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Overview: maintenance therapy in psychiatry: I. Schizophrenia.

Hospital psychiatry has evolved from long-term "treatment" programs that were primarily custodial to the successful pharmacological treatment of acute psychotic episodes. Unfortunately, many patients still return to the hospital with relapses. This so-called revolving door syndrome draws attention to the critical importance of preventing as well as treating acute episodes. In the first part of this overview, the author reviews the clinical literature on prophylactic treatment of schizophrenia with maintenance antipsychotic drugs. The second part will review the literature on prophylactic treatment of affective disorders with lithium and tricyclics. In the opinion of the author these drugs provide the potential for truly preventive psychiatry.

Antipsychotic Agents

Cyclophosphamide (NSC-26271) maintenance therapy after a second remission of childhood acute lymphoblastic leukemia: comparative clinical trial (standard dose versus intermittent high dose versus cyclophosphamide plus cytosine arabinoside (NSC-63878)).

Children with acute lymphoblastic leukemia who had experienced only one relapse were reinduced into remission using a 6-week induction course of prednisone and vincristine. One hundred fifty-one children who achieved a second complete marrow remission were randomly assigned to one of three cyclophosphamide treatment groups for maintanence. Forty-one children received standard-dose cyclophosphamide (3 mg/kg/day), 55 received intermittent high-dose cyclophosphamide (10 mg/kg/day for 4 days out of 14), and 55 received a combination of oral cyclophosphamide (3 mg/kg/day) plus cytosine arabinoside (3 mg/kg/week im). The standard-dose cyclophosphamide regimen resulted in a remission maintenance time of 109 days and was the least toxic of the three maintenance regimens. Giving cyclophosphamide on an intermittent high-dose schedule or combining it with cytosine arabinoside did not increase the remission maintanence time (105 days).

Bone Marrow

Maintenance therapy of adult acute nonlymphoblastic leukemia: an argument against the need for central nervous system prophlyaxis.

The need for prophylactic therapy of the central nervous system in adult acute nonlymphoblastic leukemia has been suggested but no proven. Over a 4-year period from January 1973, to December 1976, we have maintained 40 patients achieving complete remission on a regimen consisting of monthly courses of Cytosine Arabinoside and 6-thioguanine. Twenty patients remain in remission with a predicted median remission duration for the entire group of 14.5 months. Thirty nine of the patients did not have central nervous system leukemia at diagnosis, and only one of these patients (2.6%) has had remission tenance regimen there is little need for central nervous system prophylaxis in adult acute nonlymphoblastic leukemia.

Adolescent

Plasma quantitation of warfarin and warfarin alcohol by gas chromatography chemical ionization mass spectrometry in patients on warfarin maintenance therapy.

A quantitative method has been developed to measure plasma concentrations of warfarin and warfarin alcohol. The analytical procedure uses deuterated analogues as internal standards, and the technique of selected ion monitoring following gas chromatography methane chemical ionization mass spectrometry of the 4'-methyl ethers of warfarin and warfarin alcohol. Concentrations of warfarin and warfarin alcohol have been measured in plasma samples from 43 patients maintained on chronic warfarin therapy and compared with the 'apparent warfarin' concentration as measured by a fluorometric procedure. The study demonstrated a high degree of correlation between the gas chromatography mass spectrometric derived sum of the individual concentrations of warfarin and warfarin alcohol, and the 'apparent warfarin' concentration determined from a spectrofluorometric assay.

Chromatography, Gas

Bioavailability of three commercial sustained-release tablets of quinidine in maintenance therapy.

The bioavailability of three quinidine formulations was estimated during a dosing interval at steady state following their administration in 12 selected patients in accordance with a Latin-square 3 x 3. Each subject received the three dosage forms as two tablets every 12 hr for 6 days. Blood and urine samples were taken on the 7th day during the regular 12-hr dosing interval. Unchanged quinidine was determined by a reported spectrofluorometric procedure. The total fluorescence of plasma quinidine and metabolites also was monitored. The data obtained indicate that one dosage form gave a high peak level followed by a fall in the concentration. The two other forms presented a relatively lower peak followed by a plateau and then a decline. The differences between the dose-corrected values of Cp,max were statistically significant. Secondary effects were observed particularly with one dosage form and could be related to the high Cp,max value and/or the high percentage of quinidine liberated rapidly in the GI tract. Blood and urinary data indicated an equivalent degree of absorption. The dissolution behavior of the formulations and their absorption data suggest that there is a correlation between the quantity dissolved at 30 min and Cp,max.

