O-02
Effect of new-generation antipsychotic blonanserin on cognitive impairment in schizophrenia: A randomized double-blind comparison with risperidone.

Nobumi MIYAKE, Seiya MIYAMOTO, Ai TAKEUCHI, Satoko YAMADA, Masanori TADOKORO, Naoko OSAKO, Sachiko TSUKAHARA, Kiriko ANAI, Takako ENDO, Yumiyo MOROKAWA, Noboru YAMAGUCHI

Department of Neuropsychiatry, St. Marianna University School of Medicine. 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, JAPAN.

We sought to clarify the neurocognitive features of schizophrenia, and compared the efficacy of blonanserin, a new antipsychotic, with that of risperidone on cognitive impairment in an 8-week, randomized, double-blind study. Mini-Mental State Examination (MMSE), Wechsler Memory Scale-Revised (WMS-R) logical memory I/II, Wisconsin Card Sorting Test (WCST), Wechsler Adult Intelligence Scale-Revised (WAIS-R) digit symbol and similarities test assessments, and Positive and Negative Syndrome Scale (PANSS) were performed at baseline and week 8. The same neurocognitive tests were performed for 10 healthy volunteers and compared with those of the patients (N=26). The patients were significantly impaired in cognitive function reflected by WMS-R logical memory I/II scores, number of category from WCST and WAIS-R digit symbol test score. For WMS-R logical memory I/II scores and PANSS total score, the both groups improved significantly from baseline. For WAIS-R digit symbol test score, the blonanserin group improved significantly from baseline. There were no significant differences between the groups in terms of all of the assessed endpoints. These results suggest that blonanserin has clinical efficacy similar to risperidone, and both medications possess a beneficial effect on immediate and delayed recall of verbal memory, and furthermore suggest that blonanserin has particular efficacy for attention and processing speed.

Ishii K, Miyata H, Morita M, Ando T, Sannomiya M, Nakayama K

Department of Psychiatry, Jikei University School of Medicine, Tokyo, Japan

Objective: PER has been conventionally used three times a day because of short half-life of plasma concentration. However, recent PET study demonstrated that striatal D2 receptor occupancies of PER at 16mg were higher than estimated occupancies (Arakawa et al, 2007). Therefore the present study was aimed to clarify efficacy and safety of twice a day of PER in patients with schizophrenia.
Methods: Seven patients (4 women and 3 men) who met DSM-IV-TR criteria for schizophrenia participated in this study. All of them were free from any medication before the study (5 first episode and 2 relapse). Initial dose was 16mg per day and was increased to the sufficient doses. BPRS and CGI scores were used for evaluation. All the participants provided informed consent.
Results: Two patients showed marked improvement, 4 showed moderate improvement, and 1 resulted in dropout because of the adverse effect (acute dystonia). Hallucination, anxiety, excitement, delusion, and tension showed good improvement in this order. PER exhibited moderate or more improvement in 6.3 weeks at a dose of 26.7mg.
Conclusions: The present study indicated 1) twice a day of PER with the initial dose of 16mg exhibited earlier and more marked improvement in schizophrenia, and 2) also caused more adverse effects including EPS, but its incidence was still low like atypical antipsychotics.

Hideyuki Nakane¹⁾, Takahiro Fukusako²⁾, Keiko Hatada³⁾, Yasuhiro Tagawa⁴⁾, Hiroki Ozawa1)

１）Department of Neuropsychiatry, Unit of Translational Medical Sciences, Medical and Dental Sciences, Nagasaki University Graduate School of Biomedical Sciences
２）Miyahara Hospital
３）Michinoo Hospital
４）Tagawa Hospital

We carried out a multicenter joint research entitled "The investigation about the validity and the safety of an Olanzapine Zydis to schizophrenia" under cooperation among general hospitals, psychiatric hospitals and clinics in Nagasaki prefecture mainly focusing on the Department of Neuropsychiatry, Nagasaki University.
51 subjects with schizophrenia diagnosed based on ICD-10 and DSM-IV could be the object of interim analysis. Regarding the evaluation items below, we examined for 24 weeks after the first drug administration.
We obtained the information of subjects regarding socio-demographic variables and clinical profile, and the subjects were interviewed and assessed based on different scales: BPRS, PANSS-EC and CGI for psychiatric symptoms, Euro-QOL, and SAI-J for QOL and insights, DAI-10 and ROMI for medications and adherence. Furthermore, we also checked vital signs, blood, body weight and extra pyramidal system symptoms for the safety of the medications.
As a present result of the analysis, in terms of BPRS, significant improvement (-15.4 point) was observed after 24 weeks compared to the baseline.　Regarding psychiatric symptoms, significant improvement was also observed right after four weeks of the medical treatment with Olanzapine Zydis.　Furthermore, significant improvement was similarly observed in terms of QOL, insight of disease and comfort of taking medications. These findings are suggested that the launch of Olanzapine Zydis that requires no water to take easily has contributed to the improvement of adherence and QOL.

