Myung A. Lee

The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine

RationaleClozapine is a unique antipsychotic, with efficacy against positive symptoms in treatment-resistant schizophrenic patients, and the ability to improve cognition and treat the negative symptoms characteristic of this disease. Despite its unique clinical actions, no specific molecular mechanism responsible for these actions has yet been described.Objectives and methodsTo comprehensively profile a large library of neuropsychiatric drugs, including most antipsychotics, at human monoamine receptors using R-SAT, an in vitro functional assay.ResultsProfiling revealed that N-desmethylclozapine (NDMC), the principal metabolite of clozapine, but not clozapine itself, is a potent and efficacious muscarinic receptor agonist, a molecular property not shared by any other antipsychotic. To further explore the role of NDMC muscarinic receptor agonist properties in mediating the physiological actions of clozapine, systemically administered NDMC was found to stimulate the phosphorylation of mitogen-activated protein kinase (MAP kinase) in mouse CA1 hippocampal neurons, an effect that was blocked by scopolamine, confirming central M1 muscarinic receptor agonist activity in vivo. Lastly, an analysis of clozapine and NDMC serum levels in schizophrenic patients indicated that high NDMC/clozapine ratios better predicted improvement in cognitive functioning and quality of life than the levels of either compound alone.ConclusionsThe muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.

Plasma glycine and serine levels in schizophrenia compared to normal controls and major depression: relation to negative symptoms

Previous studies have suggested decreased N-methyl-D-aspartate (NMDA)-type glutamate receptor function may contribute to increased negative symptoms in patients with schizophrenia. Consistent with this hypothesis, glycine, a co-agonist at NMDA receptors, has been reported to improve negative symptoms associated with the illness. This study was performed to determine if plasma levels of glycine or its ratio to serine, a precursor of glycine, are decreased in patients with schizophrenia compared to normal control subjects or patients with major depression. We also tested the hypothesis that these amino acids were correlated with negative symptoms in subjects with schizophrenia. Plasma levels of glycine, serine, and their ratio, were compared in 144 patients with schizophrenia, 44 patients with major depression, and 49 normal control subjects. All subjects were medication-free. Psychopathology was evaluated using the Brief Psychiatric Rating Scale (BPRS). Plasma glycine levels and glycine/serine ratios were decreased in patients with schizophrenia relative to control subjects and patients with major depression. By contrast, serine levels were increased in patients with schizophrenia compared to normal subjects but not compared to major depression. Patients with major depression also had increased plasma serine levels and decreased glycine/serine ratios compared to normal controls, but glycine levels were not different from those of normal controls. In subjects with schizophrenia, glycine levels predicted the Withdrawal-Retardation score (BPRS), whereas no such correlation was found in subjects with major depression. These results provide additional evidence that decreased availability of glycine may be related to the pathophysiology of negative symptoms. The decreases in plasma glycine levels support the evidence for an abnormality in the glutamatergic system in schizophrenia, and provide additional support for efforts to improve negative symptoms by augmentation of antipsychotic drugs with agonists at the glycine site of the NMDA receptor.

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.

Neuroendocrine responses to serotonergic agents in alcoholics

Previous studies have suggested a possible deficit in serotonergic function in alcoholism. In order to further assess the serotonergic system in alcoholism, the plasma cortisol and prolactin (PRL) responses following 6-chloro-2-[1-piperazinyl]pyrazine (MK-212), a direct-acting serotonin2 (5-HT2)/5-HT1c receptor agonist, L-5-hydroxytryptophan (L-5-HTP), a precursor of 5-HT, and placebo were compared in male alcoholics and normal controls. The increase in plasma cortisol following L-5-HTP was significantly lower in the alcoholic subjects compared with the normal controls. The plasma PRL, but not the plasma cortisol response, following MK-212 was also significantly lower in the alcoholics. L-5-HTP had no significant effect on plasma PRL levels in either group. The basal plasma cortisol and PRL concentrations of the alcoholics and normal controls were not significantly different. These data are consistent with previous reports of a serotonergic abnormality in alcoholism.

Inhibitory effect of ritanserin on the 5-hydroxytryptophan-mediated cortisol, ACTH and prolactin secretion in humans

Oral administration of the serotonin (5-HT) precursorl-5-hydroxytryptophan (5-HTP), 200 mg, significantly increased plasma cortisol levels in man.l-5-HTP had no significant effect on the plasma prolactin levels. A borderline effect of 5-HTP on plasma ACTH levels was found. Pretreatment with the 5-HT2/5-HT1C antagonist ritanserin (5 mg, PO, b.i.d. for 2 days) significantly inhibited 5-HTP-induced cortisol secretion. Ritanserin had no effect on the basal plasma cortisol or prolactin levels. These data are suggestive that 5-HTP stimulates cortisol secretion in man via 5-HT2/5-HT1C receptor mechanisms.

