P-02
A Study Examining Pharmacokinetics of Rapid Acting Intra-muscular Olanzapine in Japanese Agitated Patients with Schizophrenia

Hisae Ono ¹⁾, Kazuyoshi Tanaka ²⁾, Yumiko Nishimura ²⁾,Tetsushi Nakata ¹⁾, Daisuke Shuto ¹⁾, Michiaki Akira ¹⁾, Kazunori Uenaka ¹⁾, Shinji Fujikoshi ¹⁾, Michihiro Takahashi ¹⁾

１）Lilly Research Laboratories Japan, Eli Lilly Japan K.K.
２）Iguchi Medical Corporation, Koyodai Hospital

BACKGROUND: Rapid acting intramuscular formulation of olanzapine (olanzapine IM) is an atypical antipsychotic agent which has been used in overseas, but olanzapine IM is still under clinical trial stage in Japan. We conducted a clinical trial examining pharmacokinetics in a clinical therapeutic dose of olanzapine IM.
METHODS: This clinical study was an open-label study. The study subjects were in-patients diagnosed (DSM-IV-TR) with schizophrenia whose PANSS-EC score was at least 14 with a score of 4 or more in each item. All patients provided written informed consent of their own free will after the procedures had been fully explained to them in writing. Pharmacokinetics of olanzapine 10 mg was examined until 96 hours after the injection. The efficacy and safety were also examined as secondary objectives in the study.
RESULTS & CONCLUSION: Olanzapine IM 10 mg was administered to 10 patients. Nine patients completed the study. Olanzapine was absorbed rapidly and reached the maximum drug concentration (tmax: 0.28 hours), then the plasma olanzapine concentration decreased rapidly to about 2 hours reflecting distribution, then decreased monoexpoentially thereafter following first-order elimination (geometric t1/2: 42.4 hours) In this study, olanzapine IM was effective and well tolerated in agitated Japanese subjects with schizophrenia.

Shin OGINO¹⁾, Seiya MIYAMOTO¹⁾, Nobumi MIYAKE¹⁾, Takako ENDO¹⁾, Hiroshi KUBOTA²⁾, Hiroyuki TAKAGI³⁾, Noboru YAMAGUCHI¹⁾

１）Department of Neuropsychiatry, St. Marianna University School of Medicine,
２）Ofuji Hospital, ３）Seimo Hospital

Recent practical clinical trials found few differences in effectiveness in first-generation and second-generation antipsychotics (SGAs) in non-refractory schizophrenia. It has been suggested that there is a strong correlation between Subjective Well-being under Neuroleptic treatment (SWN), quality of life, and adherence, which could affect the long-term outcome in schizophrenic patients treated with antipsychotics. We compared the SWN in 40 inpatients and outpatients with schizophrenia at St. Marianna University School of Medicine Hospital or Ofuji Hospital, treated with aripiprazole, olanzapine, risperidone, or low-dose (?5 mg/day) haloperidol (HPD) monotherapy for at least 4 weeks. Although no significant differences were seen among the drugs in terms of clinical symptoms or extrapyramidal symptoms, the SWN total score and the 10-item Drug Attitute Inventory (DAI-10) score tended to be higher in the low-dose HPD. While a significant positive correlation was observed between the HPD dose and the SWN self-control score, no dose relationships were found in any of the others. These results suggest that there is little difference among SGAs, when used at an appropriate dose in a monotherapy, in terms of subjective well-being and adherence, and that HPD, as well, when used at a low dose in a monotherapy, can provide a similar level of adherence.

Takako Endo ¹⁾, Seiya Miyamoto ¹⁾, Shin Ogino ¹⁾, Nobumi Miyake ¹⁾, Itaru Utagawa ¹⁾,
Yasuo Sasuga ¹⁾⁴⁾, Shigetoshi Takeda ²⁾, Hiroshi Kubota ³⁾, Junichi Nakanishi ⁴⁾, Hisashi Higuchi ¹⁾, Hiroyuki Takagi ^{1) 2)}, Noboru Yamaguchi ¹⁾

１）Department of neuropsychiatry, St. Marianna University School of Medicine,
２）Seimo Hospital,３）Ofuji Hospital,４）Ikuta Hospital

It is generally accepted that monotherapy is the best way to realize the benefits of atypical antipsychotics. However, there are many instances in which other psychotropic agents are haphazardly prescribed for concomitant use. We therefore conducted a survey to determine what psychotropic agents are currently being prescribed to patients with psychotic disorder being treated with olanzapine (OLZ). We investigated the prescriptions of outpatients and inpatients diagnosed with schizophrenia spectrum disorders in April 2007 at St. Marianna University School of Medicine Hospital, Ikuta Hospital, Seimo Hospital or Ofuji Hospital and who were prescribed OLZ. Our survey revealed that: 1) OLZ monotherapy was prescribed to 67.2% of outpatients and 54.8% of inpatients, so the percentage of OLZ monotherapy was greater among outpatients; 2) the most common antipsychotics concomitant used with OLZ was risperidone among outpatients, and levomepromazine among inpatients; 3) the most common mood stabilizer concomitantly used with OLZ was carbamazepine among outpatients, and valproic acid among inpatients; 4) anticholinergics were used concomitantly with OLZ by 37.4% of outpatients and 34.8% of inpatients. In addition to unpleasant anticholinergic adverse effects being a cause for concern, in order to realize the benefits of OLZ, something needs to be done about the haphazard coadministration of anticholinergics.