Toshiki Harada¹⁾, Takashi Hamamura ²⁾, Masazumi Kodama¹⁾, Akira Wake¹⁾,
Tatsuaki Namba¹⁾ , Tsutomu Noritake¹⁾, Takatoshi Seno¹⁾, Kazuyo Watabe¹⁾

１）Takahashi Hospital
２）Hamamura Clinic.

It is widely accepted that quetiapine(QTP) produces very low rates of extrapyramidal symptoms(EPS) . However, we recently experienced four cases with oral dyskinesia (OD) during long-term QTP treatment. The four cases included three men and one woman from 61 to 84 years old. Clinical diagnoses were respectively general paralysis, organic mental disorder, drug dependence and insomnia, and senile dementia. The OD occurred between 6 and 22 months after the beginning of QTP treatment, suggesting a close resemblance to tardive dyskinesia. However, none of the 4 cases had ever shown acute EPS such as Parkinsonism. The doses of QTP at the occurrence of OD were from 100 to 500 mg, and valproic acid or donepezil were concomitantly prescribed for two cases. The OD did not seem to be withdrawal dyskinesia because an extended period had passed after cessation of the previous drugs. Recently we proposed a classification of antipsychotics based on a tonic/phasic dopamine transmission theory. According to this theory, QTP inhibits the tonic component preferentially (Hamamura and Harada, Psychopharmacology 2007). This suggests the possibility that inhibition of even the tonic component of dopamine transmission (extra-synaptic D2 receptor) can induce TD despite the rare incidence of acute EPS.

Toshiaki ISOTANI1)²⁾, Tomoko INAGAKI1)²⁾, Hiroshi UNEMOTO¹⁾, Sanae SATO¹⁾,
Hiroshi MAEDA1)²⁾, Naomi TADA1) and Toshihiko Kinoshita2)

１）Department of Psychiatry, Kansai Memorial Hospital (Hirakata, Osaka, 573-1137, JAPAN)
２）Department of Neuropsychiatry, Kansai Medical University (Moriguchi, Osaka, 570-8506, JAPAN)

We evaluated the clinical effects and extrapyramidal symptoms for the treatment with a new antipsychotic “aripiprazole” functioning as a dopamine-2 partial agonist, in 41 schizophrenic patients (15 males and 26 females, mean age and SD = 42.0±14.4 years) using the Brief Psychiatric Rating Scale, Keio university version (BPRS-K) and the Drug-induced Extrapyramidal Symptoms Scale (DIEPSS). The patients were classified as 13 hebephrenic and 28 paranoid schizophrenia according to ICD-10 criteria, whose mean morbidity-period and SD was 13.9±11.1 years. Three patients were treated with aripiprazole only, while 20 patients were able to discontinue treatment with other antipsychotics, and 18 continued previous treatment in addition to aripiprazole. Wilcoxon signed-rank tests were used for each score of BPRS-K and DIEPSS in between pre- and during the aripiprazole treatment. Mean aripiprazole dose and SD was 18.4±8.1mg/day. Total BPRS-K score did not significantly change (from 43.9±15.2 to 40.6±16.8), but 7 sub-item (somatic concern, anxiety, emotional withdrawal, guilt, depression, motor retardation and blunted affect) scores were significantly improved after administration. Total DIEPSS score and 6 sub-item scores improved significantly. However, “positive symptoms” such as auditory hallucination and delusion did not improve, excluding a few first-episodic cases.

Takamitsu Kosaka1) ⁴⁾, Shinsuke Nakanishi¹⁾, Nariaki Iijima¹⁾, Tetsuo Takeuchi²⁾,
Noriyuki Washino³⁾, Kousuke Kanemoto⁵⁾, Ikukatsu Suzuki³⁾

１）Yahagigawa Hospital
２）Akeai Clinic Hospital
３）Suzuka University of Medical Science
４）Akatsuka Pharmacy
５）Aichi Medical University

Objective: Cognitive dysfunction is frequently observed among patients with mental disorder. One of the contributory factors for the cognitive dysfunction is separation from society due to long-term hospitalization and also long-term medication of various kinds and massive dose of medicine which make them harder to rehabilitate to society. Also, the cognitive dysfunction is a major symptom of schizophrenia and makes patients difficult to keep Quality-of-Life and social recuperation.
In this study, we have investigated the efficacy of Guarana which many reports show positive effect to improve cognitive function, especially to see if we can see any improvement in cognitive function of patients who are diagnosed with schizophrenia.
Guranara is a nut originally come from South America and has been commercially available, being taken as medicine or as nutrient drink.
Procedure：Eleven patients (five males and six females) in remission condition with schizophrenia were assigned to receive Guarana.
The dose of Guarana was 9 capsules three times daily and continued for 6 months. For assessment procedure, we applied WCST (Wisconsin card sorting test) and SANS (scale for the assessment of negative symptoms) and have done an assessment for each patient before and after the dose.
Efficacy study: On WCST the average score improved by 6.6 from 13.1 to 19.7 and highest improvement among individuals was 16. Also, significant improvement in category perseveration and fewer numbers of perseverative errors was found on the test. On SANS, no significant improvement was found on average total score from 85 to 72.6 but found significant improvements in such symptom complexes as disturbance of attention and anhedonia/asociality. The former is from 12.8 to 5.6 and the latter from 24.2 to 17.8.
Conclusion: Guarana contained in some food products has a possible efficacy in improvement of schizophrenia. Consequentry, it indicates the possibility that ingredients from Guarana such as catechin and tannin act synergically and have effects on cognitive functional disorder in schizophrenia.

