Dopamine metabolism and disposition in schizophrenic patients. Studies using debrisoquin.

Debrisoquin sulfate, a monoamine oxidase inhibitor that does not enter the brain, was administered to 23 schizophrenic subjects. Plasma, cerebrospinal fluid (CSF), and urine samples were obtained before and during debrisoquin administration and were assayed for their content of norepinephrine and dopamine metabolites, ie, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and dihydroxyphenylacetic acid. The severity of the patient's schizophrenic symptoms was also assessed with several types of rating scales. During debrisoquin administration there were significant reductions in plasma, urine, and CSF MHPG levels. Regression analyses suggested that the reduction in CSF MHPG level was probably due to the reduction in plasma MHPG level, which contributes to the CSF MHPG pool. Debrisoquin administration was not associated with changes in CSF HVA level, although it did produce marked reductions in plasma and urinary HVA and dihydroxyphenylacetic acid levels. Significant correlations between plasma and CSF concentrations of HVA were noted during, but not before, debrisoquin administration. Before debrisoquin administration there were trends toward positive relationships between symptom severity and plasma HVA concentrations, which became stronger and statistically significant during debrisoquin administration. These data suggest that debrisoquin may be used as a research tool to create a condition in which measures of HVA in peripheral body fluids reflect dopamine system function and metabolism within the central nervous system.

Studies of catecholamine metabolism in schizophrenia/psychosis--II.

Acutely psychotic schizophrenic patients were maintained on debrisoquin (DBQ) throughout 5 weeks of treatment with haloperidol. Treatment with haloperidol caused initial increases in urinary homovanillic acid (HVA) output that returned toward baseline by the 5th week. During haloperidol treatment, plasma levels of HVA tended to decrease, concurrent with increased renal clearance of HVA. Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and urinary MHPG output both decreased over the course of treatment. The differences in HVA and MHPG metabolism suggest differential effects of treatment on dopamine and norepinephrine systems. Neuroleptic treatment also abolished the marked morning decreases in plasma HVA concentrations (reported in part I).

Studies of catecholamine metabolism in schizophrenia/psychosis--I.

Acutely psychotic schizophrenic patients not taking antipsychotic medications and control subjects were studied before and during treatment with debrisoquin (DBQ), an inhibitor of monoamine oxidase, which does not penetrate into brain. Homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in plasma, urine, and cerebrospinal fluid (CSF). Significant differences between patients and control subjects were more easily discerned during treatment with DBQ. In patients, HVA was increased in plasma but not in urine or CSF, although MHPG was increased in all three fluids. There were many significant correlations between plasma MHPG and HVA levels and clinical ratings of psychoticism. Plasma MHPG correlated positively with both the severity of positive and negative symptoms and plasma HVA correlated only with positive symptom severity. These data suggest that both dopamine and norepinephrine (NE) metabolism are disturbed in acutely psychotic schizophrenic patients; disturbed NE metabolism may relate to negative symptoms as well.

Effects of debrisoquin on CSF and plasma HVA concentrations in man.

Data from animal studies indicate neuroleptic drugs act via their properties as antagonists of CNS dopamine (DA) receptors and this finding has led to the suggestion that alterations in CNS DA neuronal function are associated with psychotic disorders. Clinical investigations of this hypothesis, however, have been hindered by the lack of the availability of a direct and relatively easily obtained index of CNS DA neuronal activity. The work reported here was aimed at the development of such an index. Using a double blind design, human male subjects were given either placebo or debrisoquin, which is a monoamine oxidase inhibitor which does not penetrate brain. On the baseline day (no debrisoquin) and after 6 and 13 days of drug administration blood samples were obtained. In addition, for some patients CSF specimens were obtained via lumbar puncture on the baseline day and after 13 days of drug administration. It was found that debrisoquin produced a highly significant decrease in plasma homovanillic acid (HVA) concentrations whereas the concentrations of HVA in CSF were unchanged. In addition, it was found that the correlation between CSF and plasma HVA prior to debrisoquin was non-significant (r = 0.39, p = N.S., N = 10) whereas after 13 days of debrisoquin treatment the correlation was highly significant (r = 0.95, p less than .01, N = 7). These findings suggest that the administration of debrisoquin produces a situation in which plasma HVA reflects CNS HVA production, and as such debrisoquin may be a useful tool for the clinical investigator who is interested in studying relationships in human subjects between CNS DA neuronal system function and psychopathological states or other disorders which may be mediated via brain DA systems.

Cerebrospinal fluid HVA, central brain atrophy, and clinical state in schizophrenia.

In 16 patients with chronic schizophrenia, cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA) showed a significant negative correlation with computed tomographic measures of brain third ventricle size. Clinical state during a drug-free period was also significantly correlated with CSF HVA level, but not with third ventricle size when the effect of CSF HVA was partialed out. The authors propose that these findings may reflect an atrophic process involving structures around the third ventricle and a decrease in dopaminergic activity.

Antipsychotic prescribing patterns in the Texas prison system.

Although prison inmates are reported to exhibit elevated rates of psychotic disorders, little is known about antipsychotic pharmacotherapy in correctional settings. Therefore, the purpose of this study is to describe antipsychotic prescribing patterns in one of the nation's largest prison systems. The study population consisted of 3,750 Texas Department of Criminal Justice (TDCJ) inmates diagnosed with schizophrenic disorders, nonschizophrenic psychotic disorders, or both. In 1998, among inmates diagnosed with schizophrenic disorders, 14.6 percent were prescribed atypical antipsychotic agents, and 85.4 percent were prescribed typical antipsychotic agents. Among inmates diagnosed with nonschizophrenic psychotic disorders, 89.3 percent were prescribed typical antipsychotic agents, while 10.7 percent were prescribed atypical antipsychotic agents. Black males and females were prescribed atypical antipsychotic agents less frequently than their counterparts. Understanding such prescribing patterns is integral to the efficient and cost-effective planning of correctional mental health care.

Treatment outcome for substance misuse patients with personality disorder.

Treatment outcome was compared for three groups of patients in a chemical dependency unit--14 patients with personality disorder, 16 patients with traits of personality disorder, and 34 patients with no personality disorder. Patients with personality disorder were as likely as other patients to complete the 4-month aftercare program and to maintain abstinence while in the aftercare program.

Fluoxetine and desipramine in major depressive disorder.

The efficacy and safety of fluoxetine and desipramine were compared in a 6-week double-blind, parallel group study of patients with major depression. Twenty-five were studied while hospitalized for treatment, and 33 were studied as outpatients. Improvement on the Hamilton Rating Scale for Depression was significant for both treatments from week 1 through the end of the study and did not differ between the two treatments at any week. Overall, 64% of fluoxetine-treated patients and 68% of desipramine-treated patients had at least a 50% reduction in Hamilton Depression score. We assessed whether improvement relatively early in treatment was predictive of categorical response at 6 weeks. Among fluoxetine-treated patients, but not desipramine-treated patients, the week 3 change in the Hamilton Depression mood item was significantly predictive of the response at 6 weeks. Patients treated with fluoxetine had significantly fewer side effects than those treated with desipramine. Desipramine, but not fluoxetine, caused a persistent increase in heart rate. The results suggest that early signs of response to fluoxetine are not dependent on achieving steady-state levels of the drug.