Expression of dihomo-γ-linolenic acid and FADS1/2 and ELOVL2/5 in term rabbit placentas.

Long-chain polyunsaturated fatty acids (LCPUFAs) are essential for both fetal and placental development. We characterized the FA composition and gene expression levels of FA-metabolizing enzymes in rabbit placentas. Total FA compositions from term rabbit placentas (n = 7), livers, and plasma (both n = 4) were examined: among LCPUFAs with more than three double bonds, dihomo-γ-linolenic acid (DGLA) was the most abundant (11.4 ± 0.69 %, mean ± SE), while arachidonic acid was the second-most rich component (6.90 ± 0.56 %). DGLA was barely detectable (<1 %) in livers and plasma from term rabbits, which was significantly lower than in placentas (both p < 0.0001). Compared with the liver, transcript levels of the LCPUFA-metabolizing enzymes FADS2 and ELOVL5 were 7- and 4.5-fold higher in placentas (both p < 0.05), but levels of FADS1 and ELOVL2 were significantly lower (both p < 0.01). Our results suggest a placenta-specific enzyme expression pattern and LCPUFA profile in term rabbits, which may support a healthy pregnancy.

Possible association of CUX1 gene polymorphisms with antidepressant response in major depressive disorder.

Association between response to antidepressant treatment and genetic polymorphisms was examined in two independent Japanese samples of patients with major depressive disorder (MDD). Genome-wide approach using the Illumina Human CNV370-quad Bead Chip was utilized in the analysis of the 92 MDD patients in the first sample. In all, 11 non-intergenic single-nucleotide polymorphisms with uncorrected allelic P-value <0.0001 were selected for the subsequent association analyses in the second sample of 136 MDD patients. Difference in allele distribution between responders and nonresponders were found in the second-stage sample for rs365836 and rs201522 of the CUX1 gene (P=0.005 and 0.004, respectively). The allelic P-values for rs365836 and rs201522 in both samples combined were 0.0000023 and 0.0000040, respectively. Our results provide the first evidence that polymorphisms of the CUX1 gene may be associated with response to antidepressant treatment in Japanese patients with MDD.

Genes for interleukin-2 receptor beta chain, interleukin-1 beta, and schizophrenia: no evidence for the association or linkage.

We studied a CA repeat polymorphism of the interleukin-2 receptor beta chain (IL-2RB) gene and a C/-514/T variation of the interleukin-1 beta (IL-1B) gene in Japanese schizophrenia patients. Both a case-control association study (54 patients and 54 controls) and a linkage study using six multiplex families (the number of the affected > or =4 in each family) were employed. No evidence for the association or the linkage was obtained either for the IL-2RB or IL-1B gene.

Mortality rate of schizophrenic patients with tardive dyskinesia during 10 years: a controlled study.

We examined mortality rates (MR) during 10 years between schizophrenic inpatients with and without tardive dyskinesia (TD). The TD group had a significantly higher MR (41%), as compared with the control group (20%). However, we could not reveal critical factors to explain why the TD patients had the higher MR.

Behavioral stimulation without alteration of beta and 5-HT receptors and adenylate cyclase activity in rat brain after chronic sertraline administration.

Effects of chronic treatment with selective 5-HT reuptake inhibitors (SSRIs) on the monoaminergic functions have not been much investigated in compared with tricyclic antidepressants. Therefore, we compared the effects of 3-week treatment with sertraline, a potent SSRI, to those of imipramine (10 mg/kg, IP, twice a day), on monoamine receptors and adenylate cyclase (AC) activity in rat brain. Two-week treatment with both sertraline and imipramine reduced immobility in the water wheel test to the comparable extent. Sertraline treatment did not affect Kd and Bmax of [3H]CGP12177 and [3H]ketanserin bindings or cAMP, accumulation by norepinephrine, isoproternol, 5'-guanylylimidodiphosphate [Gpp(NH)p] and forskolin in the cortical membrane compared with vehicle-treated rats. On the other hand, imipramine treatment decreased Bmax of both bindings and norepinephrine- or isoproternol-stimulated cAMP accumulation. Treatment with either antidepressant induced no apparent changes in [3H]8-OH-DPAT [2-(N, N-dipropylamino)-8-hydroxy-1,2,3,4-tetrahydronaphthalene] binding in the hippocampal membrane. These results suggested that chronic treatment of sertraline induced little effect on monoamine receptors and AC activity in the brain and that the alteration of these functions may not be primarily involved in antidepressive effects of antidepressants, at least of SSRIs.