Reiji Yoshimura, Masae Mitoma, Wakako Umene, Atsuko Sugita, Hikaru Hori, Nobuhisa Ueda, Asuka Katsuki, and Jun Nakamura

Department of Psychiatry, Univ. of Occup. and Envir. Health, Kitakyushu, JAPAN

We investigated the effects of paroxetine, a SSRI, or malnacipran, a SNRI, on serum BDNF levels and plasma levels of IL-1β, IL-6, and TNFα in depressed patients. Forty-two patients were randomly administered paroxetine (21 cases) or malnacipran (21 cases). Thirty sex- and age-matched healthy subjects were prepared as a control group. Serum BDNF levels and plasma levels of cytokine were measured by ELISA before and 8 weeks after the start of treatment with antidepressants. The average daily dose of paroxetine or milnacipran was 31±13 mg and 83±31 mg, respectively. The Ham-D scores had significantly decreased by 4 weeks after paroxetine or milnacipran treatment. Fourteen of 21 (67%) in the paroxetine group and 12 of 51 (57%) in the milnacipran group were found to be responders by 8 weeks of treatment with each antidepressant. No significant difference was found with respect to the response rate or remission rate between groups. There was a negative correlation between serum BDNF levels and baseline Ham-D scores in all 42 depressed patients (r=-0.34, p=0.04). The baseline serum BDNF levels were significantly lower than those in the control group (p=0.02). Treatment with paroxetine or milnacipran equally increased serum BDNF levels at 8 weeks, but not 4 weeks. Serum BDNF levels increased 2.6-fold and 1.8-fold in responders to paroxetine and milnacipran, respectively, which was not statistically different in either group. Regarding plasma levels of cytokines, plasma IL-6 levels in depressed patients were significantly higher than those in the control group, in addition, responders to paroxetine or milnacipran significantly decreased the plasma IL-6 levels, however, nonresponders did not. These results suggest that blood levels of BDNF and IL-6 might be associated with the response to the both antidepressants.

Yukihiro Moritoki, Takafumi Yoshida, Takashi Nakamae, Kenji Fukui

Department of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine

【Introduction】Activation syndrome is due to central nervous system stimulation by antidepressants like SSRIs, showing irritation, aggressiveness causing self-harm or suicidal feelings, impulsivity, akathisia, or mania. We report a case of OCD with prolonged personality changes due to activation syndrome, even after discontinuation of paroxetine.
【Case】A 31-year-old male presented with a 3-year history of superstitious obsessions, and showed compulsive symptoms of symmetry and imperfections. He was treated with paroxetine and CBT. After hospitalization, he improved on paroxetine 60 mg and CBT, but irritability increased after discharge, he could not control himself, and lost his job due to problems. Small matters caused extreme outbursts. He realized the personality change. Paroxetine was gradually decreased and discontinued, but obsessive ideas resurged. He was hospitalized again. The obsessive symptoms improved on CBT only, but he showed sudden outbursts of anger and verbal abuse of other patients, so-called “short-temperedness,” which continued after discharge, leading to work and family-related problems.
[Discussion] There are two possible reasons why activation syndrome due to paroxetine may be prolonged in this case: j Actual symptoms of activation syndrome are prolonged. k Behavioral changes due to activation syndrome became a behavioral pattern and a strong stress-releasing factor, thus continuing.

Reiji Yoshimura, Hikaru Hori, Atsuko Sugita, Wakako Umene, Nobuhisa Ueda, Asuka Katsuki, and Jun Nakamura

Department of Psychiatry, Univ. Occup. and Envir. Health, Kitakyushu, JAPAN

In the present study, we investigated the atypical antipsychotic drugs on refractory depression, especially, psychotic depression in order to clarify the pathogenesis of refractory depression regarding brain-derived neurotrophic factor (BDNF) and cytokines. Twenty-seven patients met the DSM-IV criteria for major depressive disorder and the rest of 8 patients met those for bipolar I disorder (most recent episode depressed). Fifteen were male　and 20 were female. Their mean age was 56±17 years. All patients had not good response to the treatment with at least two different types of antidepressants or mood stabilizers. Then, atypical antipsychotic drugs (22 patients in risperidone, 5 patients in olanzapine, 5 patients in perospirone, 3 patients in aripiprazole) were added to the ongoing antidepressants or mood stabilizers. The mean Ham-D scores had significantly decreased from 27.7±6.9 at baseline (before administration of atypical antipsychotic drugs) to 18.5±13.1 at 4 weeks after administration of atypical antipsychotic drugs. The response rate to atypical antipsychotic drugs to antidepressants or mood stabilizers for refractory depression was 42%. Plasma BDNF levels were significantly lower in the depressed group than those in the control group, however, no difference was found between the refractory depressed group and the SSRI/SNRI responded group. Plasma IL-6 levels were significantly higher in depressed group than those in the control group. Particularly, plasma IL-6 levels in the refractory depression patients were higher than those in the SSRI/SNRI responded patients. In addition, responders to atypical antipsychotic drugs addition were significantly increased plasma BDNF levels to same levels as the control group. In contrast, plasma TNFα levels were not different between the depressed group and the control group. These results suggest that plasma IL-6 levels might be associated with the pathogenesis of refractory depression.

