Faculty Bibliography

Reviews 12 studies (1976-1996) on the relationship between clozapine plasma levels and clinical response in patients with treatment-resistant schizophrenia according to methodologic criteria described in the article. The range of clozapine plasma levels appears to be wide e.g., ranging from 200 ng/mL to 450 ng/mL. The target plasma level for the vast majority of patients might be around 250 ng/mL, while higher plasma levels would be accompanied by increasing sedation and other side effects. This finding may mean clinically that patients who have not responded at a plasma level of 250 ng/mL after 6 wks of treatment should be raised to above 420 ng/mL. This strategy will result in increased responsiveness of some patients. Variability in the ratio of plasma level per dose has been great from study to study. The range of oral doses used, which yielded plasma levels associated with clinical response was between 250 mg and 650 mg. This range may represent an estimated optimal mean dose for a vast majority of patients at 6 wks, but individual patient variables need to be considered in determining the final dose.

Reviews studies that have used response to the serotonergic challenge probe metachlorophenylpiperazine (m-CPP) to investigate central serotonin (5-hydroxytryptamine [5-HT]) receptor sensitivity and treatment response prediction in schizophrenia. Results concerning hormonal and other physiologic effects, behavioral effects, and the heterogeneity of behavioral and hormonal responses in m-CPP challenge studies are discussed as well as the blockade of m-CPP response by clozapine and the limitations of the m-CPP paradigm.

Negative symptoms in schizophrenia comprise a psychopathologic and pathophysiologic syndrome which is absent from normal mental function. Renewed interest in negative symptoms has led to the development of better measuring instruments, among which is the Positive And Negative Syndrome Scale (PANSS), which provides a way of measuring and reporting positive and negative symptoms in a balanced and convenient form. A number of strategies are being investigated for treating negative symptoms. Dopamine agonists such as levodopa, amphetamines and bromocriptine have been shown to produce improvements in negative symptoms, although good, well-controlled clinical trials are lacking. Partial dopamine agonists, such as MAR 327, are also currently under investigation and results are expected soon. Tricyclic, selective serotonin reuptake inhibitors and monoamine oxidase antidepressants appear to be able to modify negative symptoms in schizophrenia, although, once again, carefully designed trials are needed. Modification of GABAergic transmission has shown little promise, but the use of glycine to augment transmission at N-methyl-D-aspartate (NMDA) synapses suggests that the strategy may be beneficial. These results also imply that altered glutamate receptor function may be partly responsible for negative symptoms. One strategy that has been shown to have a beneficial effect against negative symptoms is combined serotonin/dopamine antagonism. Clozapine was found to have this profile after its introduction, and the recently introduced antipsychotic, risperidone was developed intentionally to be a combined 5-HT2/D2 antagonist. Both risperidone and clozapine have been shown to be effective against negative symptoms. One problem associated with the assessment of drug effects on negative symptoms, however, is that drugs can act on both primary and secondary negative symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to examine the effect of neuroleptic medication on the factor structure of schizophrenic symptomatology, 517 DSM-III-R schizophrenic in-patients enrolled in a multicenter phase II drug study were evaluated on their pre-existing neuroleptic at screening on the Positive and Negative Syndrome Scale (PANSS) and after a one-week drug-free period. Separate principal components analyses of the PANSS were done at each time point. PANSS total and component scores were assessed for differences utilizing paired t-tests. Both factor analyses confirmed the five factor model (negative, positive, cognitive, excitement and depression components) explaining 51.7 and 56.2% of the variances at each time point. After medication wash-out psychopathology significantly worsened as measured by total PANSS score and by each of the components. The overall worsening of component scores appeared global and uniform, as evidenced by the fact that at washout, the proportion of individual component scores to total psychopathology remained constant for most components. The lack of change of most components in proportion to the psychopathology total is evidence for the stability of these individual psychopathological dimensions of patients while on and off neuroleptics. The results further support the validity of the five-factor model of schizophrenic psychopathology as measured by the PANSS.

Reviews research by the author and others on the Positive and Negative Syndrome Scale (P

Schizophrenic psychopathology is heterogeneous and multidimensional. One of the more fruitful strategies to investigate more homogenous domains of psychopathology has been the positive-negative syndrome approach. However, this approach is unable to address a number of important issues. Most schizophrenics present a mixed syndrome; the criteria for what constitutes a positive and negative syndrome are variable; distinguishing primary from secondary negative symptoms can be difficult. In order to address some of these problems, we propose the introduction of a 5-syndrome model based on a reanalysis of factor-analytic procedures used on 240 schizophrenics assessed with the Positive and Negative Syndrome Scale: A negative, positive, excitement, cognitive and depression/anxiety factor. This 5-factor solution is supported by 4 independent and comparable factor analyses. Data on internal consistency of the 5 factors and on initial validation using demographic and clinical variables are presented

Phencyclidine induces a psychotomimetic state by blocking neurotransmission at N-methyl-D-aspartic acid (NMDA) receptors. In a double-blind, placebo-controlled fashion, 14 medicated patients with chronic schizophrenia were treated with glycine, a potentiator of NMDA-receptor-mediated neurotransmission. Significant improvement in negative symptoms occurred in the group given glycine but not in the group given placebo, suggesting that potentiation of NMDA-receptor-mediated neurotransmission may represent an effective treatment for neuroleptic-resistant negative symptoms in schizophrenia