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Biomedical subjects

H Y Meltzer

Publications and source records attributed to H Y Meltzer.

At least 127 records · Page 7Linked to original sources
PubMed1996

Acute administration of buspirone increases the escape of hypothalamic-pituitary-adrenal-axis hormones from suppression by dexamethasone in depression.

Recently, our laboratory found a significant enhancing effect of L-5-hydroxy-tryptophan (L-5-HTP) on post-dexamethasone (DST) plasma adrenocorticotropic hormone (ACTH) and cortisol levels in major-but not in minor-depression. To further elucidate the effects of central serotonin (5-HT) activity on the negative feedback of glucocorticoids on hypothalamic-pituitary-adrenal (HPA)-axis function in depression, this study investigates the effects of buspirone, a 5-HT1A receptor agonist, on post-DST ACTH and cortisol levels in 75 depressed subjects. Plasma post-DST ACTH and cortisol concentrations were significantly increased by the acute administration of buspirone (30 mg PO) compared to placebo. There were no differences in buspirone-induced post-DST ACTH or cortisol responses between minor and major depression. There were significant correlations between post-DST ACTH and cortisol, and between post-DST-buspirone ACTH and cortisol. The buspirone-induced post-DST cortisol responses were significantly higher in depressed women than men. It is concluded that buspirone may augment ACTH and, consequently, cortisol escape from suppression by dexamethasone in major as well as in minor depression.

Adrenocorticotropic Hormone↗
PubMed1996

Neuropsychologic deficits in schizophrenia: relation to social function and effect of antipsychotic drug treatment.

Cognitive impairment is present in the majority of schizophrenic patients, even at the onset of psychosis. It is a relatively stable characteristic in most patients, usually with little progression over the course of illness, but sometimes progresses to severe dementia. The results of studies of the effects of typical neuroleptic drugs on cognitive functioning in schizophrenia are conflicting. Clozapine, which has superior antipsychotic effects compared to typical neuroleptic drugs, has been reported to improve executive function, verbal fluency, attention, and recall memory in two of three studies. Cognitive measures predict work function and overall outcome on clozapine as assessed by the Global Assessment Scale and Quality-of-Life Scale in neuroleptic--resistant schizophrenia. Improvement in cognitive function by clozapine may be a major reason for expanding its currently limited utilization.

Antipsychotic Agents↗
PubMed1996

Stimulatory effects of L-5-hydroxytryptophan on postdexamethasone beta-endorphin levels in major depression.

Recently it has been shown that acute administration of 200 mg L-5-hydroxytryptophan (L-5-HTP) PO may increase post-dexamethasone (DST) adrenocorticotropic hormone (ACTH) and cortisol levels in major, but not minor, depressed subjects. This study aimed to examine the effects of 200 mg L-5-HTP PO on post-DST beta-endorphin levels in the same depressed subjects. It was found that in major, but not minor, depressed subjects, L-5-HTP significantly increased post-DST beta-endorphin concentrations as compared to placebo. The L-5-HTP-induced post-DST beta-endorphin responses were significantly higher in major than in minor depressed subjects. There was a significant and positive relationship between L-5-HTP-induced post-DST beta-endorphin and ACTH or cortisol responses. There was a significant and positive relationship between L-5-HTP-induced post-DST beta-endorphin values and the Hamilton Depression Rating Scale (HDRS) score. The results show that the acute administration of L-5-HTP may increase the escape of beta-endorphin secretion from suppression by dexamethasone in major, but not minor, depression.

Adult↗
PubMed1996

Marked elevations of serum creatine kinase activity associated with antipsychotic drug treatment.

Serum creatine kinase (SCK) activity of the skeletal muscle (MM) form is sometimes moderately increased in acutely psychotic patients and may be massively increased as a result of muscle damage. The objective of this study was to characterize the SCK increases in patients treated with novel antipsychotic drugs. SCK activity and myoglobinuria, an index of gross muscle damage, were monitored at varying intervals in schizophrenic or schizoaffective patients treated with antipsychotic drugs. Possible causes of increases in SCK activity, such as trauma, excessive physical activity, exacerbation of psychosis, were assessed. Fifteen instances of massive increases in SCK activity were observed in 11 out of 121 patients (10%) treated with the following antipsychotic drugs: clozapine, loxapine, haloperidol, melperone, risperidone, or olanzapine. These increases in SCK activity were of the MM type and ranged from 1,206 to 177,363 IU/L (median, 9,600 IU/L). Thus, they were much larger than the increases usually found in acutely psychotic patients or patients with neuroleptic malignant syndrome (range, 500-3,000 IU/L). Only the patient with SCK activity of 177,363 IU/L had rhabdomyolysis as evidenced by myoglobinuria. The onset of the increases was from 5 days to 2 years after initiating treatment, and the increases lasted 4 to 28 days (median, 8 days). Flulike symptoms were present in two of the patients, but the others were asymptomatic. The increases were self-limiting in three cases, despite continuing treatment. Two of three cases rechallenged with the same drug again developed large increases in SCK activity within a week. It is unlikely these increases in SCK activity are related to acute psychosis, trauma, or the neuroleptic malignant syndrome. The increase in SCK activity may reflect the ability of the drugs to increase intermittently cell membrane permeability, especially in skeletal muscle, in some vulnerable subjects. A possible role of serotonin in this process is suggested by the pharmacology of most of the offending drugs. However, in some instances, the increases may have been unrelated to drug treatment. There was no evidence that these increases in SCK activity, despite their magnitude, compromised renal function. Routine monitoring of SCK activity of myoglobinuria during treatment with the antipsychotic drugs studied here is probably not necessary.