Junzo Watanabe¹⁾, Yutaro Suzuki¹⁾, Kazushi Sawamura¹⁾, Takuro Sugai¹⁾, Naoki Fukui¹⁾,
Shin Ono¹⁾, Satoshi Kumada²⁾, Yuji Suzuki³⁾, Toshiyuki Someya¹⁾

１）Department of psychiatry, Niigata university graduate school of medical and dental sciences
２）Niigata prefectural mental health center
３）Suehirobashi-hospital

Sudden unexplained death in psychiatric patients may be due to drug-induced arrhythmia, of which lengthening of the QT interval on the electrocardiogram is a predictive marker. The QT interval has daily variation and it is influenced by plasma concentration of antipsychotic agents. Therefore, we investigated the effect of atypical antipsychotic agents on the corrected QT interval using ambulatory electrocardiographic (Holter) recording.
The subjects were 32 Japanese patients being treated with atypical antipsychotic agents. All participants gave their informed written consent. Ambulatory electrocardiographic recording and standard 12-lead electrocardiogram tracing were obtained.
Mean daily dose of olanzapine was 23.4±8.7 mg (N=19), that of risperidone was 5.4±2.7 mg (N=9), and that of quetiapine was 486±248 mg (N=7). The mean QTc interval of ambulatory electrocardiographic recording at risperidone group was significantly longer than that at olanzapine group (434.2±23.1 vs 410.9±19.3 msec, P=0.017). Whereas, there was no significant difference of the QTc intervals among three drugs measured with standard 12-lead electrocardiogram.

Tsuruhei Sukegawa¹⁾, Kiyoshi Doi¹⁾, Yoshinari Hayashi¹⁾, Takaaki Ikenari¹⁾,
Yoshihiko Matsushima¹⁾, Izumi Sakamoto¹⁾, Kokichi Takata¹⁾, Toru Kashiwagi¹⁾, Ataru Inagaki²⁾

１）National Hospital Organization, Tottori Medical Center
２）Graduate School of Health Management, Keio University

Aims: To obtain the relationship between pharmacotherapy and survival rate on inpatients with schizophrenia. Subjects: One hundred seventy two schizophrenia patients who are less than 65 years old and are in Tottori Medical Center on September 1st, 2000. Methods: The relationship between pharmacotherapy and the survival rate was analyzed using Cox proportional Hazard Method. Results: There was a significant relationship among these factors; Age, administration of Diuretics and Antihypotensives. Every Diuretics administered patients were receiving Digitalis. Discussion: There is no doubt that there is a significant relationship between age and survival rate. It is thought to be lower survival rate on the patient with heart failure treated with Diuretics and Digitalis. Antihypotensives are used to treat the adverse effect of antipsychotics. Although hypotension induced by antipsychotics is thought to be due to effect of α1 antagonist, appearance of the symptom is different in each individual. For the patients necessary for antihypotensives, the side effect on autonomic nervous system seems to be appearing more often. For this reason, the survival rate is lower on the patient on antihypotensives.

Atsuko Ikenouchi-Sugita¹⁾, Reiji Yoshimura¹⁾, Hikaru Hori¹⁾, Wakako Umene¹⁾, Kazuko Shimizu¹⁾, Kazuyoshi Saito²⁾, Yoshiya Tanaka²⁾, Jun Nakamura¹⁾

University of Occupational and Environmental Health Japan
１）Department of Psychiatry
２）The first department of Internal Medicine

Background: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious but potentially treatable disease. IgG index, IL-6, and IFN-α are often used for the assessment of the severity of NPSLE. However, these biological markers do not reflect the severity of psychotic symptoms of NPSLE. Recently, it has been reported that brain derived neurotrophic factor (BDNF) is associated with the pathogenesis of several neuropsychiatric disease such as schizophrenia, depression and multiple sclerosis. In addition, blood BDNF levels　is considered a state marker for the severity of depression. However, no previous reports exist about investigating serum BDNF levels in patients with NPSLE. Objective: We hypothesized that serum BDNF levels might be a biological marker for reflecting the severity of psychotic symptoms of NPSLE. Then we investigated the relationship between serum BDNF levels and the severity of NPSLE. Method: 33 SLE patients were enrolled in this study and divided into three groups: NPSLE with the psychiatric symptoms, NPSLE without the psychiatric symptoms, SLE without NPSLE. An enzyme-linked immunoabsorbent assay (ELISA) method was used to measure serum level of BDNF. Result: Serum BDNF levels were increased in serum from NPSLE patients with the psychiatric symptoms compared with those in the other two groups. (p<0.05). In addition, serum BDNF levels were decreased according to the recovering from the disease. Conclusion: Serum BDNF levels can be useful for predicting the severity of psychotic symptoms in NPSLE. Further studis using a larger and homogeneous samples are needed to confirm our preliminary results.

