Jack Hirschowitz

Haloperidol plasma and red blood cell levels and clinical antipsychotic response.

Two investigators have recently suggested therapeutic ranges for plasma haloperidol in the treatment of schizophrenia. An apparent optimal therapeutic range of red blood cell haloperidol as early as day 7 of the drug trial is described in this article. With continued treatment, an optimal plasma haloperidol range for response could be observed by day 14 of treatment. The previously described correlation between response at day 7 and plasma/red blood cell haloperidol ratio was confirmed but was found not to predict response at day 14 of drug treatment in this cohort of DSM-III schizophrenic patients.

Clinical relevance of thiothixene plasma levels.

The authors examined plasma levels of thiothixene and clinical response in 19 DSM-III diagnosed inpatient schizophrenics, using an improved methodology. A significant curvilinear correlation was demonstrated between clinical response and plasma levels for thiothixene (p < 0.02). Optimal clinical response to thiothixene appears to be associated with plasma levels from 2.0 to 15.0 ng/ml (p < 0.05). These findings suggest that laboratory measurement of thiothixene levels may assist in determining the minimum effective dose for individual patients.

Kinetic analysis of platelet monoamine oxidase in chronic schizophrenia

Abstract Km and Vmax values for platelet monoamine oxidase (MAO) were determined in 16 chronic schizophrenics and 18 controls utilizing three substrates, tyramine (TYR), benzylamine (BZ), and phenylethylamine (PEA). In the chronic schizophrenics decreased Km and Vmax values were found for TYR and BZ but not PEA. When prior neuroleptic drug exposure was considered, a trend toward lower kinetic parameters was found in schizophrenics with a history of prior neuroleptic usage. We conclude that platelet MAO activity is, in chronic schizophrenics, both quantitatively reduced and qualitatively different from control enzyme. We suggest that the measurement of Km in addition to the measurement of Vmax may be a useful biological marker for chronic schizophrenia providing that the appropriate substrates are employed.

Combined thioridazine and desipramine: early antidepressant response

The authors examined the effect of combined thioridazine (THI) and desipramine (DMI) for an early antidepressant response in 14 patients with a DSM III diagnosis of major depressive disorder with melancholia. All 14 patients received a constant dose of 200 mg DMI/day for 21 days while 7 patients received 100 mg THI/day for only the first 7 days. A significantly greater improvement from baseline Hamilton Depression Scale (HDS) scores occurred during the first 7 days in patients receiving both drugs. Possible mechanisms for this early antidepressant action are discussed.

Membranes, Methylation and Lithium Responsive Psychoses

Data are presented showing that the erythrocyte ghost membranes of lithium-responsive and non-responsive schizophrenic-like patients are different from control membranes. In both groups of patients there was a significant decrement of phosphatidylcholine (PC) which was largely compenstated for by an increase in sphingomyelin. The decrement in PC may in part be associated with a decrease in phospholipid methylation which converts phosphatidylethanolmine (PE) to PC. Interestingly, in the lithium-responsive but not the non-responsive patients, lithium stimulates methylation activity. This stimulation may affect a variety of membrane functions, e.g. adenyl cyclase activity, which would be involved in lithiums therapeutic actions.

Platelet monoamine oxidase activity in the psychoses: Relationship to symptoms and lithium response

The kinetics of platelet monoamine oxidase (MAO) were studied in 100 psychotic and manic patients and 36 controls. No relationship was found between MAO activity and response to lithium in the schizophrenic-like illnesses. However, the data do suggest there is an association between enzyme affinity (Km) and specific symptom clusters. Patients with the low Km variant of platelet MAO are enriched in depressive symptoms, while those with the high Km variant are enriched in manic symptoms.

Fluphenazine plasma levels and clinical response

Plasma levels of fluphenazine and clinical response were examined in 19 inpatient schizophrenics (DSM-III diagnoses) using a constant dose, steady-state methodology. A significant curvilinear correlation was demonstrated between clinical response and steady-state plasma levels of fluphenazine (p less than .05). A therapeutic range of plasma fluphenazine is suggested in the range of .13-.70 ng/ml. The lowest plasma level detected (.13 ng/ml) appeared to be well within the therapeutic range. The 9 patients with plasma fluphenazine levels in this range demonstrated a mean clinical improvement of 59% compared to 34% for patients with plasma levels above .70 ng/ml (p less than .01).

Heterogeneity of the psychoses: II. Neuro-degenerative psychosis

cesses of plasma 3-methoxy-4-hydroxy-phenylglycol (pMHPG). The dopamine psychosis patients were diagnostically (DSM-III) heterogeneous: 40% schizophrenia, 13% schizophreniform disorder, and 47% affective psychoses. SADS symptom clusters did not differentiate the dopamine psychotics from other psychoses. A superior antipsychotic response by the dopamine psychotics was evident by day 4 following initiation of antipsychotic drug. ANCOVA with baseline +BPRS scores as the covariate revealed superior antipsychotic response discernible by the 4th day of drug treatment (F = 10.1, p < 0.007). Plasma haloperidol levels did not differ between the two groups (4.1 + 3.0 vs. 4.7 + 2.4 at day 7; 7.1 _+ 6.7 vs. 7.3 + 2.9 at day 14). From day 10-28 of drug treatment, the slopes of response were essentially parallel in the highand low-pHVA groups. The difference in response rates during the first 7 days of treatment set the course for the remainder of the treatment period. The pedigrees of dopamine psychosis probands exhibited additional members with psychotic disorders. It may be necessary to segregate pedigrees by markers of the underlying disease (such as pHVA) for the next generation of genetic linkage studies in the psychoses.

Physostigmine and lithium response in the schizophrenias

Conflicting reports concerning cholinomimetic-induced reduction of schizophrenic symptoms prompted the authors to study such changes in schizophrenic symptoms following physostigmine infusions in subgroups of patients with schizophrenic-like illness. These subgroups were defined by the presence or absence of antipsychotic response during a 2-week trial of lithium alone after physostigmine infusion. Patients who showed significant but temporary improvement in their thinking disturbance on serial Brief Psychiatric Rating Scale scores following physostigmine infusion subsequently responded to lithium; patients who failed to improve following physostigmine also failed to respond to lithium. The authors suggest that some schizophrenic-like illnesses may be biologically similar to mania both with respect to physostigmine and lithium-induced changes in symptomatology.