Adult↗
PubMed1996

Lower plasma CC16, a natural anti-inflammatory protein, and increased plasma interleukin-1 receptor antagonist in schizophrenia: effects of antipsychotic drugs.

Recently, it was suggested that in vivo activation of the monocytic and T-lymphocytic arms of cell-mediated immunity (CMI) may occur in schizophrenia and that antipsychotic drugs may modify CMI. The aim of the present study was to examine plasma soluble interleukin-2 receptor (sIL-2R), soluble suppressor/cytotoxic antigen (sCD8), interleukin-1 receptor antagonist (IL-1RA), and Clara cell protein (CC16) concentrations in normal controls, nonmedicated schizophrenic patients, and schizophrenic patients treated with risperidone or loxapine. Plasma concentrations of IL-1RA were significantly higher in nonmedicated schizophrenic patients than in normal controls. Plasma CC16 was significantly lower in nonmedicated and loxapine-treated schizophrenic patients than in normal controls, whereas risperidone-treated patients had plasma CC16 levels which were not significantly different from normal controls. Plasma CC16 levels were significantly and positively related to age at onset of schizophrenia. Plasma sIL-2R was significantly higher in schizophrenic patients who were treated with risperidone than in normal controls and nonmedicated schizophrenic patients. The results show that (i) schizophrenia is accompanied by an activation of the monocytic arm of CMI (i.e., increased plasma IL-1RA) and lower plasma levels of a natural anti-inflammatory and immunosuppressive agent, i.e. CC16, and that the latter may constitute a trait market of schizophrenia; and that (ii) chronic treatment with atypical antipsychotic agents, i.e., risperidone, may normalize lower plasma CC16 and increase plasma sIL-2R.

Adult↗
PubMed1996

Pre-morbid asociality in neuroleptic-resistant and neuroleptic-responsive schizophrenia.

The purpose of this study was to evaluate whether childhood and adolescent pre-morbid asociality differed in neuroleptic-responsive and neuroleptic-resistant schizophrenia. Pre-morbid asociality was assessed with the Pre-morbid Asociality Adjustment Scale in 411 patients meeting DSM-III-R criteria for chronic schizophrenia or schizoaffective disorder categorized as being either neuroleptic-responsive or neuroleptic-resistant. Patterns of childhood and adolescent asociality were found to be different in neuroleptic-resistant and neuroleptic-responsive patients. Pre-morbid asociality during the pre-adult years was not consistently worse in patients with poor response to neuroleptic treatment. Greater impairment in late adolescent psychosexual functioning was predictive of poor outcome with regard to neuroleptic treatment.

Adolescent↗
PubMed1996

Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor.

We describe the cloning and characterization of a human 5-HT6 serotonin receptor. The open reading frame is interrupted by two introns in positions corresponding to the third cytoplasmic loop and the third extracellular loop. The human 5-HT6 cDNA encodes a 440-amino-acid polypeptide whose sequence diverges significantly from that published for the rat 5-HT6 receptor. Resequencing of the rat cDNA revealed a sequencing error producing a frame shift within the open reading frame. The human 5-HT6 amino acid sequence is 89% similar to the corrected rat sequence. The recombinant human 5-HT6 receptor is positively coupled to adenylyl cyclase and has pharmacological properties similar to the rat receptor with high affinity for several typical and atypical antipsychotics, including clozapine. The receptor is expressed in several human brain regions, most prominently in the caudate nucleus. The gene for the receptor maps to the human chromosome region 1p35-p36. This localization overlaps that established for the serotonin 5-HT1D alpha receptor, suggesting that these may be closely linked. Comparison of genomic and cDNA clones for the human 5-HT6 receptor also reveals an Rsal restriction fragment length polymorphism within the coding region.

Adenylyl Cyclases↗
PubMed1996

Alterations in plasma dipeptidyl peptidase IV enzyme activity in depression and schizophrenia: effects of antidepressants and antipsychotic drugs.

