Risperidone in treatment of choreoathetosis of Huntington's disease.
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Clozapine↗
Biomedical subjects
H Y Meltzer
Publications and source records attributed to H Y Meltzer.
Effects of trazodone and fluoxetine in the treatment of major depression: therapeutic pharmacokinetic and pharmacodynamic interactions through formation of meta-chlorophenylpiperazine.
It has been suggested that (1) the clinical efficacy of the heterocyclic antidepressant trazodone in depression may, in part, be attributed to its metabolite meta-chlorophenylpiperazine (mCPP); and (2) the enhancement of the efficacy of trazodone by the addition of fluoxetine, a selective serotonin reuptake inhibitor, may, in part, be ascribed to fluoxetine-induced plasma concentrations of trazodone. After a washout period of 10 days, 27 inpatients with major depression were treated with trazodone 100 mg/day (orally). One week later (T0), fluoxetine 20 mg/day, placebo, or pindolol 7.5 mg/day was added. Plasma concentrations of mCPP and trazodone were determined at T0 and 2 and 4 weeks later. Although placebo pindolol had no significant effect on the plasma concentrations of mCPP and trazodone, there was a significant increase of the concentrations of these compounds associated with the combination of trazodone + fluoxetine. The results suggest that fluoxetine-induced increases in plasma mCPP and trazodone concentrations contribute to the clinical efficacy of the combination of fluoxetine + trazodone. It is suggested that desensitization of 5-HT2C receptor function by mCPP as well as fluoxetine may contribute to the antidepressant effects of this combination.
Adult↗
Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: relationship with immune-inflammatory markers.
Recently, there have been some reports that changes in serum lipid composition may be related to suicide, major depression and immune-inflammatory responses. Findings from our laboratory suggest that major depression is accompanied by reduced formation of cholesteryl esters and perhaps by impairment of reverse cholesterol transport. The latter is reportedly accompanied by lower serum high-density lipoprotein cholesterol (HDL-C). The aim of this study was to examine whether (i) major depression is accompanied by lower serum HDL-C or by abnormal levels of serum total cholesterol, triglycerides, low-density lipoprotein-C (LDL-C) or vitamin E, (ii) suicidal attempts are related to lower serum HDL-C and (iii) there are significant associations between serum HDL-C and immune/inflammatory markers. A total of 36 subjects with major depression, of whom 28 patients showed treatment resistance, as well as 28 normal control subjects, had blood sampled for the assay of the above lipids, serum zinc (Zn), albumin (Alb) and flow cytometric determination of the T-helper/T-suppressor (CD4+/CD8+) T-cell ratio. In total, 28 depressed subjects had repeated measures of these variables both before and after treatment with antidepressants. Serum HDL-C and total cholesterol, as well as the HDL-C/cholesterol ratio, were significantly lower in subjects with major depression than in normal controls. Serum HDL-C levels were significantly lower in depressed men who had at some time made serious suicidal attempts than in those without such suicidal behaviour. Treatment with antidepressants for 5 weeks did not significantly alter either serum HDL-C or other lipid variables. Serum HDL-C levels were significantly and negatively correlated with the (CD4+/CD8+) T-cell ratio, and positively correlated with serum Alb and Zn. These results suggest that (i) lower serum HDL-C levels are a marker for major depression and suicidal behaviour in depressed men, (ii) lower serum HDL-C levels are probably induced by the immune/inflammatory response in depression and (iii) there is impairment of reverse cholesterol transport from the body tissues to the liver.
Adult↗
Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance.
OBJECTIVE: The age at onset of schizophrenia for males has usually but not always been reported to be less than that for females. Early onset has also been associated with poor response to neuroleptic treatment and worse long-term outcome. The authors compared age at onset in neuroleptic-resistant and -responsive schizophrenic patients to determine whether the gender difference in age at onset is related to response to neuroleptic treatment. METHOD: The subjects were 322 patients with schizophrenia or schizoaffective disorder who were consecutively admitted to a university hospital-based research program. RESULTS: Analysis of variance showed significant relationship between age at onset and both gender and longterm responsivity to neuroleptic drugs. The mean ages at onset in the neuroleptic-responsive men (mean = 21.2 years, SD = 6.1, N = 75), neuroleptic-resistant men (mean = 19.4 years, SD = 4.7, N = 119), and neuroleptic-resistant women (mean = 20.1 years, SD = 6.3, N = 77) were fairly similar, whereas that of the neuroleptic-responsive women (mean = 24.2 years, SD = 8.7, N = 51) was significantly greater than for all other groups. A simple effects model indicated that male and female neuroleptic-resistant patients did not differ significantly in mean age at onset, whereas male and female neuroleptic-responsive patients did. The effect of gender and neuroleptic responsivity on age at onset was related to schizophrenic subtype. CONCLUSIONS: These results confirm previous data indicating neuroleptic resistance is associated with early onset. The finding that the difference in age at onset between males and females is smaller in neuroleptic-resistant patients than in neuroleptic-responsive patients suggests that neuroleptic-resistant patients differ premorbidly as well as after onset of illness.
