysiology or pathogenesis of major depression.

Adult↗
PubMed1994

Effect of clozapine treatment on serotonin-2-receptor binding in the blood platelets of schizophrenic patients.

The effect of clozapine and typical neuroleptic drug treatment on platelet serotonin2 (5-HT2) binding kinetic constants (Kd, Bmax) was studied in schizophrenic patients. Both treatments increased Bmax by a comparable amount, indicating increased numbers of 5-HT2 sites, although not all typical neuroleptic drugs were effective in this regard. Clozapine, but not typical neuroleptic drugs, increased Kd, indicating a lower affinity of the 5-HT2 sites for 5-HT. In a multiple regression model, low Bmax at baseline predicted poor outcome on Brief Psychiatric Rating Scale measures in the clozapine-treated patients but not the neuroleptic-treated patients.

Adult↗