Recently, our laboratory reported that the activity of dipeptidyl-peptidase IV (DPP IV) was significantly lower in the peripheral blood of major depressed patients than in normal controls. The present study examines plasma DPP IV activity in 43 major depressed and 13 schizophrenic subjects versus 21 normal controls and the effects of antidepressants and antipsychotic drugs on plasma DPP IV activity. DPP IV activity was significantly lower in major depressed subjects than in normal controls and schizophrenic subjects. There was a trend towards higher DPP IV activity in schizophrenic patients than in normal controls. There were no significant effects of antidepressants or neuroleptics on plasma DPP IV activity in depressed and schizophrenic patients, respectively. There were no significant relationships between plasma DPP IV activity and plasma cortisol or immune-inflammatory markers, such as serum interleukin-6 (IL-6) or soluble IL-2 receptor. A significant and positive correlation was found between plasma DPP IV and prolyl endopeptidase (PEP) enzyme activity in the study group as a whole and in schizophrenic subjects. The results support the hypothesis that lower and higher plasma DPP IV activities are trait markers of major depression and schizophrenia, respectively. It is concluded that alterations in the enzyme activity of peptidases, such as DPP IV and PEP, play a role in the pathophysiology of major depression and schizophrenia.

Adult↗
PubMed1996

Clozapine for treatment-refractory mania.

OBJECTIVE: The efficacy of clozapine for treatment-resistant mania was examined in a prospective trial for patients with bipolar or schizoaffective disorder. METHOD: The subjects were 25 acutely manic patients with either bipolar disorder (N = 10) or schizoaffective disorder-bipolar subtype (N = 15) for whom lithium, anticonvulsants, and neuroleptics had been ineffective, had produced intolerable side effects, or both. After a 7-day washout, the patients were treated with clozapine monotherapy. They were evaluated over 13 weeks with the Young Mania Rating Scale and the Brief Psychiatric Rating Scale (BPRS). RESULTS: Of the 25 patients, 18 (72%) exhibited marked improvement on the Young Mania Rating Scale, and eight (32%) exhibited marked improvement on the BPRS. The bipolar patients as compared to schizo-affective patients, and the nonrapid as compared to rapid cyclers, had significantly greater improvement in total BPRS score. CONCLUSIONS: These results suggest that clozapine is an effective therapy for treatment-resistant bipolar and schizoaffective mania.

Adult↗
PubMed1996

PET measurement of neuroreceptor occupancy by typical and atypical neuroleptics.

UNLABELLED: The goal of this study was to use PET and 11C-N-methylspiperone (11C-NMSP) to measure the difference in relative occupancy of serotonin (5-hydroxytryptamine-2 or 5-HT2A) and dopamine-2 (D2) neuroreceptors in subjects being treated with typical or atypical antipsychotic drugs. METHODS: We used PET and single-dose 11C-NMSP to measure receptor indices and relative receptor occupancy of 5-HT2A receptors in frontal cortex and D2 receptors in basal ganglia in five subjects who were neuroleptic free, five subjects who were being treated with typical antipsychotic drugs and five subjects who were being treated with clozapine, an atypical antipsychotic drug. RESULTS: Among the three groups, there were significant differences in 5-HT2A indices, D2 indices and the ratio of 5-HT2A to D2 indices. With no overlap, the 5-HT2A index separated all subjects who received clozapine and the D2 index separated the remaining two groups. CONCLUSION: Typical antipsychotic and atypical antipsychotic subjects do have differing patterns of 5-HT2A and D2 relative receptor occupancy when measured with a single PET scan, single 11C-NMSP radiotracer dose and no separately injected "cold" pharmaceutical.

Adult↗
PubMed1996

Frequency analysis of large CAG/CTG trinucleotide repeats in schizophrenia and bipolar affective disorder.

Much interest has recently been focussed on the possibility of the involvement of unstable DNA in the etiology of schizophrenia and bipolar affective disorder (BPAD), following several publications that report increases in frequency of large CAG/CTG repeats in affected individuals. Using the Repeat Expansion Detection (RED) technique, we have performed a matched control pair analysis for both disorders. No significant differences in CAG/CTG repeat sizes were observed for 52 bipolar affecteds and matched controls (P = 0.15), and borderline significance was observed for 54 schizophrenia affecteds and matched controls (P = 0.05), using a (CTG)10 oligonucleotide (one-tailed t-tests for paired samples). Furthermore, using a (CTG)17 oligonucleotide, no significant differences were observed for 58 bipolar affecteds and 55 schizophrenia affecteds compared to 81 unmatched controls. No significant sex effect was observed for either group, and no significant differences in repeat size were found for responders and non-responders to drug treatments. More importantly, there was no significant correlation (either positive or negative) between age of onset of disease and size of repeat. We thus cannot conclude that CAG/CTG trinucleotides are involved in psychotic disorders and that either the differences observed in similar studies may be the result of population stratification, or that the increased frequency of larger repeats amongst affected individuals is a much smaller effect than previously thought.