Adolescent↗
Treatment-resistant schizophrenia--the role of clozapine.
Treatment-resistant schizophrenia is the object of intense interest because of recent developments in its treatment and aetiology. The actual definition of treatment-resistant schizophrenia is, however, still controversial. It should reflect the legitimate and varied needs and perspectives of people with schizophrenia, their family members, mental health care givers, mental health administrators, public health officials, and those who fund the direct and indirect costs of treating schizophrenia. The most common definition of treatment-resistant schizophrenia denotes patients with schizophrenia who, despite at least two adequate trials of classical neuroleptic drugs, have persistent moderate to severe positive, or disorganisation, or negative symptoms together with poor social and work function over a prolonged period of time. This definition reflects the viewpoint of people with this illness, their family members, and mental health care givers. Approximately 30% (range 10-45%) of schizophrenic patients meet these criteria. While this definition is adequate for many purposes, it should be realised that the remaining 70% of schizophrenic patients, whose positive symptoms respond adequately to neuroleptic treatment, may also have clinically significant negative symptoms, poor social and work function, clinically significant cognitive dysfunction, poor quality of life relative to the normal population, and constitute a significant burden to family and society. The lifetime suicide rate in both treatment-resistant and responsive schizophrenic patients is 9-13%, indicating that conventional definitions of neuroleptic response do not convey lower risk of suicide. However, before defining a patient as treatment resistant, it is important to consider whether the patient has received an inadequate duration of treatment, and/or too low, or possibly too high, doses of neuroleptic drugs. Using these stringent criteria, treatment resistance may be present at the time of initial diagnosis and treatment, but if not present initially, it will usually develop subsequently-sometimes not until after multiple acute exacerbations over a period of years. During the first months and years after the diagnosis of schizophrenia has been made, clinicians should be especially alert in identifying a patient as treatment resistant in order to diminish the severe social disability and suicidality which may ensue if it is not recognised and correctly treated. Once present, treatment resistance is usually permanent. However, some treatment-resistant patients may again become responsive to treatment or undergo spontaneous remission of positive symptoms in later life. The treatment of patients with schizophrenia who are treatment resistant is generally much more expensive that that of neuroleptic-responsive patients because their symptomatology and disturbed behaviour leads to more frequent and longer duration hospitalisations. Patients with treatment-resistant schizophrenia may manifest one or more of the classical subtypes of schizophrenia which may differ biologically in terms of neurochemistry and structural brain abnormalities, e.g. ventricular enlargement. They usually have poorer premorbid function, an earlier age at onset of positive symptoms, are more likely to be male than female, and may have various quantitative types of cortical or ventricular abnormalities evident with computer tomography or magnetic resonance imaging scans. There are no established qualitative differences in cognitive dysfunction between the two groups of patients with schizophrenia, but cognitive impairment is more severe in treatment-resistant patients. Treatment-resistant schizophrenia does not usually respond to increased dosages of neuroleptic drugs, switching to other types of neuroleptics, or adding adjunctive agents such as benzodiazepines, antidepressants, anticonvulsants or lithium carbonate. (ABSTRACT TRUNCATED)
Adolescent↗
Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats.