Event-related potentials and thought disorder in schizophrenia.

We examined the relationship between event-related potentials and thought disorder in schizophrenia. The subjects were 29 chronic schizophrenic patients. Thought disorder was assessed using the Comprehensive Index of Positive Thought Disorder developed by Harrow and colleagues (Harrow and Quinlan, 1985; Marengo et al., 1986). Auditory event-related potentials were recorded during a standard oddball task. The P300 amplitude correlated negatively with the severity of the thought disorder. The P300 amplitude in the patients with thought disorder was significantly smaller than in the patients without thought disorder. These results suggest that a reduction in P300 amplitude is associated with a fundamental impairment of information processing in schizophrenic patients.

The differential ACTH responses to combined dexamethasone/CRH administration in major depressive and dysthymic disorders.

In a preliminary study, we performed the combined dexamethasone/CRH test on patients with major depressive and dysthymic disorders as well as healthy controls. The ACTH response was significantly enhanced in the major depression group compared to the control group and tended to be heightened compared to the dysthymia group. The cortisol response was not significantly different among the three groups. We assume that major depression and dysthymia are neuroendocrinologically distinct disorders, although whether the difference is quantitative or qualitative remains to be examined.

Effects of imipramine and sertraline on protein kinase activity in rat frontal cortex.

Three-week administration of sertraline or imipramine to rats (10 mg/kg, intraperitoneally, twice a day) increased ex vivo cyclic AMP-dependent protein kinase activity in the soluble but not in the particulate fraction of the frontal cortex. However, cyclic AMP-dependent protein kinase activity was not affected in either fraction of the parietotemporal cortex and hippocampus. Neither antidepressant altered protein kinase C activity in the soluble and particulate fractions or Ca2+/calmodulin-dependent protein kinase II activity in the frontal cortex. Therefore, sertraline and imipramine both selectively enhance cyclic AMP-dependent protein kinase activity in the frontal cortex. This enhancement might be involved in their biochemical mechanisms.

Induction of cysteine string protein after chronic antidepressant treatment in rat frontal cortex.

We have previously identified 204 partial cDNA fragments (ADRG1-204) as antidepressant related genes/expressed sequence tags. Then, we developed our original cDNA microarrays, on which the 194 clones out of ADRG1-204 were spotted. With this ADRG microarray, we found that the expression of a spot, ADRG55, which representing cysteine string protein (CSP), was significantly increased in rat brain after chronic treatment with a selective serotonin reuptake inhibitor, sertraline. In the present study, reverse transcription-polymerase chain reaction analysis confirmed the induction of CSP at mRNA levels in rat frontal cortex after chronic treatment with two different classes of antidepressants, imipramine or sertraline. Western blot analysis also revealed that CSP-immunoreactivity was increased after antidepressant treatment. In conclusion, our data suggest that CSP is one of the common functional molecules induced after chronic antidepressant treatment.

P300 and disability of daily life in schizophrenia.

1. The relationship between the P300 component of event-related potentials and disability of daily life was examined in schizophrenia. The subjects were 26 chronic schizophrenic patients. 2. Disability of daily life was assessed by using the Life Assessment Scale for Mental Illness (LASMI). 3. Auditory event-related potentials were recorded during a standard oddball task. 3. P300 amplitude correlated negatively with general psychopathology scale of PANSS (r = -0.416) and Work of LASMI (r = -0.417). P300 latency did not correlate with any of PANSS or LASMI score. 4. These results indicate that P300 amplitude can be an index for disability of daily life in schizophrenia.

