A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia.

CX516, a positive modulator of the glutamatergic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor, improves performance in tasks requiring learning and memory in animals. CX516 was added to clozapine in 4-week, placebo-controlled, dose-finding (N = 6) and fixed-dose (N = 13) trials. CX516 was tolerated well and was associated with moderate to large, between-group effect sizes compared with placebo, representing improvement in measures of attention and memory. These preliminary results suggest that CX516 and other "ampakines" hold promise for the treatment of schizophrenia.

Suppression of hepatocyte nuclear factor-4alpha by acyl-CoA thioesters of hypolipidemic peroxisome proliferators.

Hepatocyte nuclear factor-4alpha (HNF-4alpha) modulates the expression of liver-specific genes that control the production (e.g. apolipoprotein [apo] A-I and apo B) and clearance (e.g. apo C-III) of plasma lipoproteins. We reported that the CoA thioesters of amphipathic carboxylic hypolipidemic drugs (e.g. clofibric acid analogues currently used for treating hyperlipidemia in humans and substituted long-chain dicarboxylic acids) were formed in vivo, bound to HNF-4alpha, inhibited its transcriptional activity, and suppressed the expression of HNF-4alpha-responsive genes. Hypolipidemic PPARalpha (peroxisome proliferator-activated receptor alpha) activators that were not endogenously thioesterified into their respective acyl-CoAs were shown to be effective in rats but not in humans, implying that the hypolipidemic activity transduced by PPARalpha in rats was PPARalpha-independent in humans. The suppressed acyl-CoA synthase of PPARalpha knockout mice left unresolved the contribution made by the acyl-CoA/HNF-4alpha pathway to the hypolipidemic effect of PPARalpha agonists in rodents. Hence, suppression of HNF-4alpha activity by the CoA thioesters of hypolipidemic "peroxisome proliferators" may account for their hypolipidemic activity independently of PPARalpha activation by their respective free carboxylates. The hypolipidemic activity of peroxisome proliferators is mediated in rats and humans by the PPARalpha and HNF-4alpha pathways, respectively.

Clozapine in the treatment of refractory psychotic mania.

OBJECTIVE: The efficacy of clozapine was examined in a group of patients with treatment-refractory bipolar disorder, manic type with psychotic features. METHOD: Twenty-two subjects with treatment-refractory bipolar disorder with active manic and psychotic symptoms participated in a 12-week open-label trial of clozapine. After a 2-10-day drug washout period, patients began treatment with clozapine at 25 mg/day; the dose was increased 25 mg/day (as tolerated) to a maximum level of 550 mg/day. Patients were evaluated longitudinally over the course of the study with the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale, and the Clinical Global Impressions (CGI) scale. RESULTS: Fourteen of the 22 subjects in the study continued taking clozapine for at least 10 of the 12 weeks. Among the entire group, mean improvements of 56. 7%, 56.6%, and 39.1% were seen on the BPRS, Young Mania Rating Scale, and CGI, respectively. Seventeen of the 22 subjects (77.3%) experienced at least a 20% improvement in scores on all three scales. CONCLUSIONS: The findings from this open-label study, which are consistent with previous retrospective studies, case reports, and one other open-label prospective study, suggest that clozapine is an effective agent for patients with treatment-refractory psychotic mania.

Obsessions and compulsions as a distinct cluster of symptoms in schizophrenia: a neuropsychological study.

Using neurocognitive testing, the present study assessed whether obsessions and compulsions could represent a distinct cluster of symptoms in schizophrenia. We formulated our hypothesis based on data from nonschizophrenic patients, expecting to find that schizophrenic patients with obsessive-compulsive (OC) symptoms would experience more difficulties in the same cognitive areas as nonschizophrenic patients with obsessive-compulsive disorder (OCD). Patients had separate psychiatric and cognitive evaluations. The OC and non-OC schizophrenic subjects did not differ significantly on the positive and negative symptom scores. However, compared with non-OC schizophrenic patients, those with OC symptoms performed worse on cognitive areas thought to be impaired (i.e., visual-spatial skills, delayed nonverbal memory, and cognitive shifting abilities). In addition, the severity of OC scores correlated with poor performance in these areas of cognition. Our results support our hypothesis, specifically that OC symptoms may constitute a distinct cluster separate from psychosis in schizophrenia and raise the possibility of a distinct subtype of schizophrenia. The theoretical and clinical implications of these findings are discussed.

Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha.

Dietary fatty acids specifically modulate the onset and progression of various diseases, including cancer, atherogenesis, hyperlipidaemia, insulin resistances and hypertension, as well as blood coagulability and fibrinolytic defects; their effects depend on their chain length and degree of saturation. Hepatocyte nuclear factor-4alpha (HNF-4alpha) is an orphan transcription factor of the superfamily of nuclear receptors and controls the expression of genes that govern the pathogenesis and course of some of these diseases. Here we show that long-chain fatty acids directly modulate the transcriptional activity of HNF-4alpha by binding as their acyl-CoA thioesters to the ligand-binding domain of HNF-4alpha. This binding may shift the oligomeric-dimeric equilibrium of HNF-4alpha or may modulate the affinity of HNF-4alpha for its cognate promoter element, resulting in either activation or inhibition of HNF-4alpha transcriptional activity as a function of chain length and the degree of saturation of the fatty acyl-CoA ligands. In addition to their roles as substrates to yield energy, as an energy store, or as constituents of membrane phospholipids, dietary fatty acids may affect the course of a disease by modulating the expression of HNF-4alpha-controlled genes.

Differential relationships between positive and negative symptoms and neuropsychological deficits in schizophrenia.

UNLABELLED: This study assessed the relationships between positive and negative clinical symptoms and specific neuropsychological deficits in a group of stable schizophrenic patients. METHOD: Thirty patients were assessed using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia and a battery of cognitive tests. The PANSS assessments were done by a group of raters blind to the results of cognitive tests, while the cognitive tests were conducted by a different group of raters who remained blind to the PANSS scores. RESULTS: We found that, although positive and negative symptoms showed a trend toward direct correlation with each other, they correlated with distinct cognitive deficits. Patients with higher negative scores had more perseverative responses, perservative errors, and completed fewer categories on the Wisconsin Card Sorting Test; they also experienced more difficulties on trail making and verbal fluency tests. On the other hand, positive symptoms were associated with poor performance on the Digit Span, particularly the Digit Span Forward. CONCLUSIONS: Our findings are in agreement with previous reports that negative symptoms may be associated with poor performance on cognitive tests reflecting particularly frontal function. Positive symptoms, on the other hand, seem to be associated with poor attention, specifically of auditory type, and thus, possibly with dysfunction within the more widespread neural networks underlying attention. Our findings support the hypothesis that positive and negative symptoms may be associated with distinct neuropsychological deficits and thus with distinct neurological substrates and point to the need to address both positive and negative dimensions when studying schizophrenia.

Thyromimetic mode of action of peroxisome proliferators: activation of 'malic' enzyme gene transcription.

Peroxisome proliferators induce thyroid-hormone-dependent liver activities, e.g. 'malic' enzyme, mitochondrial glycerol-3-phosphate dehydrogenase, glucose-6-phosphate dehydrogenase, S14[Hertz, Aurbach, Hashimoto and Bar-Tana (1991) Biochem. J. 274, 745-751]. Here we report that the thyromimetic effect of peroxisome proliferators with respect to 'malic' enzyme result from transcriptional activation of the 'malic' enzyme gene, mediated by binding of the peroxisome proliferator activated receptor (PPAR alpha)/retinoid X receptor (RXR alpha) heterodimer to a 5'-flanking enhancer of the 'malic' enzyme promoter. The enhancer involved is distinct from the thyroid hormone response element of the 'malic' enzyme promoter and is partly homologous with that which mediates transcriptional activation of peroxisomal acyl-CoA oxidase by peroxisome proliferators. Hence transcriptional activation of thyroid-hormone-dependent liver genes by xenobiotic or endogenous amphipathic carboxylates collectively defined as peroxisome proliferators is mediated by a transduction pathway similar to that involved in transcriptional activation of peroxisomal beta-oxidative genes and distinct from that which mediates thyroid hormone action.