Akira Hokyo¹⁾, Takafumi Mizuno¹⁾, Hiroki Kikuyama¹⁾, Tadahito Hanaoka¹⁾, Takehiko Okamura¹⁾, Hiroshi Yoneda¹⁾

１）Osaka medical collage, Department of Neuropsychiatry

[Objective]
We got possible to prescribe Aripiprazole in Japan in June 2006, so prescribed Aripiprazole for the patient of the schizophrenia for six month and reviewed efficacy and safety.
[Methods]
We aimed at Aripiprazole monotherapy as antipsychotic after a start as much as possible during six months. Using PANSS, we evaluated the symptom a dosage ago, three months later, and six months later. About the safety, we reviewed a blood sugar level, serum lipid level, serum prolactin level, a change of the weight. Also, we used POM (Preference for Medication), and assessed of a feeling of taking medicine of the patients. .
[Results]
Of the 40 observed patients, 27 patients completed the 6-month observation period. (67.5%) As for mean PANSS total score, before dosage was 84.3, 3 months later72.1, 6 months later 68.0. As for mean PANSS positive symptom score, before dosage were 20.0, 3 months later16.6, 6 months later15.7. As for mean PANSS negative symptom score, before dosage were 21.5, 3 months later18.4, 6 months later17.7. (LOCF). Also the fall (3.7kg) of the weight statistically were found.
[Conclusions]
Aripiprazole was effective and in safety for the treatment of schizophrenia.

Hikaru Hori, Reiji Yoshimura, Atsuko Sugita, Wakako Umene, Nobuhisa Ueda, Asuka Katsuki, and Jun Nakamura

Department of Psychiatry, Univ. Occup. and Envir. Health, Kitakyushu, JAPAN

In the present study, we examined the effect of aripiprazole on plasma levels of catecholamine metabolites and serum BDNF levels in schizophrenic patients. Ten patients met schizophrenia (DSM-IV) treated with aripiprazole were enrolled the study. Clinical improvement and extrapyramidal symptoms in the present were evaluated using PANSS and DIEPSS, respectively. The plasma levels of MHPG and HVA were measured by HPLC-ECD, and serum BDNF levels were assayed by ELISA at before, 2, 4, and 8 weeks after aripiprazole administration. Three of 10 patients were firstly administered only aripiprazole, and the rest of 7 patients were added aripiprazole to the ongoing antipsychotic drugs, and the ongoing antipsychotic drugs were tapered. The daily average dose of aripiprazole was 22.9±9.3 mg. The scores of PANSS-P and PANSS-N were significantly reduced 8 weeks after aripiprazole treatment. The scores of DIEPSS were not changed during the treatment with aripiprazole. The plasma HVA levels were transiently increased at 2 weeks, and gradually reduced at 8 weeks after aripiprazole treatment. On the other hand, the plasma MHPG levels were gradually increased at 8 weeks after aripiprazole treamnet. Serum BDNF levels were not altered during the treatment period. Recently, we have reported that treatment with risperidone decreased plasma HVA levels at 2 weeks, and increased plasma MHPG levels at 4-8 weeks after the treatment. We have also demonstrated that olanzapine decreased plasma HVA levels at 4 weeks, and increased plasma MHPG levels at 8 weeks after the treatment. These results suggest that effect of aripiprazole on plasma catecholamine levels might be different from those in other atypical antipsychotic drugs.

Naoki Fukui¹⁾, Suzuki Yutaro¹⁾, Kazushi Sawamura¹⁾, Takuro Sagai¹⁾, Junzo Watanabe¹⁾,
Shin Ono¹⁾, Satoshi Kumada¹⁾, Michio Saito²⁾, Yoshifumi Suzuki³⁾, Yuji Suzuki⁴⁾,
Hiroshi Tochikura⁵⁾, Kiyoshi Nagashima⁶⁾, Shigeo Murata⁷⁾, Toshiyuki Someya¹⁾

１）Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan　
２）Itsukamachi Hospital, Niigata, Japan　３）Minamihama Hospital, Niigata, Japan
４）Suehirobashi Hospital, Niigata, Japan　５）Sagata Hospital, Niigata, Japan
６）Manomizuho Hospital, Niigata, Japan　７）Iizuka Hospital, Niigata, Japan