Comparison of therapeutic efficacy of neuroses between CM6912 (ethyl loflazepate) and diazepam in a double-blind trial.

1. The therapeutic efficacy on several neuroses between CM6912 and diazepam (DZP) was comparatively investigated by means of intergroup comparison method in a double-blind trials. CM6912 was given to CM-1 group on the basis of twice daily dose of 1 mg each in the morning and evening and to CM-2 group on the basis of once daily dose of 2 mg only in the evening and DZP was given to another group on the basis of three times each dose of 2 mg. 2. As for the overall evaluation, no significant differences were found in the percentages of final global improvement rating among three groups. It resulted in "markedly improved" by 22% in CM-2 group, 18% in CM-1 group and 15% in DZP group in order, and "more than moderately improved" by 62% in CM-2 group, 56% in DZP group and 51% in CM-1 group in order. 3. As for the overall safety rating, no differences were found in the incidence of adverse reactions. 4. As for the global utility rating, it resulted in "extremely useful" by 22% in CM-2 group, 14% in CM-1 group and 8% in DZP group in order, showing significant superiority of CM-2 group to DZP group (p less than 0.05). It resulted in "more than useful" by 58% in CM-2 group, 52% in DZP group and 50% in CM-1 group in order.

The first open study of zonisamide, a novel anticonvulsant, shows efficacy in mania.

1. Zonisamide, an anticonvulsant developed in Japan, is structurally similar to serotonin. Zonisamide has been proven to have a pharmacological profile that is very similar to that of carbamazepine. Thus, the effect of zonisamide was examined in 24 psychiatric patients: 15 with bipolar manic state, 6 with schizoaffective manic state, and 3 schizophrenic excitement. 2. Approximately 25% of all the patients and 33% of the bipolar manic patients showed remarkable global improvement with the addition of zonisamide. Approximately 71% of all the patients and 80% of the bipolar group had more than moderate global improvement. 3. No serious adverse reactions were found and no patients required zonisamide withdrawal. One patient developed both leukocytosis and mildly abnormal liver function test. One developed leukocytosis and another reported mild sleepiness. These reactions disappeared when zonisamide was discontinued.

Encephalopathy during amitriptyline therapy: are neuroleptic malignant syndrome and serotonin syndrome spectrum disorders?

This report describes a case of encephalopathy developed in the course of amitriptyline therapy, during a remission of unipolar depression. This patient could have been diagnosed as having either neuroleptic malignant syndrome (NMS) or serotonin syndrome (SS). The major determinant of the symptoms may have been dopamine/serotonin imbalance in the central nervous system. The NMS-like encephalopathy that develops in association with the use of antidepressants indicates that NMS and SS are spectrum disorders induced by drugs with both antidopaminergic and serotonergic effects.

Measurements of both hippocampal blood flow and hippocampal gray matter volume in the same individuals with Alzheimer's disease.

We evaluated both hippocampal blood flow and hippocampal gray matter volume using single photon emission tomography and magnetic resonance imaging in the same individuals with Alzheimer's disease (AD) and in age-matched controls. The hippocampal blood flow was not significantly lower in mild AD patients (n = 21, Mini-Mental State Examination (MMSE) 23.3+/-2.1) than in controls (n = 16) with a 57% overlap. The hippocampal blood flow was significantly lower in advanced AD patients (n = 22, MMSE 15.4+/-3.2) than in controls. The hippocampal gray matter volume was significantly smaller in mild AD patients than in controls, although a 43% overlap was present. There was no significant difference in the hippocampal gray matter volume between the mild and advanced AD patients. The combination of measurements of hippocampal blood flow and gray matter volume discriminated 71% of mild AD patients from controls. These results suggest the usefulness of a combined analysis of hippocampal blood flow and gray matter volume for the early diagnosis of AD.