Adjunctive nadolol in the treatment of acutely aggressive schizophrenic patients.

BACKGROUND: This study assessed the safety and efficacy of nadolol 120 mg/day compared with placebo, when administered adjunctively to neuroleptic in a group of acutely aggressive schizophrenic patients. METHOD: Thirty-four male patients enrolled in this double-blind, placebo-controlled trial. The subjects were evaluated with the Brief Psychiatric Rating Scale (BPRS) and the Simpson Angus Neurologic Rating Scale for extrapyramidal effects. The total BPRS score as well as three factors, thought disturbance, hostility, and activation, was analyzed. RESULTS: Compared with those who received placebo, the patients taking nadolol showed significant improvement on total BPRS score, particularly on the thought disturbance and activation factors, after the first treatment week (p = .05). By the end of the second treatment week, the patients taking placebo also began to show improvement, and the group differences were no longer significant. The patients treated with nadolol showed significantly more improvement on Simpson-Angus scores than those who received placebo (p = .03). However, there was no significant correlation between BPRS and Simpson-Angus changes. In the nadolol group, patients with and without akathisia showed no significant difference in their BPRS scores. CONCLUSION: These findings suggest that adjunctive nadolol may be useful in the treatment of acutely aggressive schizophrenic patients by inducing a more rapid and consistent decrease of overall psychiatric symptoms and by reducing the extrapyramidal effects. Our results raise the possibility that the mechanism of action of nadolol on psychiatric symptoms in schizophrenic patients may be different from the mechanism of improvement of neuroleptic-induced extrapyramidal symptoms and akathisia. Nadolol may be a helpful adjunctive treatment for schizophrenic patients in general and not just for those with a high hostility level.

Regional cerebral blood flow changes associated with risperidone treatment in elderly schizophrenia patients: a pilot study.

Although there is evidence that some schizophrenia patients may have altered regional cerebral blood flow patterns, few studies have addressed the relationship between cortical activity and changes in psychiatric symptoms following treatment, particularly in the elderly. We took advantage of an existing safety and tolerance study of risperidone in the elderly and examined the possible relationship between changes in psychiatric symptoms following risperidone and changes in relative cortical perfusion in a group of 6 elderly schizophrenia patients. All subjects were at least 65 years old and diagnosed with schizophrenia according to DSM-III-R criteria. The patients were assessed using the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) and Mini-Mental Status Examination (MMSE) and had single photon emission computed tomography (SPECT) studies before and at least 3 weeks after change of their previous neuroleptic to risperidone. The frontal/total cortex and temporal/total cortex counts in the slice ratios, and 99mTechnitium-hexamethylpropylene amine oxime (99mTc-HMPAO) percentage uptake in the whole cortical area in the slice were used for data analysis. With risperidone, patients (age 66-81) scored better on the PANSS, particularly in the positive symptom subtests. The changes in positive symptom scores correlated directly with those in frontal and temporal relative activity and 99mTc-HMPAO percentage uptake in the whole cortical area in the slice. Our findings suggest that the improvement in psychotic symptoms after risperidone is associated with a decrease in frontal and temporal activity and a reduction in 99mTc-HMPAO percentage uptake in the entire cortical area in the slice and agree with data from younger populations. Comparative studies assessing the therapeutic impact of neuroleptics on cortical activity in different age groups could be helpful in examining both the mechanisms of action of various drugs and the links between symptoms and specific brain areas.

Activation of gene transcription by prostacyclin analogues is mediated by the peroxisome-proliferators-activated receptor (PPAR).

