A preliminary double-blind controlled study on the prophylactic effect of carbamazepine on recurrent manic-depressive psychotics was conducted with 22 patients using an inert placebo in ten subjects as a control drug. Carbamazepine in the dosage of 200-600 mg was administered for 1 year. Among the 22 carbamazepine subjects, carbamazepine was found to be effective in 60% of the cases and inert placebo in 22.2% (U-test, P less than 0.10). It is suggested that carbamazepine is a useful drug for the prophylaxis of manic-depressive illness.

A multi-institutional study comparing the antimanic effect of carbamazepine (CBZ) and lithium carbonate (Li) was performed using a double-blind group comparison design in a series of 105 patients with bipolar disorders. CBZ and Li were given for four weeks using a fixed-flexible method at an equipotent dose ratio of 1:1, starting from an initial dosage of 400 mg with a maximum dosage of 1200 mg. The final global improvement rate, based on the number of cases showing moderate to marked amelioration of manic symptoms, was 62% in the CBZ group and 59% in the Li group, with no significant difference being found between the two groups. Incidence of cutaneous side-effects was significantly higher in the CBZ group. The mean daily dosage and serum level of CBZ in the fourth week were 674 +/- 239 mg and 7.3 +/- 2.4 micrograms/ml respectively; these were within the therapeutic range. The daily dose and serum level of Li, however, were 710 +/- 239 mg and 0.46 +/- 0.22 mEq/l, and the Li level seemed to be too low to compare its therapeutic effect with that of CBZ. Prior to the present study, approximately 80% of the patients in both groups had been receiving antipsychotic medication, equivalent to 8.0 mg of haloperidol on average, without favorable response. This medication was maintained unchanged during treatment. While the shortcomings of the present study limit the interpretation of the data, it may be suggested that the usefulness of CBZ as a drug for the treatment of manic states is comparable to that of Li.

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A multi-institutional double-blind study comparing the therapeutic effect of adjunctive carbamazepine and placebo with standard neuroleptic treatment was performed on 162 patients with DSM-III diagnosis of schizophrenic (n = 127) or schizoaffective disorders (n = 35) who had excited states or aggressive/violent behavior that responded unsatisfactorily to neuroleptic treatment. The patients participated in a 4-week trial of carbamazepine plus neuroleptics (n = 82) or placebo plus neuroleptics (n = 80). The sum of patients with marked and moderate improvement was modestly larger in the carbamazepine group (48 vs. 30%, P less than 0.05). There was no significant difference between the carbamazepine and placebo groups in the changes of total BPRS scores, although the carbamazepine group showed more improvement on the items suspiciousness, uncooperativeness and excitement. The results suggest that carbamazepine, when used in combination with neuroleptics, is a useful drug for the treatment of excited states of patients with schizophrenic and schizoaffective disorders.

The concentrations of amitriptyline (AMT) and its demethylated metabolite nortriptyline (NRT) in the serum and in specific brain regions were determined periodically after acute or chronic administration of 20 mg/kg of AMT in rats. Both AMT and NRT declined from the serum in a biexponential manner and were eliminated monoexponentially from the brain regions, with no significant difference in elimination among the eight brain regions examined. In the brain, both AMT and NRT were unevenly distributed after chronic administration, whereas an even distribution was observed after acute administration. The AUCbrain:AUCserum ratio of AMT was higher than that of NRT, indicating greater transport of AMT into the brain regions. The AUCAMT value in the serum increased 1.6 times after chronic administration, whereas no significant changes were observed in the brain regions. The AUCNRT values increased 9.0 times in the serum and 6.8 times in the brain, with the increase in the serum being greater. These results suggest inhibited distribution of the drugs into the tissues, including the brain regions, and enhanced metabolism of AMT.

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Although the etiology of manic-depressive psychosis is still obscure, its genetic study and the efficacy of somatic treatments such as electroconvulsive shock and psychotropic medication in manic-depressive psychosis would seem to suggest that depression might have a somatic causes). Imipramine type drugs and monoamine oxidase inhibitors (MAOI) affect brain monoamines-catecholamines and 5-hydroxytryptamine (serotonin)-, and the monoamine metabolism has come to be regarded by many workers to have an essential importance in affective disturbances6J8.31). Jensen") and others*) reported that reserpine reduced monoamines in the brain, and that about 15% of hypertensive patients treated with reserpine for long periods of time developed severe depression.Strom-Olsen and weil-Malherbe34) and Shinfuku et al.30) have found higher urinary excretion of norepinephrine in the manic than the retarded depressed phase of the disease. Based on those findings Schildkraut26.27) proposed the catecholamine hypothesis of affective disorders. The hypothesis is as follows: depressions are associated with an absolute or relative decrease in catecholamines, particularly norepinephrine, available at central adrenergic receptor sites.On the other hand Twarog and Page36) and Woolley and Shaw") gave an attention to the role of serotonin in the central nervous system. Brodie et al.5) emphasized that the tranquilizing action of reserpine is associated with variations in brain serotonin level and not in brain norepinephrine level. Coppen et al.7) found that the urinary excretion of tryptamine in depressive patients was about half of normal and that it returned to normal on clinical recovery. Ashcroft et a1.2) and Dencker et al.11) found that the cerebrospinal fluid in depressive patients contained reduced amounts of 5-hydroxyindolacetic acid (SHIAA), a metabolite of serotonin. Stevens et al.33) demonstrated the presence of a positive correlation between mood and urinary excretion of 5HIAA. However, the amount of urinary 5HIAA is markedly influenced by water and alcohol intakelo.2*). On the metabolism of serotonin in vivo, Hosodal6) reported that, in addition to the pathway to SHIAA, there exist several different metabolic pathways of serotonin leading either to serotonin-o-glucuronite, or 5-hydroxytryptophole etc. Therefore, it is more reliable to determine serum serotonin than the urinary excretion of 5HIAA. No report has been published on the serum serotonin level in manic-depressive