Aim: Hyperprolactinemia may result in sexual dysfunction, amenorrhea, galactorrhea and osteoporosis, hence, hyperprolactinemia is notable adverse effect of antipsychotic medication. In this study, we investigated the effects of - 141C Ins/Del polymorphism that situated in the promoter region of D2 dopamine receptor gene (DRD2).
Method: We studied 144 adult schizophrenic patients (83 men and 61 women; mean age, 41 year; SD, 14) treated with antipsychotic agents (main agent: Olanzapine 70, Risperidone 38 and Others 40). Forty subjects were treated by two or more antipsychotic agents and others were treated by an antipsychotic agent. Blood sampling for measurement of prolactin (PRL) concentration was performed early in the morning before taking antipsychotic agents. The - 141C Ins/Del polymorphism was genotyped using TaqMan 5’-exonuclease assay. This study was approved by the Ethics Committee on Genetics of the Niigata University School of Medical, and written informed consent was obtained from all subjects.
Results: The - 141C Ins/Del genotype frequency was 0.69 (n=99) for Ins/Ins, 0.28 (n=41) for Ins/Del and 0.028 (n=4) for Del/Del. No significant differences were noted for gender, age and antipsychotic dose between Del carriers and non carriers. Fourteen subjects had extreme hyperprolactinemia (PRL ≧ 100 ng/ul), moreover, 9 (0.62) of the 14 subjects were Del carriers (P = 0.005). On the other hand, we did not find significant association between the - 141C Ins/Del genotype and over normal range of PRL level.
Conclusion: We found the association between extreme hyperprolactinemia induced by antipsychotics and the - 141C Ins/Del polymorphism of DRD2 gene. Since PRL level was influenced by various factors such as age, gender, antipsychotic agent and antipsychotic dose, we might not find the association between the polymorphism and weak phenotype such as over normal range of PRL level.

Authors
Kazushi Sawamura, Yutaro Suzuki, Junzo Watanabe, Naoki Fukui, Satoshi Kumada, Takuro Sugai, Shin Ono, Toshiyuki Someya

Affiliation
Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Aim
We investigated the effects of adiponectin SNP 45T/G polymorphism on weight gain induced by olanzapine in Japanese schizophrenic patients.
Method
We started olanzapine at 5 or 10 mg/day, and followed at 24 weeks for 35 drug-naive schizophrenic patients 《male:21, female:14, age:25.8±9.8 (mean±SD)》.
Body weight was recorded at baseline, week 4, 8 and 24 (endpoint). BMI was calculated by measurements of body height and body weight. In 26 patients, we identified adiponectin SNP 45T/G polymorphism used by Taqman polymerase chain reaction method. The subjects received an explanation of the objectives of the study, and only those who gave written consent to participate in the study were enrolled.
Result
The frequency of patients with BMI gain above 5 % in G allele carrier was higher than G allele non-carrier at week 24 (p=0.046). However, the frequency of patients with BMI gain above 5 % in G allele carrier was higher than G allele non-carrier at week 4, .week 8.
Conclusion
It is suggested that adiponectin SNP 45T/G polymorphism may be associated with continuous weight gain induced by olanzapine.

Authors
Naoki Uchida ¹⁾, Nobuaki Egashira 2) ³⁾, Ayumi Ishibashi ²⁾, Syozo Chidori ¹⁾, Michihiro Fujiwara ²⁾, Ryoji Nishimura ¹⁾.

Facilities
１）Department of psychiatry, School of Medicine, Fukuoka University
２）Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University
３）Department of Pharmacy, Kyusyu University Hospital

Major depression is often associated with　dysfunction of hypothalamic-pituitary　-adrenal (HPA) axis. Most studies on the dysfunction of HPA axis in major depression have focused on cortisol but not, dehydroepiandrosterone (DHEA) in depressed patients. DHEA is a substrate for androstenedione and testosterone synthesis, and plays a role as an adrenal androgen. Furthermore, DHEA has been known to act on the central nervous system and oppose the action of glucocorticoids. However, the physiological role of DHEA remains unknown. In general, measurement of peripheral adrenal steroids levels, especially in plasma or urine, is used for investigate the function of HPA axis. In recent years, components of saliva have gained increasing interest as indicators of bodily changes following stress. In the present study, we examined whether salivary cortisol and DHEA are biological markers in major depression. Salivary DHEA levels were increased in depressive patients compared with controls. On the other hand, levels of salivary cortisol in depressive patients were not different from those in controls. These results suggest that salivary DHEA may be a marker in major depression.

Hidemichi Suga, Ken Oshita, Taro Suwa

Department of Psychiatry, Graduate school of Medicine, Kyoto University

Objective: We investigated the clinical outcome of 1-year follow-up after ECT for patients with refractory depression.
Sampling and Methods: ECT were undergone to a total of 18 patients with refractory depression who had no response to augmentation of more than two kinds of antidepressants for one year or more as major depressive disorder by DSM-IV-TR. For the outcome of 1-year follow-up, GAF and the level of rehabilitation into society were assessed.
Results: The rate of ECT-response with 50% improvement of HAM-D was 88.9%, and 95% in GAF. For the outcome of 1-year follow-up after ECT, the improvement of 50% and the deterioration of 33.3% in GAF, and the reinstatement of 22.2% and steady life at home of 33.3% and depressive withdrawal state of 33.3% in the level of rehabilitation into society were admitted. For continuous treatments, drug therapy was undergone to 100% of the patients, c-ECT to 50%, family therapy to 50%, and CBT to 16.7%. The recurrences of depressive state were admitted in 50% of the patients, however c-ECT or family therapy was significantly effective for the prevention of recurrences.
Conclusion: It was suggested that continuous combined treatments using ECT, family therapy, CBT and drug therapy were effective for the rehabilitation into society for the patients with refractory depression.