The serotonin (5-HT)(2A/2c) agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT2C agonist 6-chloro-2-[1-piperazinyl]-pyrazine and the 5-HT2A partial agonist m-chloro-phenylpiperazine (mCPP) were injected bilaterally into the medial prefrontal cortex of male rats. DOI and mCPP, but not 6-chloro-2-[1-piperazinly]-pyrazine, elicited a dose-dependent head-twitch response (HTR). DOI-induced HTR had an ED50 of 12.8 nmoles/0.5 microl/side and was inhibited by the 5-HT2A antagonists ketanserin and MDL 100,907 but was not blocked by pretreatment with the selective 5-HT(2C/2B) antagonist SDZ SER 082. The HTR to mCPP demonstrated a bell-shaped dose-response curve with an ED50 of 1.5 nmoles/0.5 microl/side and a peak effect after 3 nmoles/side. The response to mCPP was greatly diminished by both ketanserin and MDL 100,907 and was partially reversed by SDZ SER 082. These findings suggest that the HTR produced by the direct injection of serotonergic agonists into the medial prefrontal cortex is, in part, mediated by the activation of 5-HT2A receptors. Pretreatment of rats with the 5-HT1A agonist (+/-)-8-hydroxy-dipropylaminotetralin hydrobromide inhibited the HTR to DOI. This is consistent with other evidence that suggests a functional antagonism between 5-HT1A and 5-HT2A receptor activation. The HTR to DOI was potentiated by the novel 5-HT1A selective antagonist WAY 100,635, which suggests that 5-HT1A receptors tonically regulate this behavioral response to stimulation of cortical 5-HT2A receptors.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
R(+)-8-OH-DPAT, a 5-HT1A receptor agonist, inhibits amphetamine-induced serotonin and dopamine release in rat medial prefrontal cortex.
Pretreatment with R(+)-8-OH-DPAT, a selective serotonin (5-HT)1A receptor agonist (50 micrograms/kg, s.c.), inhibited D-amphetamine sulfate (1.0 mg/kg, s.c.)-induced increases in extracellular levels of both 5-HT and dopamine (DA) in rat medial prefrontal cortex, as determined by in vivo microdialysis. The inhibitory effect of R(+)-8-OH-DPAT was completely reversed by the selective 5-HT1A receptor antagonist WAY 100,635 (100 micrograms/kg s.c.) administered 5 min prior to R(+)-8-OH-DPAT. These results suggest that stimulation of 5-HT1A receptors may inhibit amphetamine-induced release of 5-HT and DA in the medial prefrontal cortex.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Effects of meta-chlorophenylpiperazine on neuroendocrine and behavioral responses in male schizophrenic patients and normal volunteers.
Functional alterations in the central serotonergic system, including presynaptic and postsynaptic function, have been reported in schizophrenia. Recently, there have been conflicting reports that the increase in plasma cortisol or prolactin concentrations induced by meta-chlorophenylpiperazine (mCPP) was significantly blunted in schizophrenic patients compared with normal volunteers. Studies of the behavioral effects of mCPP, a serotonin (5-HT) receptor partial agonist with high affinity for 5-HT1C binding sites, have also yielded conflicting results in schizophrenic patients. The purpose of this study was to examine plasma levels of prolactin and cortisol, body temperature, and behavioral responses to mCPP and placebo in a single-blind study in 25 schizophrenic and 15 normal men. No differences either between schizophrenic patients and normal volunteers or between paranoid and undifferentiated/residual subtypes of schizophrenia were found in mCPP-induced prolactin, cortisol, or temperature responses. Schizophrenic patients and normal volunteers reported significant increases in feeling calm and feeling strange of comparable magnitude following mCPP. No significant differences between normal volunteers and schizophrenic patients were found in post-mCPP behavioral ratings, such as anxiety, irritability, depression, restlessness, or arousal.
Adult↗
Genetic variant near cytosolic phospholipase A2 associated with schizophrenia.
Two studies were undertaken to determine a possible genetic basis for alterations in phospholipid metabolism in schizophrenia. Initial results demonstrated an association in 65 schizophrenics compared with a matched normal control population. A follow-up haplotype relative risk study of 44 triads (mother, father, affected offspring), confirmed the results seen in the association study. Results suggest that a genetic variant near the promotor region of the gene for cytosolic phospholipase A2, the rate-limiting enzyme in the synthesis of prostaglandins from arachindonic acid, is associated with schizophrenia.
Female↗
Acute and long-term effectiveness of clozapine in treatment-resistant psychotic depression.
The treatment of refractory major depression, including the psychotic subtype, is a therapeutic challenge. Three cases of resistant psychotic depression were treated with clozapine monotherapy, an atypical antipsychotic drug effective in treatment-resistant schizophrenia and mania. Both psychotic and mood symptoms responded well to clozapine monotherapy, although response was delayed in one case. Tardive dyskinesia improved markedly, and tardive dystonia improved moderately in one patient. No patient relapsed during a follow-up period of 4-6 years of clozapine treatment. Clozapine was well-tolerated with few side effects. These observations suggest controlled trials of clozapine in the treatment of psychotic depression that fails to respond to electroconvulsive therapy or typical neuroleptics plus tricyclic antidepressants are indicated. The same is true for the use of clozapine in maintenance treatment for psychotic depression in those cases in which typical neuroleptic drugs are required, in order to reduce the risk of tardive dyskinesia and dystonia.