Adult

Pharmacokinetics of methadone during maintenance therapy: pulse labeling with deuterated methadone in the steady state.

A technique is presented for study of steady state kinetics of methadone using pulse labeling with deuterated methadone (d3) and mass fragmentography to measure both unlabeled and labeled methadone in blood. Seven subjects maintained on methadone for at least 10 months were admitted to a closed metabolic ward. The daily dose of unlabeled methadone (d0) was substituted by one dose of methoadone-d3 and plasma levels of methadone-d0 and methadone-d3 were followed for 48 h using a precise (SD +/- 5%) and sensitive (30 pmol/ml) mass fragmentographic technique. Plasma half-lives (T1/2) for both methadone-do and methadone-d3 were calculated from samples obtained 8--24 H following the dose of methadone-d3. The t1/2 of oral methadone-d3 was shorter (22 +/- 2 h) than that of methadone-d0 (52 +/- 20 h). The same pattern was observed after intravenous administration. The results indicate multiple pools of methadone in the body.

Administration, Oral

Disopyramide plasma levels in cardiac patients on maintenance therapy.

The antiarrhythmic agent disopyramide, in a dosage of 200 mg/8 h, was given to 7 cardiac patients. The drug was fairly rapidly absorbed, and the mean peak plasma concentration (3.5 microgram/ml) was measured 1 h after administration of the first dose. The mean biological half-life (7.8 h) was slightly prolonged compared to that reported in normal volunteer subjects. Mean steady state plasma concentrations within the therapeutic range were attained 24--32 h after the start of medication. The fluctuations in the plasma levels were in the order or 30 percent; however, a wide spread of the values was observed. The drug was well tolerated.

Adult

Controlled trial of synthetic D-penicillamine and prednisone in maintenance therapy for active chronic hepatitis.

In view of promising, but uncontrolled, reports of the use of D-penicillamine in active chronic hepatitis, a randomised, prospective, controlled trial of this drug against prednisone was carried out. Of the 35 patients entered, 18 received D-penicillamine (increasing to 1-2 g daily) and 17 prednisone (15 mg daily). In all patients the disease had already been brought under biochemical control with corticosteroids. During the first year of the trial, the treatment of nine patients in the D-penicillamine group was discontinued (two because of lack of disease control and seven because of side-effects) compared with six patients in the prednisone group (four because of lack of disease control, one because of side-effects, and one because of the development of carcinomatosis. Detailed statistical analysis of the liver function tests in the patients remaining in the trial at the end of the year showed no significant differences. D-penicillamine is associated with a higher frequency of side-effects than is prednisone. However, in some patients it is as satisfactory as prednisone in keeping the disease under control.

Adolescent

The expectation of outcome from maintenance therapy in chronic schizophrenic patients.

The results from a prospective follow-up study of a group of schizophrenic patients suggest that a significant proportion (41 per cent) are likely to relapse during a two-year period despite the prescription of long-acting injectable neuroleptic drugs. Some will relapse because of a failure of the regime, but others (32-37 per cent) because the pharmacological protection of these drugs would appear to be less effective in certain patients. Even with the major advantages of the long-acting injectable neuroleptics over oral medication, the schizophrenic patient population remains a group with a high incidence of psychiatric and social morbidity which continues to require the full resources of both the hospital and community services.

Brief Psychiatric Rating Scale

Weight gain and edema on methadone maintenance therapy.

Methadone HCl is currently legally dispensed to approximately 80,000 heroin addicts in the United States. It is widely heralded as being virtually free from other than narcotic side effects. This report describes in detail three patients with massive fluid gain in a population of 420 addicts treated at the Hope Center methadone program in Tucson, Arizona. In no patient was there a prior history of edema, and an intensive search failed to reveal a cause for the swelling. Weight gain uniformly began 3 to 6 months after initiation of methadone or a sharp increase in the dosage, and in all three patients during periods when they sharply reduced or discontinued methadone, edema was resolved associated with a concomitant loss of weight.

Adult