Motoki Kuramochi ¹⁾,Noriko Takagaki ²⁾, Shinji Fujikoshi ³⁾，Shinichi Nishiuma ¹⁾
and Michihiro Takahashi ¹⁾

１）Clinical Research Physician, Neuroscience Products, Lilly Research Laboratories Japan, Eli Lilly Japan
２）Postmarketing study planning and management, Global Product Safety Japan, Eli Lilly Japan
３）Statistics Planning, Japan Clinical Research, Lilly Research Laboratories Japan, Eli Lilly Japan

The efficacy and safety of olanzapine were evaluated in 583 acute schizophrenic Japanese patients in a post marketing surveillance. Brief Psychiatric Rating Scale (BPRS) positive symptom sub-scale, the Clinical Global Impression-Severity of illness (CGI-S): schizophrenia, Parkinsonism, Akasthsia and Agitation-Calmness Evaluation Scale (ACES) were evaluated for 6 weeks. Weight gain, blood sugar and continuation rate of olanzapine were also evaluated.　Significant improvements in BPRS and CGI-S: schizophrenia were observed. It has been shown that the improvements of BPRS were significantly correlated to the average dosage and the starting dosage of olanzapine. ACES score improved continuously. There were no patients with serious adverse events, including weight gain, blood sugar elevation and over sedation .The discontinuation rate due to adverse events was 3.50% (n: 21/ 583）. The continuation rate of olanzapine treatment for 6 weeks was 85.76%.　It was shown that olanzapine was effective for the treatment of acute schizophrenic Japanese patients, and the adequate dosage of olanzapine was effective in improvement of positive symptoms. Safety results will be discussed.

Yoshimura N.¹⁾, Otsubo T.¹⁾, Kumada T.¹⁾, Toriya R.¹⁾,Ishiwata Y. ^{1) 2)}, Yamagata B. ¹⁾, Ota H.¹⁾, Sano N.¹⁾, Watanabe S. ¹⁾, Tanaka K.³⁾, Inamoto J.¹⁾, Mimura M.¹⁾, Kato N.¹⁾

１）Department of Psychiatry, Showa University School of Medicine
２）Hiyoshi Hospital
３）Department of Occupational Mental, Graduate School of Medical Sciences, Kitasato University

Objective: Acute agitation is a common presentation in emergency departments and is often secondary to an underlying psychotic condition. The aim of this study was to compare the effectiveness of four antipsychotics (risperidone2mg, olanzapine5mg, haloperidol3mg,quetiapine200mg) in the treatment of psychotic agitation for up to 2 hours.
PATIENTS: We recruited 38 patients with acute psychosis who were admitted at the Showa University Karasuyama hospital, from November 2005 to August 2007.
FINDINGS: Aggressive behavior, as measured by Positive and Negative Syndrome Scale-Excited Component and Agitation-Calmness Evaluation Scale, significantly improved in three groups(risperidone,haloperidol,quetiapine).While in olanzapine, we cannot find significant improvement. As for the safety profiles, as measured by Drug Induced Extra-Pyramidal Symptoms Scale and vital sign, there are no significant between-group differences.
CONCLUSIONS: Our results show that in the clinical practice setting of emergency psychiatry risperidone2mg, quetiapine200mg, haloperidol3mg are effective. More amount than 5mg of olanzapine is required improvement in aggressive behavior. Further studies using more amounts are warranted to improve this study.

Naoki Hashimoto¹⁾, Tomoo Ogawa²⁾, Ichiro Kusumi¹⁾,Yasuya Nakato¹⁾, Koki Ito¹⁾,
Tomohiro Abekawa¹⁾, Tsukasa Koayama¹⁾

１）Dept. of Psychiatry, Hokkaido University Graduate School of Medicine
２）Dept. of Psychiatry, Kushiro City General Hospital

The object of this study is to investigate the long-term efficacy and tolerability of the
aripirazole (APZ). The second goal is to investigate the characteristics of the patients
who successfully continued the use of APZ for 26 weeks. The study has done
retrospectively, and all information has been collected from their medical records.
Among 86 patients, 57% (49/86) patients completed the 26 week use of APZ. The mean
CGI-severity score at week 8 was 3.7 and was also 3.7 at week 26 (LOCF).They were
statistically lower than the CGI score at week zero which had been 4.0.
We compared the patients who could complete the use of APZ for 26 weeks and those
who could not. There were no statistical differences between those two groups about
their background (age, the duration under antipsychotic treatment, total amout of
antipsychotics before they stat the use of APZ). , or initial dose of the APZ. On the other
hand, the patients whose dose of the former main antipsychotic had started being
reduced two weeks or more later since the start of the APZ could use it significantly
longer than the patient whose reduction of the former antipsychotic had started earlier.

