Shigeru Morishita

Effect of the tricyclic antidepressant desipramine on protein kinase C in rat brain and rabbit platelets in vitro

Abstract  Protein kinase C (PKC), which participates in cellular responses to various stimuli such as hormones, neurotransmitters and growth factors, is essential for cell proliferation and differentiation. Desipramine, which is a tricyclic antidepressant, inhibited PKC activity in concentrations starting from 0.1 mmol/L in rat brain and its inhibitory effect on PKC activity did not involve competitive inhibition with calcium. However, rabbit platelets incubated with desipramine showed a biphasic dose—response change in PKC activity in vitro. The stimulatory effect of desipramine on PKC activity in rabbit platelets was observed over a concentration range of 0.5–2.0 mmol/L, and an inhibitory effect on PKC activity in platelets began to be seen at a concentration of 3.0 mmol/L desipramine. The stimulatory effects of desipramine and calcium on PKC activity in platelets appear to be occurring by the same mechanism. Several lines of evidence indicate that neurotransmitter uptake is linked to PKC activation. The present study supposes that the inhibitory effect of desipramine on neurotransmitter uptake may, at least in part, be associated with its inhibitory or stimulatory effect on PKC.

Effects of tricyclic antidepressants on protein kinase C activity in rabbit and human platelets in vivo.

BACKGROUND The purpose of this study was to examine the effects of tricyclic antidepressants (TCA) on protein kinase C (PKC) in vivo. METHODS PKC activity in rabbit and human platelets in vivo was measured after administration of TCA and in controls. RESULTS Administration of TCA increased PKC activity in rabbit and human platelets in vivo. CONCLUSIONS It has been reported that activation of PKC mediates inhibition of neurotransmitter uptake and down-regulation of beta-adrenergic receptor. We suppose that TCA-induced activation of PKC may be associated, at least in part, with the mechanism of TCA. LIMITATIONS Other signal transduction systems, such as those of protein kinase A, protein kinase G, and cyclic-AMP, also affect neurotransmitter uptake and/or down-regulation. In this study, the relationship between the TCA-PKC system and other signal transduction systems was not investigated.

Clonazepam as a therapeutic adjunct to improve the management of psychiatric disorders

Abstract Clonazepam, which is a benzodiazepine structurally related to chlordiazepoxide hydrochloride, diazepam and nitrazepam, has been available for the treatment of seizure disorders in the USA since 1976 and in Japan since 1981. Increasingly, clonazepam has been used in the treatment of a variety of psychiatric disorders. Six representative case studies are presented and specific guidelines for the use of clonazepam are discussed.

Different effect of desipramine on protein kinase C in platelets between bipolar and major depressive disorders

Protein kinase C (PKC) activity was investigated in platelets from affective disorder subjects and healthy volunteers. The PKC activity of platelets incubated with desipramine was determined in vitro. The PKC activity of the major depressive disorder subjects and healthy volunteers was inhibited by desipramine, whereas that of the bipolar disorder subjects showed both inhibition and activation. In addition, the base PKC activity incubation with antidepressants of the major depressive disorder patients was significantly higher than of the bipolar disorder patients. These preliminary results suggest that the function of PKC may, at least in part, be associated with the mechanism of affective disorder.

Clonazepam in the treatment of prolonged depression

BACKGROUND The purpose of this paper was to examine the optimal adjunctive dose of clonazepam for the treatment of prolonged depression. METHODS Sixty nine patients with prolonged depression were enrolled in an open trial over a 4 week period during which clonazepam was added to their medication. RESULTS A daily dose of 3.0 mg clonazepam as augmentation was significantly more effective than doses of 1.5 mg and below. Most of the improved patients showed a rapid onset of action within 2 weeks, and side effects were not severe. CONCLUSION A daily dose of at least 3.0 mg clonazepam as augmentation of ongoing antidepressant treatment should be considered in prolonged depressive patients with suboptimal improvement. LIMITATIONS The effect on clonazepam alone on prolonged depression was not established, and its effect of on severe depression is unknown. High dose treatment was not carried out in this study.