Keiichi Uemura, Yoshito Takahashi, Kiyoshi Mori, Motoji Yasuda

Sapporo City Hospital Seiryoin

Current guidelines for the initial treatment of bipolar depression recommend avoiding the use of antidepressant drugs due to concerns over drug-induced manic switch episodes. However, lamotrigine and bupropion can use as first line for bipolar depression. Meanwhile, additional SSRI therapy has disadvantages of manic switch episodes, rapid cycling and arising nausea.
We retrospectively identified enrolled patients with bipolar depression (ICD-10: F31.3-F31.5) who had SLP prescription treatment between April 2004 and May 2007 for improving depressive episodes.
Eight patients have met the requirements, whose average age was 54.4±13.8 years old, and three of them were men and the others women. After two weeks from starting SLP therapy, 62.5% (5/8) of the patients were medium improvement; after one year 36.5% (3/8) of them remarkable improvement.
The average optimum dose was 39.6 ± 19.6 mg/day.　No extra pyramidal symptoms including tardive was appreciated, and some side effects were raised; amenorrhea, lactation with rises of serum prolactin value and hypomanic switch. All side effects were improved after reducing SLP. As a result, SLP could be expected to efficacy for bipolar depression with low dose about 40mg/day, and it was suggested that the appearance of effects was earlier than lithium and other antidepressants, and also the response rate was higher. We will intend to plan open trial.

Hiroaki Jitsuiki ¹⁾, Yasumasa Okamoto ¹⁾, Shigeru Morinobu ¹⁾, Satoru Izumitani ²⁾,
Yasuhiro Kimura ²⁾, Katsuji Suzuki ³⁾, Teruaki Tanaka ³⁾, Takeshi Inoue ³⁾, Tsukasa Koyama ³⁾,
Ken Wada ⁴⁾, Yukari Masaoka ⁴⁾, Takanobu Sasaki ⁴⁾, Reiji Yoshimura ⁵⁾, Jun Nakamura ⁵⁾,
Satsuki Sumitani ⁶⁾, Tetsuro Ohmor ⁶⁾, Shigeto Yamawaki ¹⁾

１）Department of Psychiatry and Neurosciences, Graduate School of Biomedical Sciences, Hiroshima University,
２）Department of Pharmaceutical Services, Hiroshima University Hospital
３）Department of Psychiatry, Hokkaido University Graduate School of Medicine
４）Department of Psychiatry, Hiroshima City Hospital
５）Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health
６）Department of Psychiatry, University of Tokushima Graduate School

Objective: The appropriate therapeutic serum valproate level in maintenance therapy for bipolar disorder (BP) is not well known.
Method: In the present study, we introduce the hypothesis that serum valproate level, which was achieved in the cases of BP where treatment was continued for an extensive period and relapse was also prevented for an extensive period, might be its optimum serum level in the maintenance therapy for BP. To determine such a serum valproate level, we studied the serum valproate level in forty-one outpatients meeting the DSM-IV criteria for BP who had been treated with almost stable doses of valproate successfully for at least 12 months as prophylactic therapy.
Results: The serum valproate levels estimated by Bayesian estimation of BP-I and BP-II patients were 52 - 68 μg/ml and 41 - 56 μg/ml, respectively. A greater trend towards a higher trough serum level (p=0.07) and median serum level (p=0.09) was indicated in the BP-I group than in the BP-II group.
Conclusion: We speculate that these are the optimum serum valproate levels in maintenance therapy for BP. There may be a correlation between the blood level of valproate required for stabilization and the severity of the bipolar disorder.

Wakako Umene ¹⁾, Reiji Yoshimura ¹⁾, Hikaru Hori ¹⁾, Hideki Nakano ¹⁾,
Atsuko Sugita ¹⁾, Masayuki Shimono ²⁾, Kenichi Takano ²⁾, and Jun Nakamura ¹⁾

Department of
１）Psychiatry,
２）Pediatrics Univ. of Occup. and Envir. Health, Kitakyushu, JAPAN