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 withneuroleptic-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 64neuroleptic-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.

Recent advances in the pharmacotherapy of schxzophrenia

The major advance in the psychopharmacology of schizophrenia has been the rediscovery of clozapine and the development of other novel antipsychotic drugs, all of which are superior to typical neuroleptic drugs with regard to extrapyramidal symptoms. Clozapine, the best studied of these agents, is also superior in efficacy with regard to psychopathology and cognitive function and has been shown not to cause tardive dyskinesia. A variety of other novel agents, e.g., risperidone, olanazpine, amperozide, seroquel, sertindole, zaprisidone and melperone, must be further studied to establish their efficacy relative to clozapine or the typical neuroleptics, or both. It is likely that these novel agents will displace the typical neuroleptic drugs as the primary treatment of schizophrenia.

Prediction of the ability of clozapine to treat negative symptoms from plasma glycine and serine levels in schizophrenia

We previously reported that plasma levels of glycine, a co-agonist at N-methyl-D-asparate (NMDA)-type glutamate receptors, are decreased in patients with schizophrenia, and that glycine levels are negatively correlated with negative symptoms. The aim of the present study was to determine if glycine, or its ratio to serine, a precursor of glycine, predicts change in negative symptoms in subjects with schizophrenia during treatment with clozapine, an atypical antipsychotic drug with multiple effects on glutamatergic activity. Plasma levels of glycine, serine, and their ratio, were measured in 44 patients with schizophrenia who were subsequently treated with clozapine. Baseline glycine levels or glycine/serine ratios predicted the Scale for the Assessment of Negative Symptoms - Sum of the Global Scales and Avolition-Apathy after 6 wk of clozapine treatment. These results indicate the association of these amino acid measures with response to clozapine in terms of negative symptoms in patients with schizophrenia.

Neuroendocrine measures of dopaminergic function in chronic cocaine users

Plasma prolactin (PRL) and growth hormone (GH) levels are determined, in part, by the effects of dopamine (DA) at pituitary and hypothalamic DA receptors, respectively. To determine if chronic cocaine abuse alters dopaminergic activity, basal PRL and GH concentrations were measured in 16 male patients meeting DSM-III-R criteria for cocaine dependence (8 cocaine users and 8 cocaine + alcohol users) and 8 normal controls. In addition, the functional responsivity of DA receptors was assessed in the same group of patients by measuring the change in plasma PRL and GH concentrations following the administration of the direct-acting DA agonist, apomorphine (0.01 mg/kg, s.c.) or saline. No difference in basal plasma PRL and GH levels or plasma PRL and GH responses to apomorphine administration was found between the entire group of cocaine patients and normal controls. However, three of the cocaine patients had basal plasma PRL levels that were more than 2.5 SD greater than that of the normal controls, suggesting that some interference of dopaminergic inhibition of PRL secretion might be present in at least some cocaine users. Although baseline plasma PRL levels were elevated in a subgroup of cocaine users, these data do not support the hypothesis that chronic cocaine abuse produces consistent abnormalities in dopaminergic function at the pituitary or hypothalamus.

A randomized trial comparing clozapine and typical neuroleptic drugs in non-treatment-resistant schizophrenia

Clozapine has been shown to be superior to typical neuroleptic drugs for treating positive symptoms in treatment-resistant (TR) schizophrenia. Long-term data from randomized clinical trials comparing clozapine with typical neuroleptics in non-TR schizophrenia are rare. We previously reported that clozapine was superior to typical neuroleptic drugs in some domains of cognition in recent onset non-TR schizophrenia. We now present data on psychopathology and quality of life from this randomized, flexibly dosed, 24-month study of clozapine vs. typical neuroleptics in non-TR schizophrenia patients. Both treatments produced significant improvement in measures of psychopathology, quality of life, and global function, with minor exceptions. There was no difference in extrapyramidal side effects between the patients treated with clozapine or typical neuroleptics. However, significantly more relapse/rehospitalization drop-outs occurred in the typical neuroleptic group. Two patients treated with typical neuroleptics, but none treated with clozapine, became non-responsive to treatment. Clozapine was associated with significantly greater weight gain. Clozapine and typical neuroleptic drugs appear to produce equivalent improvement in psychopathology in patients with non-TR schizophrenia. Clozapine may be more effective than typical neuroleptics for treatment retention and prevention of relapse, but it produces more severe metabolic side effects. These considerations should be taken into account in decisions of how best to utilize clozapine in the treatment of schizophrenia.