Motoki Kuramochi ¹⁾,Noriko Takagaki ²⁾, Shinji Fujikoshi ³⁾，Naohiro Nakahara ¹⁾,
Michihiro Takahashi ¹⁾

１）Clinical Research Physician, Neuroscience Products, Lilly Research Laboratories Japan, Eli Lilly Japan
２）Post marketing study planning and management, Global Product Safety Japan, Eli Lilly Japan
３）Statistics Planning, Japan Clinical Research, Lilly Research Laboratories Japan, Eli Lilly Japan

The effects of olanzapine on health outcome in patients with schizophrenia were investigated in a post-marketing surveillance.
1,849 patients were eligible for the analysis. Adverse drug reactions (ADR) and scores of extrapyramidal symptoms (EPS), sexual/reproductive dysfunction, body weight, Clinical Global Impression-schizophrenia (CGI-SCH), Euro-QOL and social function were observed for 12 months. CGI-SCH was significantly improved in all subscales at the end of the surveillance and the rate of deterioration was less than 5% in all items.
HRQOL score was calculated according to Tariff in the Japanese version of EQ-5D and it significantly increased by 0.1658 at the endpoint compared with baseline score (p<0.001).
Housing conditions; 14.77% (118/799) of patients were inpatients at baseline and became outpatients at endpoint. Work status; patients who did not work at baseline and being able to work at the end were seen in 4.52% (68/1504). Number of social activities increased significantly at endpoint (21.87% (321/1468), p<0.001).
ADRs were observed in 23.78% of the 1,849 patients eligible for analysis. More numbers of patients showed improved scores of EPS and sexual/reproductive dysfunction than numbers of patients who deteriorated (p<0.001). Bulimia (3) appetite increased (44) obesity (11) and increased body weight (88) were reported as body weight-related ADRs.

Shinichi Nishiuma ¹⁾,　Hiroshi Ueno ²⁾, Noriko Takagaki ³⁾, Miwa Sakaridani ³⁾, Shinji Fujikoshi ⁴⁾，Michihiro Takahashi ¹⁾ and Gohei Yagi ⁵⁾

１）Clinical Research Physician, Neuroscience Products, Lilly Research Laboratories Japan, Eli Lilly Japan
２）Safety Physician, Global Patient Safety Japan, Eli Lilly Japan
３）Postmarketing study planning and management, Global Product Safety Japan, Eli Lilly Japan
４）Statistics Planning, Japan Clinical Research, Lilly Research Laboratories Japan, Eli Lilly Japan
５）SUISEI Healing Center

We report final result about efficacy and safety of olanzapine in the postmarketing prospective study. 4,014 patients were enrolled in this study. 2,557 and 3,753 patients were eligible for efficacy and safety analysis, respectively. Among patients eligible for efficacy, moderate improvement or above was observed in 37.48 % with significantly decreased use of concomitant anti-Parkinson medication and improved severity of EPS. Among patients eligible for safety analysis, adverse drug reactions (ADR) were observed in 38.45%. ADR related to weight gain was seen in 9.14% and average maximum weight gain was about 3.5kg. BS related ADR was observed in 3.97%. Of these, 6 cases were reported as serious; however no patient experienced acute metabolic issue such as diabetic ketoacidosis. Based on the Japanese guideline, 16.05％（223/1,389）with normal BS at baseline showed borderline or DM type BS at least once and 1.43%(21/1,465）with normal BS at baseline met the criteria of diabetes mellitus. FBS elevation was observed independent from duration of treatment and it was not correlated with BMI increase. Therefore, regular monitoring of BS is required regardless of duration of treatment and presence of weight gain.

Hiroyuki Kamei ^{1) 2)}, Keiko Takagi ²⁾, Yoshio Yamanouchi ¹⁾, Hiroshi Naito ¹⁾, Nakao Iwata ¹⁾

１）Department of Psychiatry, Fujita Health University School of Medicine
２）Faculty of Pharmacy, Meijo University.

The long-term goal of the treatment of schizophrenia is the prevention of recurrence. To achieve this goal, the continuation of medication is important. We considered that the continuation of medication may require improvement in insight / medication adherence, not improvement in symptoms by involuntarily medication, and evaluated the association between the severity of symptoms and insight / medication adherence. The subjects comprised 101 outpatients with schizophrenia. Psychiatric symptoms were evaluated using BPRS and CGI, illness insight using SAI, and drug adherence using DAI-10.
There was no association between BPRS and CGI or DAI-10. However, a positive correlation was observed between SAI and DAI-10. These results suggest a poor medication adherence in patients who are not aware of their own disease and no association between medication adherence and the severity of psychiatric symptoms. In terms of the long-term prognosis of schizophrenia, the continuation of medication by improving insight / medication adherence, not improvement in symptoms by involuntarily medication, is important. As a result of the continuation of medication by this approach, psychiatric symptoms may improve, leading to the prevention of recurrence.

Itaru Utagawa, Yumiyo Morokawa, Shin Ogino, Nobumi Miyake, Takako Endoh, Seiya Miyamoto, Noboru Yamaguchi

Department of Psychiatry, St. Marianna University School of Medicine

1. Objective
To clarify what prescriptions are currently being written for schizophrenia outpatients
2. Methodology and Subjects
From May to August 2005, we conducted a “Survey of the Efficacy and Adverse Reactions of Psychiatric Medications Prescribed to Outpatients” and 525 were from individuals who had been diagnosed with schizophrenia or schizoaffective disorder according to the DSM-IV-TR.
3. Results
Risperidone (RIS) accounted for most antipsychotic drug prescriptions(48.6%), followed by haloperidol. Second generation antipsychotics (SGAs) monotherapy regimens accounted for less than 30%(156/52⁵⁾, and RIS accounted for the majority of these (63.5%(99/156)). Multiple drugs regimens accounted for 59.6%(313/525). When SGAs were used concomitantly with first generation antipsychotics, they were most often used with phenothiazines. Anticholinergics were the most frequently used among patients concomitantly receiving multiple drugs, having been prescribed to 70.9% of the respondents; benzodiazepines was next, at approximately 40%.
4. Conclusions
It was inferred that both are used in a relatively carefree fashion over long periods of time, and it is believed to be important to reconsider how they are prescribed.

