Shozo Aoki

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.

Comparison of Early- and Late-Onset Rapid Cycling Affective Disorders: Clinical Course and Response to Pharmacotherapy

This study compared the clinical course and response to pharmacotherapy of patients with rapid cycling affective disorder (RCAD). A retrospective study was conducted on outpatients with affective disorder from 1991 to 1992 at Okayama University Medical School to select cases of RCAD. The subjects were 35 patients who fulfilled DSM-III-R criteria for mood disorder and had experienced at least four episodes of illness during the previous year. The subjects were divided into two groups according to their age at the first phase of affective illness: an early-onset group, consisting of patients aged 25 years or younger, and a late-onset group, consisting of patients aged 26 or older. There were 14 patients in the early-onset group and 21 in the late-onset group. Both the mean duration from onset to rapid cycling and the mean duration of each phase were shorter in the early-onset group than in the late-onset group. There were no significant differences between the groups in period of remission, character of the first episode, heredity, or thyroid function. Lithium carbonate therapy was more effective for reducing manic symptoms in the late-onset group than in the early-onset group, without maintaining a prophylactic effect in either group, whereas carbamazepine was more effective in the early-onset group. Antidepressants used in the depressive phase had a tendency to be more effective in the late-onset than in the early-onset group. However, rapid cycling induced by antidepressants was more evident in the late-onset than in the early-onset group. These findings supported the differentiation of RCAD into two groups based on age at onset, the early-onset group showing a rapid cycling course at an early stage and a good response to carbamazepine, the late-onset group having a relatively long disease duration until the appearance of a rapid cycling course and a good response to lithium carbonate in the manic phase and to antidepressants in the depressive phase.

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.

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.

Delusions and hallucinations in patients with borderline personality disorder.

Abstract  To clarify the nature of delusional and hallucinatory symptoms in borderline personality disorder (BPD), the authors investigated five patients with BPD who developed those symptoms, and discussed their duration, recurrence, types of variants and relation to the situation. The duration of these symptoms tended to vary widely, although six of 11 episodes lasted more than 7 days. Episodes tended to recur in all patients two or three times. Each episode could be classified into three types of delusions and hallucinations, such as delusions without hallucinations, complicated delusion and hallucination, and hallucinations without delusion. Delusions without hallucination occurred a total of four times in two patients and had a tendency to occur when the patient confronted personal adversities. They projected their feelings directly toward the person concerned. A complicated delusion and hallucination was observed three times in two patients. This type of symptom also tended to occur at the time of interpersonal problems but the patients attitude was more passive. Hallucination without delusion occurred a total of four times in three patients. This symptom tended to occur when the patient avoided an interpersonal relationship. In this case the patients isolated themselves from others and withdrew.

Age-dependent and region-specific alteration of parvalbumin neurons and perineuronal nets in the mouse cerebral cortex

&NA; Cognitive function declines with age. Such function depends on &ggr;‐oscillation in the frontal cortex. Pyramidal neurons, and the parvalbumin‐expressing interneurons (PV neurons) that control them, are important for the generation of &ggr;‐oscillation. The mechanism by which cognitive function declines is unclear. Perineuronal nets (PNNs) mainly surround the soma and proximal dendrites and axon segments of PV neurons in the cerebral cortex. Previous evidence indicates that PNNs inhibit neural plasticity. If this is true, an increase in the number of neurons surrounded by PNNs or in the thickness or density of the PNNs around neurons could decrease plasticity in the cortex. To determine if an aging‐related change in cortical PNNs occurs, we examined the influence of aging on PV neurons and whether Wisteria floribunda agglutinin‐positive PNNs differ depending on the cortical area. The results showed that the number of PV neurons/mm2 did not change in many areas of the cortex as mice aged. In contrast, the number of neurons in the sensory cortex surrounded by PNNs increased as mice aged. Thus, with age, PNN density increases in some cortical areas but not in others. In addition, the expression level of PV protein in PV neurons decreased with aging in the whole cortex. We suggest that decreased expression of PV protein impairs fast spiking in PV neurons. We propose that PNNs surround more neurons as age increases. This aging‐related increase in PNNs decreases plasticity in the cerebral cortex and reduces cognitive function. The first step in investigating this proposal would be to determine if PNN density increases with age. HighlightsPV neuron density remained unchanged with aging in numerous cortical areas.WFA‐positive PNN density increased with aging in the sensory cortex.The expression level of PV protein in PV neurons decreased with aging.The PV soma area was reduced with aging in numerous cortical areas.