Relapse of panic disorder induced by a single intravenous methamphetamine injection.

The authors reports a case of a 33-year-old woman who had a relapse and worsening of panic disorder following a single injection of methamphetamine after a long period of remission. Her first panic attack had occurred when she was a 14-year-old high school student, but the course had persisted only for 1 month. Soon after an intravenous injection of methamphetamine, she had a relapse of panic disorder, and depression and agoraphobia developed. Psychotropic medication was not fully effective.

[Treatment of major depressive disorder--method and selection of the treatment].

There are many ways of treatment for depression. Among them the most popular and effective treatment is pharmacotherapy. In the acute phase, pharmacotherapy with antidepressants, certain forms of psychotherapy, the combination of pharmacotherapy plus psychotherapy, and electroconvulsive treatment have clearly proven to be efficacious in most types of unipolar depressive disorders. The common augmenting agents probably are lithium, thyroid hormone, dopaminergic agents, and mood stabilizers. Certain treatments may be more effective in specific subtypes; for example, light therapy is useful for seasonal affective disorder. During the 16-24 weeks following remission, patients with antidepressant medications in the acute phase should be maintained on these agents to prevent relapse. For patient pharmacotherapy or psychotherapy has not been effective, the use of ECT may be useful. Following the continuation phase, maintenance-phase treatment should be considered for patients who have many depressive episodes to prevent recurrences of major depressive disorder.

[A survey of drug utilization in psychiatric hospitals in Japan: the basic analysis of the current status of prescription patterns].

Although concern about the prescription pattern of psychotropics is growing, there have been very few surveys in Japan. In this survey conducted in 1993, prescription data, patient characteristics, etc. were collected for 2,395 inpatients from 18 psychiatric hospitals. Their mean age was 48.4 (S.D. = 13.6). Of these patients, 1,818 (75.9%) were diagnosed with schizophrenia, 115 (4.8%) with mood disorder, and 102 (4.3%) with mental retardation. The results were as follows. 1) They were prescribed an average of 10.1 different drugs: of these, 5.6 were various psychotropics (2.6 neuroleptics, 1.2 antiparkinsonian drugs, 1.0 hypnotics). 2) The mean daily dose of antipsychotics was 1,082 mg of chlorpromazine equivalent. 3) The most commonly prescribed neuroleptic was haloperidol (53.2% of the total patients) followed by levomepromazine (48.7%), chlorpromazine (24.8%), bromperidol (18.7%), and zotepine (18.3%).

[A survey of drug utilization in psychiatric hospitals in Japan: comparison of 1973, 1979, and 1993].

This paper investigated the trend in prescription patterns in the treatment of psychiatric inpatients using a database of our 1993 survey as well as reports of surveys conducted by Ito et al. in 1973 and 1979. To make the database of our survey comparable with surveys in 1973 and 1979, we extracted and analyzed 1,164 cases which met the criteria of Ito's survey, requiring that patients were diagnosed as having schizophrenia and were hospitalized for two years or longer. The results were as follows: 1) The most common number of different drugs per patient increased from 4 in 1973 and 1979 to 8 in 1993. That of psychotropics increased from 2 to 5. That of neuroleptics increased from 2 to 3. 2) The most commonly prescribed neuroleptics were haloperidol followed by levomepromazine and chlorpromazine. While the top three neuroleptics had not changed, the mean daily dose of haloperidol rose from 8.4 mg in 1979 to 15.3 mg in 1993.

[Depression during interferon therapy in chronic hepatitis C patients--a prospective study].