Hisae Ono, Shukurin Tan, Yoshihisa Narita, Shinji Fujikoshi, Masashi Takahashi, Michihiro Takahashi

Lilly Research Laboratories Japan, Eli Lilly Japan K.K.

INTRDUCTION: Eli Lilly and Company developed Agitation-Calmness Evaluation Scale (ACESc) in 1998. Eli Lilly Japan K.K. conducted a reliability testing of the Japanese version of ACESc.
METHODS: A reliability testing was conducted at an investigator protocol-training meeting of early phase II clinical study of rapid-acting intra-muscular olanzapine. Videotaped 6 clinical vignettes were rated using the Japanese version of ACESc. The concordance rate in the ACESc scores between 59 clinical investigators and expert panel was studied. The Japanese version of ACESc was prepared by Eli Lilly Japan K.K. and was approved by Eli Lilly and Company, which is the copyright holder.
RESULTS: The concordance rate in each case was as follows: Case1 56.1%, Case2 86.4%, Case3 94.9%, Case4 66.1%, Case5 94.0%, Case6 89.7%. The average concordance rate was 81.5%. When a 1-point difference in ACESc score was allowed, the concordance rate in each case was as follows: Case1 96.5%, Case2 100%, Case3 96.6%, Case4 98.3%, Case5 98.3%, Case6 100%. The average concordance rate increased to 98.6%. DISCUSSION &　CONCLUSION: High concordance rate was revealed in the use of the Japanese version of ACESc. The possibility that the Japanese version of ACESc can be used in Japan was shown.

Hiroki Kikuyama ^1,2), Tetsufumi Kanazawa ^1,3), Atsushi Tsutsumi 1,⁴⁾, Gaku Okugawa ⁵⁾,
Toshihiko Kinoshita ⁵⁾, Kazuhiro Shinosaki ⁶⁾, Toshi Kishimoto ⁷⁾, Jun Koh ¹⁾, Hiroshi Yoneda ¹⁾

１）Department of Neuropsychiatry, Osaka Medical College.
２）Osaka Psychiatric Institute, Shin-Abuyama Hospital.
３）Ozone Hospital.
４）Shin-awaji Hospital.
５）Department of Neuropsychiatry, Kansai Medical University.
６）Department of Neuropsychiatry, Wakayama Medical University.
７）Department of Psychiatry, Nara Medical University.

Background: There are many types to antipsychotics. However, an index to predict for an individual patient whether treatment reactivity of which medicine is high is absent. Therefore we studied relations of the genetic polymorphism to develop a rational drug selection method of the schizophrenia if treatment of Risperidone and Perospirone which were SDAs was reactive. It is associated with an effect of each medicine that the receptive affinity profiles of the serotonin nervous system are different.
Methods: Therefore we conducted an investigation into serotonin transporter gene 17bpVNTR polymorphism that a significant result was reported in a meta-analysis and the relations of the PANSS degree of improvement. This study was performed as a part of the studies of "Kansai Four College Study Meeting".
Result: We reviewed interaction about a difference of the PANSS change of each medicine by the polymorphism of 17bp VNTR, but did not recognize the difference (P=0.655).
Conclusion: We cannot predict a clinical response of Risperidone and Perospirone by the polymorphism of 17bp VNTR.

Tetsufumi Kanazawa ^1,2), Hiroki Kikuyama 1,³⁾, Atsushi Tsutsumi 1,⁴⁾, Gaku Okugawa ⁵⁾,
Toshihiko Kinoshita ⁵⁾, Kazuhiro Shinosaki ⁶⁾, Toshi Kishimoto ⁷⁾, Jun Koh ¹⁾, Hiroshi Yoneda ¹⁾

１）Department of Neuropsychiatry, Osaka Medical College.
２）Ozone Hospital.
３）Osaka Psychiatric Institute, Shin-Abuyama Hospital.
４）Shin-awaji Hospital.
５）Department of Neuropsychiatry, Kansai Medical University.
６）Department of Neuropsychiatry, Wakayama Medical University.
７）Department of Psychiatry, Nara Medical University.

Background: There are many types to antipsychotics. However, an index to predict for an individual patient whether treatment reactivity of which medicine is high is absent. Therefore we studied relations of the genetic polymorphism to develop a rational drug selection method of the schizophrenia if treatment of Risperidone and Perospirone which were SDAs was reactive. It is associated with an effect of each medicine that the receptive affinity profiles of the Dopamine nervous system are different.
Methods: Therefore we conducted an investigation into rs1801028 and rs6277 polymorphisms of DRD2 gene that a significant result was reported in a meta-analysis and the relations of the PANSS degree of improvement. This study was performed as a part of the studies of "Kansai Four College Study Meeting".
Result: We reviewed interaction about a difference of the PANSS change of each medicine by the polymorphisms of rs1801028 and rs6277, but did not recognize the difference.
Conclusion: We cannot predict a clinical response of Risperidone and Perospirone by the polymorphism of DRD2.