Optimal Dosing of Risperidone and Olanzapine in the Maintenance Treatment for Patients With Schizophrenia and Related Psychotic Disorders: A Retrospective Multicenter Study

Objectives This study aims to determine the optimal tolerability dose ranges of risperidone (RIS) and olanzapine (OLZ) administered during schizophrenia maintenance phase. Methods Two-year continuation rates of prescription at discharge were examined using a retrospective cohort study method. Adult patients with schizophrenia and related psychotic disorders, receiving antipsychotic monotherapy with RIS or OLZ at discharge, were included. The primary outcome measures were the time to treatment discontinuation and 2-year continuation rates at 4 modal dose ranges of each drug. We estimated the optimal tolerability dose ranges by comparing the continuation rates at various modal doses. Results Of 648 patients, 344 received RIS and 304 received OLZ. The RIS 2-year continuation rates at 4 daily modal dose ranges were significantly different (0.5–2.5 mg: 46.0%, 3.0–5.0 mg: 40.0%, 5.5–7.5 mg: 30.0%, and 8.0–10.0 mg: 28.0%), with the difference favoring RIS at lower doses (0.5–5.0 mg) more than higher doses (5.5–10.0 mg). In contrast, there were no significant differences among OLZ 4 modal dose ranges (2.5–7.5 mg: 49.1%, 10.0–15.0 mg: 42.6%, 17.5–22.5 mg: 40.9%, and 25.0–30.0 mg: 39.0%). The time to treatment discontinuation significantly favored OLZ over RIS. However, it did not significantly differ between RIS and OLZ at lower doses. Conclusions It is suggested that the optimal tolerability dose range during maintenance treatment is 0.5 to 5.0 mg/d for RIS and 2.5 to 30 mg/d for OLZ, and that RIS at lower doses is comparable with OLZ at lower doses.

Postnatal development of GABAergic interneurons and perineuronal nets in mouse temporal cortex subregions

In human neuropsychiatric disorders, there are functional and anatomical abnormalities of GABAergic interneurons in each temporal cortex subregion. Furthermore, accumulation of amyloid‐β is observed in the temporal cortex in the early stages of Alzheimers disease. Each subregion of the temporal cortex has an important role in coordinating the input and output of the hippocampus. When subregions of the temporal cortex are impaired, memory and learning ability decrease. GABAergic interneurons control excitatory neurons, forming the cortico‐cortical and cortico‐hippocampal networks. However, in temporal cortex subregions, details of the distribution and developmental processes of GABAergic interneurons and perineuronal nets (PNNs) have not been elucidated. Here we examined the development of GABAergic interneurons and PNNs in mouse temporal cortex subregions. Results indicate that temporal cortex GABAergic interneurons have developmental stages different to those of the primary sensory cortex. In addition, the density of PNNs in the temporal cortex is lower than that in the sensory cortex. Furthermore, we found that the Wisteria floribunda agglutinin‐reactive extracellular matrix molecule is present in the upper level of layer 1 of the temporal cortex. These results support the idea that mouse temporal cortex subregions develop differently from other cortical regions and have region‐specific characteristics after maturation. The present study results suggested that the structure of the temporal cortex is significantly different from the sensory cortex and that temporal cortex may be highly vulnerable to neuropsychiatric and neurodegenerative disorders.