Adult↗
Increased prefrontal sulcal prominence in relatively young patients with unipolar major depression.
Although several studies have reported ventricular enlargement and sulcal prominence in mixed samples of patients with affective disorders (unipolar and bipolar subtypes), it is not established if these findings extend to a homogeneous sample of relatively young patients with unipolar major depression ventricular:brain ratio (VBR) and prefrontal sulcal prominence (PSP). In the present study, measures of ventricle-brain ratio (VBR) and prefrontal sulcal prominence (PSP) were compared in patients with affective disorders (n = 24, mean age = 39), medical control subjects (n = 40), patients with schizophrenia (n = 101) on ventricular : brain ratio (VBR) and prefrontal sulcal prominence (PSP). No statistically significant differences were noted in VBR in the three groups. Both patient groups had significantly greater PSP than the medical control subjects but did not differ significantly from each other. The results of the present study extend the finding of prefrontal sulcal prominence, but not ventricular enlargement, to relatively young patients with unipolar depression. Furthermore, the results of the present study suggest that patients with schizophrenia and patients with affective disorders differ only slightly or not at all in brain morphology, at the level of resolution studied.
Adult↗
No evidence for association of dopamine D2 receptor variant (Ser311/Cys311) with major psychosis.
We investigated a variant of the dopamine D2 receptor gene (Ser311/Cys311 substitution) in Caucasian patients with schizophrenia (n = 273), delusional disorder (n = 62), bipolar I affective disorder (n = 63), and controls (n = 255). No evidence for association between the receptor variant and any of the diseases was found, even when patients with younger age-of-onset (< 25 years) were compared with controls. Furthermore, in a subgroup of schizophrenia patients whom we assessed for negative symptoms, those with the Cys allele did not differ from the remainder of the group. Also, the bipolar affective disorder patients with psychotic features did not show evidence for association with the receptor variant. Thus, our results do not provide evidence for an association between this D2 receptor variant and schizophrenia, or delusional disorder, or bipolar affective disorder.
Adult↗
Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain.
The function of the phosphoinositide signal transduction system and the levels of heterotrimeric G-protein alpha-subunits were examined in postmortem prefrontal cortex regions (8/9) and region (10) from suicide victims with major depression and matched control subjects without psychiatric illness. The hydrolysis of [3H]phosphatidylinositol (PI) stimulated by phospholipase C, GTP-gamma-S, NaF, and neurotransmitter receptor agonists was measured in membrane preparations from both groups. Phospholipase C-beta activity was similar in depressed suicide and control subjects in the two regions of prefrontal cortex. In prefrontal cortex (10), but not in (8/9), the GTP-gamma-S concentration-dependent stimulation of [3H]PI hydrolysis was significantly lower (30%) in the depressed suicide group compared to the control group. Receptor-coupled, G-protein-mediated [3H]PI hydrolysis induced with carbachol, histamine, trans-1-aminocyclopentyl-1, 3-dicarboxylic acid (ACPD, a glutamatergic metabotropic receptor agonist), serotonin, or 2-methylthio-adenosine triphosphate (2mATP, a purinergic receptor agonist) in the presence of GTP-gamma-S stimulated equivalent responses in the two groups of subjects in each brain region. In prefrontal cortex (10) there was a 68% increase in the level of the 45 kDa subtype of G alpha s and in prefrontal cortex (8/9) there was a significant decrease (21%) in the level of G alpha i2 in the depressed suicide group compared to the control group. Levels of other heterotrimeric G-protein alpha-subunits (G alpha q/11, G alpha i1, and G alpha o) were not different in depressed suicide and control subjects in either brain region. Moreover, there were no differences in the levels of phospholipase C-beta or protein kinase C-alpha in the two groups of subjects in either brain region examined. These results demonstrate that in the prefrontal cortex of suicide victims with major depression compared to normal control subjects there is a region-specific alteration of G-protein-induced activation of the phosphoinositide signal transduction system and in the levels of G-protein alpha-subunits involved in cyclic AMP synthesis. These findings provide direct evidence in human brain that these two important signal transduction systems are altered in suicide subjects with major depression.
Adult↗
Clozapine-induced myoclonus and generalized seizures.
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Antipsychotic Agents↗
Serotonin1A receptors are increased in postmortem prefrontal cortex in schizophrenia.