Atsushi Tsutsumi ^1,2), Hiroki Kikuyama ^1,3), Tetsufumi Kanazawa ^1,4), Gaku Okugawa ⁵⁾,
Toshihiko Kinoshita ⁵⁾, Kazuhiro Shinosaki ⁶⁾, Toshi Kishimoto ⁷⁾, Jun Koh ¹⁾, Hiroshi Yoneda ¹⁾

１）Department of Neuropsychiatry, Osaka Medical College.
２）Shin-awaji Hospital.
３）Osaka Psychiatric Institute, Shin-Abuyama Hospital.
４）Ozone Hospital.
５）Department of Neuropsychiatry, Kansai Medical University.
６）Department of Neuropsychiatry, Wakayama Medical University.
７）Department of Psychiatry, Nara Medical University.

Background: There are many types to antipsychotics. However, an index to predict for an individual patient whether treatment reactivity of which medicine is high is absent. Therefore we studied relations of the genetic polymorphism to develop a rational drug selection method of the schizophrenia if treatment of Risperidone and Perospirone which were SDAs was reactive. It is associated with an effect of each medicine that the receptive affinity profiles of the Dopamine nervous system are different.
Methods: Therefore we conducted an investigation into 120bp TR and rs1800955 polymorphisms of DRD4 gene that a significant result was reported in a meta-analysis and the relations of the PANSS degree of improvement. This study was performed as a part of the studies of "Kansai Four College Study Meeting".
Results: As a result, when R1/R2 was genotypical polymorphism of 120bpTR, symptom degree of improvement of Risperidone was significantly higher than Perospirone (P=0.008). In perospirone, symptom degree of improvement was significantly higher rs1800955 polymorphism CT genotype than TT genotype (P=0.006).
Conclusion: It was shown that we could predict an effect of Risperidone and Perospirone by DRD4 genetic polymorphism.

Kensuke Utsunomiya ^1)*, Takahiro Shinkai ¹⁾²⁾, Shinichi Sakata ¹⁾, Yuko Fukunaka ¹⁾,
Yoshiaki Inoue ¹⁾, Wakana Yamaguchi ¹⁾, Kazuko Shimizu ¹⁾, Osamu Ohmori 1)³⁾,
Jun Nakamura¹⁾

１）Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
２）Health Management Department, Shimonoseki Shipyard & Machinery Works, Mitsubishi Heavy Industries, Ltd., Shimonoseki, 750-8505, Japan
３）Wakato Hospital, Wakamatsu-ku, Kitakyushu, 808-0132, Japan

It has been reported that the dopamine systems are involved in the promotion of water consumption. It has been reported that the administration of dopamine D1 receptor antagonist, SCH 23390, reduces water consumption in rats (Mittleman et al., J Pharmacol Exp Ther. 1994 Nov; 271(2):638-50). These findings imply that the dopamine D1 receptors may be associated with the excess of water consumption in schizophrenia. In the present study, we examined a possible association between the -48A/G polymorphism of the DRD1 gene and polydipsia in patients with schizophrenia. .
Our sample includes 347 Japanese schizophrenia patients with DSM-IV (polydipsia (-), n = 263; polydipsia (+), n = 84). Informed consent was obtained from all subjects, and this study was approved by the Ethics Committee of the University of Occupational and Environmental Health, Japan.
Genotyping was assessed by the TaqMan allele-specific assay method using ABI PRISMR 7000 (Applied Biosystems). Differences in allele and genotype distribution between cases with and without polydipsia were evaluated using the χ2 test.
No significant association between the DRD1 -48A/G polymorphism and polydipsia was found (genotype distribution:χ2 = 1.76, d.f. = 2, p =0.414; allele frequency:χ2 = 0.00, d.f. = 1, p = 0.994).
Our results suggest that the DRD1 -48A/G polymorphism may not confer polydipsia in schizophrenia.

Shinichi Sakata ¹⁾, Takahiro Shinkai ¹⁾²⁾, Kensuke Utsunomiya ¹⁾, Yoshiaki Inoue ¹⁾,
Jun Nakamura ¹⁾

１）Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
２）Health Management Department, Shimonoseki Shipyard & Machinery Works, Mitsubishi Heavy Industries, Ltd., Shimonoseki, 750-8505, Japan

Rationale: The underlying pathophysiology of primary polydipsia in schizophrenia is poorly understood. Our previous study, however, suggested that this condition may have genetic component. Serotonin (5-HT) seems to play an important role in drinking behavior. The 5-HT2a receptor (HTR2A) may play an inhibitory role in the lateral parabrachial nucleus (LPBN), the potentially important region for the control of water intake, on angiotensin II (AT II)-induced drinking. A recent mRNA expression study showed that the HTR2A T102C polymorphism may confer the differential allele-specific expression of the HTR2A gene. In view of these findings, we examined the association between polydipsia in schizophrenia and the HTR2A T102C polymorphism in a Japanese sample of schizophrenia.
Material and Methods: Our sample includes 346 patients with schizophrenia (DSM-IV) (84 with polydipsia and 262 without polydipsia). Informed consent was a premise for participation, and this study was approved by the Ethics Committee of the University of Occupational and Environmental Health. Genotyping was assessed by the TaqMan allele-specific assay method using ABI PRISMR 7000 (Applied Biosystems) at the Bio-information Research Center, University of Occupational and Environmental Health. Differences in allele and genotype distribution between cases and controls were evaluated using the χ2 test.
Results: No significant association between the HTR2A T102C polymorphism and polydipsia was found (genotype: χ2 = 0.59, d.f. = 2, p = 0.746; allele frequency: χ2 = 0.20, d.f. = 1, p = 0.653).
Conclusion: Our results suggest that the HTR2A T102C polymorphism may not confer susceptibility to polydipsia in our sample.