Adult↗
PubMed1995

Association study of dopamine D3 receptor gene and schizophrenia.

Several groups have reported an association between schizophrenia and the MscI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3). We studied this polymorphism using a North American sample (117 patients plus 188 controls) and an Italian sample (97 patients plus 64 controls). In the first part of the study, we compared allele frequencies of schizophrenia patients and unmatched controls and observed a significant difference in the total sample (P = 0.01). The second part of the study involved a case control approach in which each schizophrenia patient was matched to a control of the same sex, and of similar age and ethnic background. The DRD3 allele frequencies of patients and controls revealed no significant difference between the two groups in the Italian (N = 53) or the North American (N = 54) matched populations; however, when these two matched samples were combined, a significant difference was observed (P = 0.026). Our results suggest that the MscI polymorphism may be associated with schizophrenia in the populations studied.

Alleles↗
PubMed1995

R(+)-8-OH-DPAT, a 5-HT1A receptor agonist, inhibits amphetamine-induced dopamine release in rat striatum and nucleus accumbens.

Systemic administration of R(+)-8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), a selective serotonin (5-hydroxy-tryptamine, 5-HT)1A receptor agonist (25, 50, and 100 mu g/kg s.c.), administered 30 min prior to d-amphetamine, significantly inhibited the d-amphetamine sulfate (1.0 mg/kg s.c.)-induced increase in extracellular dopamine levels in the striatum and nucleus accumbens of freely moving rats, as determined by in vivo microdialysis. The ability of R(+)-8-OH-DPAT (50 mu g/kg s.c.) to inhibit d-amphetamine sulfate (1.0 mg/kg s.c.)-induced increase in extracellular dopamine levels was abolished by WAY 100,635 (n-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-n-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride), a selective 5-HT1A receptor antagonist (100 mu g/kg s.c.), administered 5 min prior to R(+)-8-OH-DPAT in both regions. These results indicate that the 5-HT1A receptor may exert an inhibitory effect on amphetamine-induced dopamine release.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

DOI, a 5-HT2A/2C receptor agonist, potentiates amphetamine-induced dopamine release in rat striatum.

The effects of (+-)-DOI (1-(2,5-dimethoxy-4-iodophenyl)-aminopropane) hydrochloride, a mixed 5-HT2A/2C receptor agonist, on the release of dopamine (DA) following D-amphetamine sulfate (AMP) or a DA D2 autoreceptor selective dose of (-)-apomorphine hydrochloride (APO), were investigated in rat striatum (STR) and nucleus accumbens (NAC), using in vivo microdialysis. AMP (1.0 mg/kg, s.c.) produced marked increases in extracellular DA levels in both the STR and the NAC whereas DOI (2.5 mg/kg, i.p.) alone had no significant effect on extracellular DA levels in either region. Pretreatment with DOI 30 min prior to AMP, further enhanced the AMP-induced increase in striatal extracellular DA levels. On the other hand, DOI pretreatment attenuated the APO (50 micrograms/kg, s.c.)-induced decrease in extracellular DA levels in the STR. Pretreatment with DOI did not affect the ability of either AMP or APO to modulate extracellular DA levels in the NAC. These results provide further evidence that 5-HT2A/2C receptors modulate the release mechanisms of DA in the STR. Possible mechanisms are discussed.

Amphetamine↗
PubMed1995

Alterations in plasma prolyl endopeptidase activity in depression, mania, and schizophrenia: effects of antidepressants, mood stabilizers, and antipsychotic drugs.

The activity of prolyl endopeptidase (PEP), a serine proteinase, has been found to be significantly lower in the blood of patients with major depression than in normal volunteers. The present study investigates plasma PEP activity in 25 major depressed, 10 manic, and 14 schizophrenic subjects versus 30 normal volunteers. It also examines the effects of antidepressants, valproate, and neuroleptic drugs on plasma PEP activity. PEP activity was significantly lower in major depressed subjects than in normal volunteers and in patients with mania and schizophrenia. In depressed subjects, plasma PEP activity was significantly increased during treatment with antidepressant drugs, such as fluoxetine. Plasma PEP activity was significantly increased in manic and schizophrenic subjects compared with normal volunteers. In manic subjects, short-term treatment with valproate had a significant suppressive effect on PEP activity. No significant effects of neuroleptics on PEP activity could be found in the schizophrenic patients. The results support the hypothesis that lower PEP activity could play a role in the pathophysiology of major depression, while increased PEP activity may be related to psychotic conditions, such as mania and schizophrenia.

Affect↗