Xenobiotic amphipathic carboxylates, known collectively as hypolipidemic peroxisome proliferators (e.g., aryloxyalkanoic acids), or native long-chain fatty acids induce liver peroxisome proliferation and other biological activities. This broad spectrum of effects results from modulation of transcription of specific genes mediated by binding of peroxisome-proliferators-activated receptors (PPAR) to respective sequence-specific promoter elements (PPRE). The broad specificity and relatively low potency of reported hypolipidemic peroxisome proliferators prompted us to search for specific highly potent peroxisome proliferators. Here we report that stable prostacyclin analogues may act in such a manner. mPPAR alpha-mediated expression of a reporter gene linked to the peroxisomal rat acyl-CoA oxidase promoter was dose-dependently induced by carbaprostacyclin and iloprost. The ED50 for carbaprostacyclin was 25 nM, and carbaprostacyclin was therefore 25-fold and 200-fold more effective than the most potent xenobiotic (5,18,11,14-eicosatetraynoic acid) and native (arachidonic acid) inducers, respectively. Induction was further increased by cotransfecting the cells with mPPAR alpha and an expression vector for retinoic acid-X-receptor. PPAR-mediated activation of gene expression by prostacyclin analogues was specific for PPAR and was not observed using other members of the superfamily. No activation of gene expression was induced by other prostaglandins or leukotrienes at concentrations 100-fold higher than those of the prostacyclin analogues. Induction of gene expression by prostacyclin analogues was inhibited in cells transfected with the long-chain-acyl-CoA synthase, indicating that the acidic form of prostacyclin, rather than the respective CoA derivative or a metabolite derived thereof, serves as the activator of the PPAR/PPRE transduction pathway. Hence, PPAR-mediated modulation of gene transcription by prostacyclins may form the basis for their novel role as regulators of gene expression. Xenobiotic hypolipidemic peroxisome proliferators and native long-chain fatty acids seem to exploit the PPAR/PPRE transduction pathway used by prostacyclin.

Treatment of obsessive-compulsive symptoms in schizophrenic patients with clomipramine.

Recent studies show that obsessive-compulsive symptoms may occur in many patients with schizophrenia and may predict a poor prognosis. Pilot studies have shown that some schizophrenic patients may improve if a serotonin reuptake blocker is added to their neuroleptic. We have performed a pilot, double-blind, crossover study of clomipramine (CMI) or placebo, added to maintenance psychotropic medication. Six schizophrenic patients with obsessive-compulsive symptoms were studied in a double-blind CMI versus placebo crossover protocol. The patients met DSM-III-R criteria for chronic schizophrenia, experienced obsessive-compulsive symptoms, and had been previously stabilized on their psychiatric medication. The patients were rated at baseline and longitudinally through the study with the Positive and Negative Symptom Scale for Schizophrenia (PANSS) and the Yale Brown Obsessive-Compulsive Scale (YBOCS). An analysis of covariance was used to compare the drug versus placebo effect at the final visit with the baseline rating as a covariate. Ratings on both the YBOCS and the PANSS showed that patients improved significantly more on CMI than on placebo. No patients experienced an exacerbation of psychotic symptoms. Preliminary findings from this double-blind, crossover, pilot study of CMI and placebo, designed to assess the effect of CMI in the treatment of schizophrenic patients with obsessive symptoms, suggest that CMI is superior to placebo in the treatment of obsessions and compulsions and improves overall schizophrenic symptoms. Further studies with larger samples and longer follow-up period are necessary to confirm these preliminary findings.

Obsessive and compulsive symptoms in chronic schizophrenia.

The goals of the study were to determine the prevalence of obsessive or compulsive (OC) symptoms among chronic schizophrenic patients, and to elucidate the level of function and course of illness in chronic schizophrenic patients with and without such symptoms. Therapists of 102 patients with DSM-III-R diagnoses of chronic schizophrenia reported on their patients' OC symptoms, level of function, and course of illness. Twenty-five percent of the chronic schizophrenic patients presented with significant OC symptoms. The OC schizophrenics had significantly earlier onsets of their illnesses, had spent more time in the hospital in the previous 5 years, and were judged by their therapists to have a lower level of capacity for age-appropriate function. In addition, such patients had been less often employed and less often married, and were more dependent on others. The poorer prognosis for schizophrenic patients with OC symptoms than for those without these symptoms suggests the need for new therapeutic strategies for such patients.