Takahiro Shinkai ¹⁾²⁾, Kensuke Utsunomiya ¹⁾, Shinichi Sakata ¹⁾, Yoshiaki Inoue ¹⁾,
Wakana Yamaguchi ¹⁾, Yuko Fukunaka ¹⁾, Osamu Ohmori ¹⁾³⁾, Jun Nakamura ¹⁾

１）Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
２）Health Management Department, Shimonoseki Shipyard & Machinery Works, Mitsubishi Heavy Industries, Ltd., Shimonoseki, 750-8505, Japan
３）Wakato Hospital, Wakamatsu-ku, Kitakyushu, 808-0132, Japan

Rationale: Several lines of studies suggest that serotonergic (5-hydroxytryptamine, 5-HT) systems are involved in the control of sodium and water intake. Activation of 5-HT receptors caused by central administration of several 5-HT agonists inhibits salt intake. Previous studies have demonstrated that pretreatment with bilateral injections of the 5-HT receptor antagonist methysergide into the lateral parabrachial nucleus (LPBN), a structure lying dorsolateral to the superior cerebellar peduncle in the pons, enhances the salt and water intake induced by several physiological and pharmacological stimuli. Meanwhile, it is postulated that atypical antipsychotics, clozapine most typically, are beneficial for the treatment of polydipsia in schizophrenia, which has relatively high affinity with 5-HT2a receptors compared with dopamine D2 receptors. Therefore, it may be speculated that tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of 5-HT, may be associated with polydipsia in schizophrenia. We examined the association between two single nucleotide polymorphisms (SNPs) (rs7305115 and rs1386483) and polydipsia in schizophrenia in a Japanese sample of schizophrenia.
Material and Methods: Our sample includes 346 patients with schizophrenia (DSM-IV) (84 with polydipsia and 262 without polydipsia). Informed consent was obtained from all subjects, and this study was approved by the Ethics Committee of the University of Occupational and Environmental Health. Genotyping was assessed by the TaqMan allele-specific assay method using ABI PRISMR 7000 (Applied Biosystems) at the Bio-information Research Center, University of Occupational and Environmental Health. Differences in allele and genotype distribution between cases and controls were evaluated using the ?2 test. Results: No significant association between polydipsia and rs7305115 (genotype: χ2 = 0.47, df = 2, p = 0.0.79; allele: χ2 = 0.38, df = 1, p = 0.54) or rs1386483 (genotype: χ2 = 1.96, df = 2, p = 0.38; allele: χ2 = 0.25, df = 1, p = 0.61) was found.
Conclusion: Our results suggest that the TPH2 polymorphisms may not confer susceptibility to polydipsia in schizophrenia. Related data including haplotype analysis will be presented.

Yoshiaki Inoue ¹⁾, Takahiro Shinkai ¹⁾²⁾, Hiroko Hori ¹⁾, Kensuke Utsunomiya ¹⁾, Shinichi Sakata ¹⁾, Wakana Yamaguchi ¹⁾, Yui Naoe ¹⁾, Yuko Fukunaka ¹⁾, Kazuko Shimizu ¹⁾ Osamu Ohmori ¹⁾³⁾,
Jun Nakamura ¹⁾

１）Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
２）Health Management Department, Shimonoseki Shipyard & Machinery Works, Mitsubishi Heavy Industries, Ltd., Shimonoseki, 750-8505, Japan
３）Wakato Hospital, Wakamatsu-ku, Kitakyushu, 808-0132, Japan

Rationale: It has been suggested that hypoactivity of neuropeptide Y (NPY) may be involved in the pathophysiology of schizophrenia. A post-mortem study revealed a decreased level of NPY in the brain of patients with schizophrenia (Gabriel et al., 1996). An increased level of NPY after neuroleptic treatment was also reported in animal brain and cerebrospinal fluid of patients (Sakai et al., 1995). Recently Itokawa et al. (2003) reported a positive association between the functional -485C>T polymorphism in the NYP gene and schizophrenia in a Japanese sample. The purpose of this study is to replicate their positive findings.
Material and Methods: Our sample includes 344 patients with schizophrenia (DSM-IV) and 196 control subjects. Informed consent was obtained from all subjects, and this study was approved by the Ethics Committee of the University of Occupational and Environmental Health, Japan. Genotyping was assessed by the TaqMan allele-specific assay method using ABI PRISM® 7000 (Applied Biosystems) at the Bio-information Research Center, University of Occupational and Environmental Health. Differences in allele and genotype distribution between cases and controls were evaluated using the χ2 test.
Results: No significant differences in genotype distribution or allele frequencies between patients and controls were observed.
Conclusion: Our results suggest that the -485C>T polymorphism in the NPY gene may not confer susceptibility to schizophrenia in our sample. Further studies with larger samples are warranted.

