Anri Aoba

Effects of long-term treatment with desipramine on microtubule proteins in rat cerebral cortex

The molecular mechanism of the action of antidepressants beyond the receptor level has not yet been elucidated. We have investigated the effects of long-term treatment with desipramine on the phosphorylation state of microtubule-associated protein 2 (MAP2) and microtubule assembly in the rat cerebral cortex. Phosphorylation of MAP2 was detected by immunoblotting after immunoprecipitation of MAP2 in the soluble fraction. The degree of phosphorylation of serine residues of MAP2 was significantly increased after chronic administration of desipramine without changes in the total concentration of MAP2. Microtubule assembly in crude brain extracts was monitored in terms of changes in turbidity measured at 350 nm using a spectrophotometer. Chronic but not acute treatment with desipramine inhibited microtubule assembly, assayed in the presence of a phosphatase inhibitor, calyculin A, whereas the inhibition was completely nullified in the absence of calyculin A. Desipramine had no direct effect on microtubule assembly in vitro. These results raise the possibility that the changes in the degree of phosphorylation of MAP2 and microtubule assembly represent intracellular modifications involved in functional changes elicited by long-term treatment with desipramine.

Electric convulsive therapy (ECT) increases plasma and red blood cell haloperidol neuroleptic activities

In nine schizophrenic patients (five males and four females) on haloperidol treatment, plasma and red blood cell (RBC) haloperidol neuroleptic activities were measured before and after ECT by radioreceptor assay. Five patients randomly selected from these patients also served as controls on another occasion and neuroleptic activities in plasma and RBC were examined before and after the premedication only. All patients given ECT showed a considerable increase in plasma and RBC haloperidol neuroleptic activities after ECT (% increase in plasma neuroleptic activity, 28-409%; mean + SD, 136 +/- 155%, P less than 0.005, Wilcoxon test; % increase in RBC neuroleptic activity, 11-121%; mean + SD, 59 +/- 40%, P less than 0.005). However, no significant increase was observed for either plasma or RBC haloperidol neuroleptic activity, when patients were examined after premedication only. It was suggested that ECT induced a transient redistribution of haloperidol. It remains to be studied whether this phenomenon is causally related to the previous observation that the combination therapy of ECT and neuroleptics is more effective in the treatment of schizophrenia than ECT alone.

Redistribution of haloperidol after electroshock: Experimental evidence

We have previously reported that plasma and red blood cell levels of haloperidol, a neuroleptic agent, significantly increased immediately after electroconvulsive shock therapy (ECT) in schizophrenic patients on long term haloperidol treatment. To elucidate the mechanism of this increase, we attempted to reproduce this phenomenon in female Wistar rats. After 4 successive days of ip administration of haloperidol (10 mg/kg body weight, once daily), rats were given ECT through corneal electrodes on the fifth day (a.c. 50 Herz, 55 mA, 2.0 sec). Haloperidol levels were determined in plasma and other major tissues using a radioreceptor assay for haloperidol distribution before and after ECT at appropriate time intervals. Plasma haloperidol level was significantly increased 1 min after ECT but tended to return to the control level (without ECT) after 5 min. A significant decrease in haloperidol concentration in tissues was not observed in any of the tissues examined including frontal cerebrum, striatum, and muscle tissues (gluteal muscles). However, the relatively high haloperidol level and the large volume of muscle tissues suggested that the muscle could be the source of the transient increase in haloperidol levels in plasma. This conclusion was also supported by the data showing no significant rise of plasma haloperidol level after ETC in rats previously given a muscle relaxant, succamethonium chloride.

Intraventricular infusion of leupeptin decreases Bmax of the D2 receptor in the striatum of young rats

Intraventricular infusion of a thiol protease inhibitor, leupeptin, was previously shown to induce several morphological and immunochemical manifestations of normal and pathological aging in rat brain. The present study attempted to elucidate whether this treatment also perturbs another brain function which declines in aging, dopamine D2 receptor binding in striatum. Intraventricular infusion of leupeptin (0.6 mg per day) for two weeks caused a significant (about 20%) reduction in the binding maximum (Bmax) of dopamine D2 receptors (as examined by [3H] spiperone binding) in the striatum of young male Fischer-344 rats in comparison to (saline-infused) control rats. The apparent Kd values did not differ significantly between the control and leupeptin-treated rat groups. The results suggest that decreased protein turnover may be a factor in the decline in Bmax of D2 receptors during aging.