The clinical use of milnacipran for depression

We examined the relation between dosage and efficacy, and the predictors of response to milnacipran. There was no difference between 50 and 100 mg dose. However, the 100 mg dose had a faster onset of action than the 50 mg dose. An age and an episode have been predictors of milnacipran.

Clonazepam augmentation of antidepressants: does it distinguish unipolar from bipolar depression?

BACKGROUND The authors compared the effect of clonazepam supplement treatment on unipolar depression and bipolar depression. METHODS A total of 38 protracted depression patients with unipolar depression (n = 19) or bipolar depression (n = 19) were treated with 3.0 mg clonazepam for 4 weeks. RESULTS In the unipolar depression group, 84.2% of the subjects fulfilled the response criteria (at least an 80% reduction in their HDRS score). However, in the bipolar depression group, only 10.5% of them fulfilled these criteria. CONCLUSIONS The difference in responses between the two groups supposes that the underlying abnormality in unipolar depression is not the same as that in bipolar depression. This trial also supposed that clonazepam can play active role in the treatment of protracted depression in patients with unipolar depression. LIMITATIONS This finding was made in an open study, and the effect on clonazepam alone was not established.

The Direct Effect of Lithium and Carbamazepine on Protein Kinase C in Rat Brain

Abstract: The effect of carbamazepine on protein kinase C, which is believed to phosphorylate a number of proteins, was compared with that of lithium in vitro. Lithium did not significantly inhibit the protein kinase C activity in the rat cerebral cortex in vitro, and 0.01 mM of carbamazepine had no inhibitory effect on the enzyme activity. However, inhibition did begin to appear at 1 mM. The Lineweaver‐Burk plot of carbamazepine was similar to the competitive inhibition pattern. The data suggest that lithium and carbamazepine as mood stabilizers have the same effect on the manic state, but their mechanism reducing mania may differ in the cell signal transduction pathways.

Suitable dose and duration of fluvoxamine administration to treat depression

Abstract The purpose of the present paper was to determine the suitable dose and appropriate trial duration of fluvoxamine to treat for depression. A retrospective cohort analysis was performed among depression patients who were treated in the Department of Psychiatry, Kawasaki Medical School Hospital, Kurashiki, Japan, in 2000. A total of 72 patients received fluvoxamine to treat depression. The dose–response was compared and the initial significant clinical action was examined. The percentage showing improvement after receiving a high daily dose (100–150 mg) of fluvoxamine was 73.7%, but that showing improvement on a low daily dose (50–75 mg) was 47.1%. A significant difference between the two groups was seen on Kaplan–Meier analysis and log–rank test (χ2 = 4.814; d.f. = 1; P = 0.0282). The cumulative percentage of responder patients was more than 80% at the end of a 6‐week period. Fluvoxamine is recommended at a daily dose of 100 mg or 150 mg as the initial dose. If a patient does not show improvement by the end of 6 weeks the treatment regimen of fluvoxamine should be altered.

Characteristics and response to milnacipran in painful depression

The quality of the pain experienced in depression and the improvement of pain with depression after treatment with milnacipran was studied. Thirty-three patients with pain combined with depression were studied to analyse the quality of the pain. The quality of the pain was classified into two kinds of pain (surface region pain and deep region pain) using fuzzy theory. A group of 25 patients treated with milnacipran was studied to test the improvement of pain in depression. An analysis of the quality of the pain in depression showed that it was primarily deep region pain, and that this kind of pain was improved with milnacipran treatment. Of 25 patients treated with milnacipran, 21 (84%) responded with a greater than 80% reduction in their pain syndrome. The mechanisms responsible for deep region pain and depression may be associated. Milnacipran appears to be a valuable treatment for patients with pain and depression.