Furuya Motohide¹⁾²⁾ Miyaoka Tsuyoshi ¹⁾, Kunishige Kazuhiko²⁾ Horiguchi Jun ¹⁾

１）89-1 Enya-Cho,Izumo,Shimane 693-8501,Japan
Department of Neuropsychiatry,Shimane University School of Medicine,Izumo,Japan
２）3656-1 Outu-Cho,Izumo,Shimane,693-0011,Japan
Kaisei Hospital

Background： Recently, it has attracted attention that Yi-Gan San is effective for behavioral psychological symptoms of dementia (BPSD), particularly visual hallucination of dementia with Lewy bodies (DLB). We report a case with successful adjunctive treatment of Yi-Gan San for schizophrenia with mono-therapy of atypical antipsychotics.
Case：A 25-year-old single man, began to hear a voice commenting on his behavior and insomnia at 17. Since then, total 14 times, he must have entered and left hospital. At 23, he admitted for improvement of life habit, because he could not brush his teeth even for high dosage typical antipsychotics medication. After about 10 months, though main drugs switched to atypical antipsychotics, it came to be little effect. So we administered Yi-gan san him as adjunctive treatment, thereafter, he clearly changed his face and behavior and communication ability after 4 days. Once TJ-54 discontinued for adherence issue, re-administered with his and his family’s wish, so we confirm improvement of his psychotic condition after 1 week.
Conclusion：TJ-54 is possible for adjunctive treatment of schizophrenia.

Yusuke Murata¹⁾, Daisuke Kobayashi²⁾, Kazunori Mine¹⁾

１）Department of Psychosomatic Medicine, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
２）Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

Background: Paroxetine, a selective serotonin reuptake inhibitor (SSRI), has now become the first-line treatment for depression and anxiety disorder because of its better adverse-effect profile and safety. However, discontinuation syndrome following withdrawal or dose reduction of SSRIs has been recently documented. There are no studies with regard to assess the relation of SSRI discontinuation syndrome and gene polymorphisms. In this study, we investigated the effect of the genetic polymorphisms in the CYP2D6, serotonin transporter, and serotonin receptor subtypes genes on the incidence of paroxetine-induced discontinuation syndrome.
Methods: The subjects were a series of 111 consecutive outpatients who were treated with paroxetine in Kyushu University Hospital. Paroxetine discontinuation syndrome was assessed according to the definition described by Black et al. For the assessment, pharmacists interviewed the patients after the abrupt discontinuation or dose-tapered of paroxetine treatment.
Results: Paroxetine-induced discontinuation syndrome was observed in 24.4% of the subjects. Subjects who abruptly discontinued paroxetine therapy experienced discontinuation syndrome more frequently than subjects who dose-tapered of paroxetine. No relationship was observed between the incidence of the discontinuation syndrome and serotonin-related genetic polymorphisms.
Discussion: It is concluded that the dose-tapering of paroxetine may be important to avoid the occurrence of the discontinuation syndrome.

Hidetoshi Takahashi, Masao Iwase, Ryouhei Ishii, Yuka Yasuda, Tetsuhiko Yoshida, Kazutaka Ohi, Michiyo Azechi, Kouji Ikezawa, Ryu Kurimoto, Leonides Canuet, Takayuki Nakahachi, Naomi Iike, Ryota Hashimoto, Masatoshi Takeda

Psychiatry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

The objective of the present study is to assess prepulse inhibition (PPI) and habituation (HAB) of the acoustic startle response (ASR) in Japanese patients with major depression and to examine the effect of sertraline hydrochloride on these neurophysiologic measures in these patients.
The subjects were nine patients with the diagnosis on major depression according to DSM-IV and 27 sex- and age-matched healthy controls. We measured ASR by using the Startle Eyeblink Reflex Analysis System Map1155SYS (NIHONSANTEKU Co., Osaka, Japan). Three patients were tested before and two month after they started medication of sertraline hydrochloride. Severity of the illness was assessed using the 21-item Hamilton Depression Scale (HAMD).
Compared with healthy controls, patients had significantly decreased startle amplitude in the pulse alone trial and exhibited significant deficits in HAB. However, there was no significant difference between two groups on PPI. All three patients with medication of sertraline hydrochloride showed decreased HAMD score and increased PPI at 86dB prepulse condition.
These results suggest that, under the present paradigmatic conditions, sertraline hydrochloride might increase PPI with the improvement of depression.