Relationship between efficacy of risperidone and genetic polymorphism in schizophrenia treatment

We investigated the relationship between the genetic polymorphism of the dopamine 2 receptor Taq1A in patients receiving risperidone treatment and the efficacy of drug treatment. The subjects were 19 patients with schizophrenia from whom we obtained informed consent. Their clinical symptoms were evaluated using the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), and extrapyramidal symptoms (EPS) were evaluated using the Drug-induced Extrapyramidal Symptoms Scale (DIEPSS). Genomic DNA was extracted from peripheral blood using a kit and the polymorphism of the dopamine 2 receptor Taq1A was identified by the polymerase chain reaction–restriction fragment length polymorphism method. The following results were obtained before and after risperidone treatment. General psychopathological scale score in PANSS: the A2/A2 group showed higher scores than the A1/A2 group. Total DIEPSS score: the A2/A2 group showed lower scores than the A1/A1 group. From these results the following can be concluded. Risperidone treatment tended to improve symptoms in the A2/A2 group compared with the A1/A2 group; however, no significant difference in improvement was observed between the A2/A2 group and the A1/A1 group, indicating no definitive tendency that genetic polymorphism affects risperidone treatment outcome. On the other hand, there is the possibility that the TaqA2 allele induces the expression of EPS.

The efficacy for cognitive function of donepezil hydrochloride in Alzheimer-type dementia and its related factors: comparison between medicated and non-medicated groups over 12 months

The efficacy of atypical antipsychotic drugs for delusions in schizophrenia spectrum disorders have so far been amply proved by much evidence. However, there are as yet still few studies based on brain biology, investigating how these delusions are created and at what stage of the development of these delusions atypical antipsychotic drugs are efficacious. This study focuses on the two aforementioned points. The authors carried out a series of detailed interviews with 12 patients. The criteria for patients to be included in the study were that they: (i) had been clinically diagnosed with schizophrenia spectrum disorders; (ii) were demonstrating delusional symptoms; and (iii) were demonstrating an improvement in communicative motor skills under treatment medication regimens. Analysis of the patients’ statements has brought about the theoretical model of delusions. This model is divided into three phases. The first phase is that of having imaginary and illogical expression, the second phase is that of being unable to recall the memory that normally dismisses this delusional thought, and the third phase is that of distorting rational input into an illogical conclusion. Our findings indicate that individual medications are effective at each phase.

Comparison of clinical symptoms and cognitive function between before and after switching to olanzapine in schizophrenia patients

with schizophrenia. Twenty-eight years-old monozygote female twins were treated with clozapine during 16–18 months. Their weight changes were completely different, one gained 7.4 kg and the other lost 4.2 kg. The body fat percentage, BMI, and serum leptin levels changed in parallel with each body weight. Other glucose and lipid metabolic parameters did not change markedly during treatment. The plasma ghrelin level increased in both twins. However, after the peak point of the ghrelin level, the decrease pattern was different in each twin. The overall differences in the gene expression patterns between the body weight-discordant twins were more prominent than between the control twins. Out of nine genes that changed 1.6-fold or more between the discordant twins, heme oxygenase 1 (HMOX1) is noteworthy because it is reported to be related to insulin resistance. The different change patterns of the ghrelin levels may be involved in the different body weight change in each twin. In addition, increased expression of the HMOX1 gene may be associated with insulin resistance in the twin who gained weight.

The efficacy of the long-term (1-year) use of donepezil hydrochloride in cognitive impairment therapeutic response by severity of Alzheimer-type dementia

interactions play a significant role in the pathophysiology of depression. The combined dexamethasone/corticotropine-releasing hormone (DEX/CRH) test and growth hormone releasing hormone (GHRH) test are useful neuroendocrine techniques in clinical settings. We performed these tests in depressive inpatients to investigate the effect of the antidepressants and mood stabilizers on the activity of HPA and GH axes. We recruited 32 inpatients; 57.4714.8 years, 8 males, 24 females. 29 patients were diagnosed as major depressive disorder, 2 as bipolar type II, and 1 as dysthymic disorder according to DSM-IV. There were no significant differences in both the ACTH and cortisol responses in DEX/ CRH test, and GH response in GHRH test, between the subgroup treated with SSRI and that with other antidepressants. Also no significant differences were scored between the subgroup treated with moodstabilizers and that without. The patients who relapsed within 6 months after the discharge showed lower GH response at the time of discharge compared with those that did not relapse (Po0.01). Neither the antidepressant types nor the use of mood-stabilizers changed the rate of relapse. These results suggest that the activity of HPA and GH axes reflect the pathology rather than the pharmacological actions of the prescribed drugs.