We report herein a case of Sydenham’s chorea with neuropsychiatric symptoms who was successfully treated with a low dose of risperidone. A 14-year-girl was admitted to our hospital with insomnia, restlessness, irritability, gait disturbances, involuntary movement (mild choreiform movements) of the arms and mouth, facial grimacing, emotional instability, difficulty with concentration, and decreased memory. In addition, she was experiencing persecutory delusions, and visual hallucinations, mainly well-described human figures. The family history was unremarkable, with no reported social stress or family members being affected by psychiatric or tic disorders. Brain CT and MRI scan demonstrated no abnormality. The patient’s EEG demonstrated sporadically large sharp waves and continuous slow waves in the temporal lobes, and SPECT images showed an area of irregular hyperperfusion areas in bilateral basal ganglias. Treatment with penicillin prophylaxis (ampicillin 750 mg/day) and olanzapine (10 mg/day) was started, aiming at controlling involuntary movements and neuropsychiatric symptoms. Within a week of the treatment, insomnia, visual hallucinations, and irritability were improved. After 2 weeks, gait disturbances and involuntary movements had disappeared, but hyperphagia and weight gain occurred due to the adverse effects of olanzapine treatment, in addition, emotional instability, poor concentration and persecutory delusions were persisted. Therefore, 0.5 mg/day of risperiodne was started instead of olanzapine. Two weeks after risperidone administration (4 weeks after starting administration of drugs), the patient’s involuntary movements and neuropsychiatric symptoms were completely remitted. Serum BDNF levels were increased and plasma levels of HVA and MHPG were decreased according to the recovery from the active phase of the disease. These results suggest that dysfunctions of catecholaminergic neurons and neurotrophic factors might exist in Sydenham’s chorea, and the decreasing catecholamine activities in response to risperidone might be associated with the improvement of the disease.

Yoshio Shimizu, Takehiro Kishiguchi

Department of psychiatry, National Hospital Organization Okayama Medical Center

We describe a patient of specific phobia against her mother-in-low whose phobic symptoms was improved by paroxetine. A 35-year-old female had vertigo after she lived with parents-in-low. She came for our hospital because of dizziness and chills when she met her mother-in-low. Although she had dizziness and chills, there were no other symptoms to fulfill diagnostic criteria for panic attack, social phobia and generalized anxiety disorder. She was diagnosed as suffering from adjustment disorder. The supportive psychotherapy was effective and her symptoms had been disappeared. But one year later she had palpitations, shaking, feeling of choking, dizziness and chills just after her mother-in-low said "Did you make my supper?" when her mother-in-low suddenly came back their home. Since then, she had panic attack whenever she met her mother-in-low. She suffered from serious anxiety from the morning everyday. 3mg etizolam daily wasn't effective. She fulfilled diagnostic criteria for specific phobia. 2 weeks treatment of paroxetine 10mg daily decreased the intensity of her panic attack significantly and the serious anxiety in the morning was disappeared. After 4 weeks treatment of paroxetine 20mg daily, she never suffered from panic attack and she could decrease the amount of etizolam from 3mg to1.5mg daily.

Tomoo Ota

Department of Psychiatry, Yokosuka Kyosai Hospital. 1-16, Yonegahama-dori, Yokosuka, Kanagawa, 238-8558, Japan.

The author found major effects of concomitantly administering VPA and Li in the treatment of PLE with behavioral and psychological signs of dementia (BPSD). The subject, a 55-year old female with initial symptoms of depressed mood, subsequently developed episodically disturbed convulsive seizures over one year after the onset of initial symptoms, ultimately exhibiting moderate dementia equivalent to CDR-2. With high levels of multiple tumor markers and an abnormal signal zone in the limbic system seen on cranial MRI, the patient was clinically diagnosed with PLE. Behavioral pathology in Alzheimer’s disease (Behave-AD) was used to evaluate the frequency and severity of problematic behavior. Administration of cloxazolam and levomepromazine was discontinued due to poor tolerability. Decreased scores in category C of Behave-AD and general evaluation were observed two weeks after initiating Li administration at an initiation dose of 300 mg/day; the tendency remained unchanged during the observation period. Protective functions of the central nervous system are thought to be the mechanism responsible for VPA and Li efficacy in BPSD. Our findings of positive correlation between deciduation of nerve cells in the limbic system and the degree of behavioral and cognitive disorder support the probability of the mechanism mentioned above.

Hideaki Egami, M.D., Ph.D. and Naohisa Uchimura, M.D., Ph.D.

Department of Neuropsychiatry Kurume University School of Medicine

Zolpidem is a nonbenzodiazepines and it is a selective benzodiazepine ω1 receptor modulator used for its hypnotic-sedative properties. Its side effect profile is milder than those of benzodiazepines. Here, we present two cases of paradoxical reaction associated with zolpidem administration. Case 1, a 14-year-old woman, had Adjustment disorders with prolonged depressive reaction. She had depressive mood, anxiety and insomnia. Fluvoxamine had started at 50mg/day. Three months later, due to lack of improvement, zolpidem 10mg/day, was added. Thirty minutes after zolpidem administration, she was complaining of euphoria, garrulity and walking around. Two hours later she slept. Case 2, 18-year-old woman, had somatoform disorders. She had many pain symptoms and was started on chlorpromazine 10mg/day. Five weeks later, due to lack of improvement, zolpidem 10mg/day, was added. Sixty minutes after zolpidem administration, she complained auditory hallucination, visual hallucination and nausea. Two hours later she slept. Both two cases had memory of these events in the next morning. These symptoms stopped after discontinuation of zolpidem. This report demonstrates that paradoxical reaction may be associated with the use of zolpidem. Physicians and pharmacists should be aware of these potential side effects.