Serotonin-5-HT1A receptors were measured with [3H]8-hydroxy-2-(di-n-propyl)aminotetralin ([3H]8-OH-DPAT) in postmortem prefrontal cortex of 12 pairs of subjects with schizophrenia and age-matched control subjects. The saturation binding isotherms of [3H]8-OH-DPAT revealed high- and low-affinity binding sites. The density (Bmax) of the high-affinity sites was significantly elevated by an average of 79% in subjects with schizophrenia. The dissociation constant (Kd) of the high-affinity sites in subjects with schizophrenia was not significantly different from the control subjects. These results provide further evidence for a role of the serotonergic system in the pathophysiology of schizophrenia.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Effect of pindolol on hormone secretion and body temperature: partial agonist effects.
Pindolol has been shown to be a partial agonist at 5-HT1A receptors in preclinical studies. It has also been reported to inhibit the effects of other 5-HT1A partial agonists such as ipsapirone and buspirone on hormone secretion and body temperature in man, indicating its antagonist action at 5-HT1A receptors in man. To determine if pindolol has 5-HT1A agonist as well as antagonist effects in man, pindolol, 30 mg, p.o. and placebo, were given single blind in random order to 23 normal men with indwelling venous catheters and its effects on hormone secretion and body temperature noted. Pindolol significantly increased basal plasma cortisol concentrations, whereas it decreased plasma prolactin (PRL) concentrations and body temperature. The increase in plasma cortisol due to pindolol suggests a 5-HT1A agonist action and is consistent with a 5-HT1A partial agonist mechanism in man whereas the PRL effects are consistent with an antagonist action at 5-HT1A receptors. The effects of pindolol on plasma cortisol concentration and body temperature were significantly negatively correlated. Furthermore, these results indicate significant differences in the 5-HT1A-dependent regulation of PRL and the hypothalamo-pituitary-adrenal (HPA) axis and body temperature, and suggest that human basal PRL secretion is tonically stimulated by 5-HT1A mechanism whereas the HPA axis and body temperature are not. Since rodent studies suggest differences in 5-HT1A receptor sensitivity between males and females, the results reported here need to be replicated in females. These differences in the effect of pindolol are discussed in terms of receptor reserve theory.
Adolescent↗
Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine.
The objective of this study was to report the effect of the slow withdrawal of clozapine from 19 patients with neuroleptic-responsive schizophrenia at the end of a 2-year clinical trial of clozapine and to compare this with the results of naturalistic discontinuation of clozapine treatment in 64 neuroleptic-resistant schizophrenic patients. Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic. Fifteen of the 19 neuroleptic-responsive patients experienced the return of psychotic symptoms during or after the clozapine taper, which were most severe in the ten patients in whom the withdrawal of clozapine was carried out without prior addition of neuroleptic treatment. Addition of a neuroleptic prior to clozapine withdrawal prevented the emergence of positive symptoms during clozapine withdrawal in each of eight patients. Nevertheless, psychotic symptoms emerged, usually within a week after discontinuing clozapine, in six of the eight patients. Neuroleptic treatment, with or without an anticholingergic drug, was much less effective in treating positive symptoms in these patients immediately after the clozapine withdrawal than it had been 2 years previously. Cyproheptadine, a non-selective serotonin receptor antagonist, augmented the antipsychotic effect of neuroleptics in each of four patients who relapsed following withdrawal from clozapine and relieved extrapyramidal symptoms in a fifth patient. The frequency of relapse following withdrawal of clozapine in 64 neuroleptic-resistant patients was significantly lower (25/64, 39.1%) than in the neuroleptic-responsive patients.
Adult↗
Psychosis and genes with trinucleotide repeat polymorphism.
Abnormal expansion of genes with trinucleotide repeat (TNR) polymorphism has been found in a number of neuropsychiatric disorders. These disorders and the major psychoses, schizophrenia and bipolar affective disorder, appear to share an interesting phenomenon: genetic anticipation. Because TNR expansion correlates with anticipation, these unstable DNA sites are considered important candidate loci for the major psychoses. We investigated genes with TNR polymorphisms, including B1, B33, B37, and the N-cadherin gene, in unrelated Caucasian North American and Italian schizophrenics (n = 53 to 74), and matched controls. Also, unrelated Caucasian North American patients with bipolar I affective disorder were screened for the B33 and N-cadherin genes (n = 49 and 63, respectively). No unusually long alleles that would suggest abnormal expansion of the TNR were observed for any of these genes. Also, no statistically significant results were found in tests for genetic association between any of these genes and schizophrenia. For B37, a trend toward a difference in allele counts between schizophrenics and controls was observed. However, no clear evidence for a role of these TNR-containing genes in schizophrenia or bipolar affective disorders was found.
Bipolar Disorder↗