The number of patients treated with interferon (IFN) has increased markedly in Japan since 1992, when the Health and Welfare Ministry approved the use of IFN for treating chronic active hepatitis C. It is important to identify and treat depression, which is one of the psychiatric complications of IFN therapy and often leads to discontinuation of the therapy, in patients with chronic hepatitis C. In this study we prospectively investigated the incidence of depression during IFN therapy in patients with chronic active hepatitis C. The psychiatric status of 85 patients (53 men, 32 women; mean age 49.1 years) with chronic active hepatitis C who began receiving IFN at Showa University Hospital was assessed before and 2, 4, 12 and 24 weeks after the start of IFN therapy, using the major depressive episode diagnostic criteria listed in the DSM-III-R and the Hamilton Depression Scale HDS). All of the patients provided informed consent prior to participation in this study. IFN therapy was discontinued in 5 cases (5.9%) because of physical side effects and in 4 cases (4.7%) because of depression. Two, 11, 14, 25 and 16 patients were diagnosed as having major depressive episodes before and 2, 4, 12 and 24 weeks after the start of IFN therapy, respectively. The number of patients who were asymptomatic before the start of IFN therapy but were diagnosed as having a major depressive episode at least once during IFN therapy was 31 (31/83 = 37.3%). The mean HDS scores at 2, 4, 12 and 24 weeks (5.4, 6.0, 8.8 and 6.6) were significantly higher than that before the start of IFN therapy (3.0). The patients whose first diagnosed major depressive episodes occurred more than 4 weeks after the start of IFN therapy tended to be more severely depressed than those in whom it occurred less than 4 weeks after the start of IFN therapy. Compared to the 47 patients who completed 24 weeks of IFN therapy without experiencing depression, the 31 patients who were diagnosed as experiencing major depressive episodes during IFN therapy had significantly higher neuroticism scores determined using the Eysenck Personality Questionnaire, showed a more severely depressed mood and experienced more severe sleep disturbances before the start of IFN therapy. The latter group of patients also tended to have comorbid chronic physical disorders such as hypertension or diabetes mellitus and the histories of mental disorders before the IFN therapy; however these differences were not statistically significant. There were no differences between the two groups in patient age or sex, the severity of hepatitis before the IFN therapy, the type of IFN used in the therapy or the efficacy of IFN in the treatment of the hepatitis C. Our results indicate that the decision as to whether to treat chronic active hepatitis C with IFN should be made carefully and that early intervention and careful monitoring of depression are required during IFN therapy in the treatment of chronic active hepatitis C.

[One-year outcome of panic disorder].

In this study we investigated the one-year outcome of panic disorder. The subjects were 169 panic disorder patients (69 males, 100 females; mean age 36.5 years), who attended the outpatient clinic of the Department of Psychiatry, Showa University Hospital, from September to December 1993. The outcome study was performed from October to December 1994. Patients who were being treated at Showa University Hospital during the outcome study were interviewed in person, and those who were not were interviewed by telephone. The one-year outcome of 100 patients (32 interviewed in person and 68 interviewed by telephone; 37 males, 63 females; mean age 39.5 years) was assessed. That of the remaining 69 patients was not assessed because they did not provide informed consent or had moved during the last year. The patients who were assessed (N = 100) were older and exhibited less severe phobic avoidance on their first visit to the clinic than those who were not assessed (N = 69). The frequency of panic attacks, and the severity of phobic avoidance and anticipatory anxiety decreased significantly between the time of the patients' first visit to the clinic and the time of the outcome study. Panic attacks, phobic avoidance and anticipatory anxiety disappeared in 27.0%, 32.9% and 13.6% and decreased in frequency or severity in 61.8%, 62.0% and 61.4% of the cases, respectively. Seventy-three patients felt that the severity of their panic disorder symptoms decreased between the time of the outcome study and the time of their first visit to the clinic, 20 felt that it had not changed and 7 felt that it had increased worse. The phobic avoidance and anticipatory anxiety at the time of the patients' first visit to the clinic were more severe, and the Global Assessment of Functioning Scale score was lower in the case of the former group of patients than in that of the latter two groups.