Okuda Akiko 1)³⁾, Suzuki Tatsuyo ²⁾, Yamanouchi Yoshio ³⁾, Umeda Kazunori ⁴⁾
Naito Hiroshi ³⁾, Hashimoto Shuji ⁵⁾, Ozaki Norio ⁶⁾, Iwata Nakao ³⁾

１）Department of Psychiatry, Toyota Memorial Hospital
２）Department of Psychiatry, Okehazama Hospital
３）Department of Psychiatry, Fujita Health University
４）Hamamatsu Psychiatry and Neurology Hospital
５）Division of Public Health, Fujita Health University
６）Division of Parent-Child Relationship, Department of Psychiatry, Nagoya University Graduate School of Medicine

One hundred and forty eight outpatients with major depressive disorder (men: women = 77: 71, mean age = 43 ± 15 years) were performed to analyze the relation between the time from subjective awareness of a depressed mood to start of treatment and response to treatment with fluvoxamine(FLV) and to examine the necessity of early treatment.
The therapeutic effects were evaluated using the Hamilton Depression Rating Scale (HAM-D),and multiple regression analysis and logistic regression analysis were performed.
The improvement rate in regression analysis was reduced by 2% with each 4-week delay in the start of treatment (P = 0.0002). In terms of remission, the percentage achieving remission was reduced by 10% with each 4-week delay in the start of treatment (P = 0.024). Cases of remission showed a sharp decrease in the group with a course of more than 25 weeks (P = 0.004, odds ratio: 5.59).
The period of time until treatment of major depressive disorder is related to both the improvement rate and presence or absence of remission. Early treatment within 24 weeks after subjective awareness of a depressed mood is considered to be an important factor in improving treatment outcome.

Kazuo Yamada ¹⁾, Jun Ishigooka ²⁾, Shigenobu Kanba ³⁾

１）Department of Psychiatry, Tokyo Women’s Medical University, Medical Center East
２）Department of Psychiatry, Tokyo Women’s Medical University
３）Department of Neuropsychiatry, Kyushu University, Graduate School of Medical Science

The aim of this study was to develop the evidence-based guideline for treatment of bipolar depression (major depressive episode of bipolar I or II disorder) in Japan. The data used for this guideline has been extracted from a search of the MEDLINE database and Cochrane Library, and opinions from Japanese experts in the treatment of bipolar depression were added. Lithium, antidepressants, lamotrigine and atypical antipsychotics including quetiapine and olanzapine had high-level evidence data in the treatment of bipolar depression. From these evidence data and circumstances in Japan, we attempted to prepare the evidence-based guideline for treatment of bipolar depression in Japan. Lithium (> 0.8 mmol/L) or quetiapine (300 mg/day) was recommended as a first-line treatment for acute bipolar depression. The remaining first-line treatment, the addition of a selective serotonin reuptake inhibitor (SSRI) to a first-line drug, olanzapine, lithium plus quetiapine or olanzapine, electroconvulsive therapy (ECT), or the addition of valproate or carbamazepine to a first-line drug was recommended as a second-line treatment for acute bipolar depression. Lamotrigine and olanzapine/fluoxetine are not yet available, but are presently under investigation in Japan.

Akeo Kurumaji, Kazunari Oshima, Ko Huruta, Tomoyuki Yukizane, Hidakazu Masaki, Toshiyuki Hirasawa, Hidenori Atsuta, Hiroshi Arakaki, Tomo Terada, Toru Nishikawa.

Tokyo Medical and Dental University Graduate School, Section of Psychiatry and Behavioral Sciences.

This study was carried out on 95 inpatients with mood disorders at the Psychiatric Department, Tokyo Medical and Dental University, Faculty of Medical Hospital from April 1, 2005 to March 31, 2006, after obtaining written informed consent. Sixty-seven of the 95 inpatients were diagnosed as depressive disorders, consisting of 26 patients with major depressive disorders, single episode and 41 patients with major depressive disorders, recurrent (DSM-IV-TR). Eleven of the 67 patients were treated with antidepressants as well as mood stabilizers (lithium, valproate and carbamazepine), because of hypomanic symptoms (e.g., irritable mood, more talkative and active than usual, racing thought) with or without depressive symptoms: five of the 11 patients were recognized as a depressive mixed state and the others were diagnosed as a substance-induced mood disorder. Although strict adherence to the criteria of DSM-IV-TR did not indicate to diagnose the patients with the hypomanic symptoms as bipolar disorders, the additive administration of mood stabilizers seemed to be essential on the clinical cases. Consequently, the present study suggests that there is an unsolved problem in the current diagnostic criteria for mood disorders, and that a proper guideline of pharmacotherapy for the hypomanic symptoms of depressive disorders is required.

Kunihiro Iwamoto ¹⁾, Masahiro Takahashi ¹⁾, Yukako Nakamura ¹⁾, Yukiko Kawamura ²⁾,
Ryoko Ishihara ¹⁾, Yuji Uchiyama ³⁾, Kazutoshi Ebe ³⁾, Akiko Noda ⁴⁾, Keizo Yoshida ¹⁾,
Tetsuya Iidaka ¹⁾, Norio Ozaki ¹⁾

１）Department of Psychiatry, Nagoya University, Graduate School of Medicine
２）The Meijyo University, Graduate School of Pharmaceutical Sciences
３）Toyota Central R&D Labs., Inc.
４）The Nagoya University, Graduate School of Health Sciences

Objective: The present study is designed to compare the effects of paroxetine (10 mg) and amitriptyline (25 mg) on driving performance while taking into consideration the realities of traffic accidents and cognitive function.
Methods: Seventeen healthy subjects received acute doses of paroxetine, amitriptyline, and placebo in a double-blinded, three-way crossover trial. Three driving tasks using a driving simulator−the road-tracking test, the car-following test, the harsh-braking test, and three cognitive tasks−the Wisconsin Card Sorting Test, Continuous Performance Test, and N-back test, were administered at baseline and at 1 h and 4 h post-dose.
Results: Amitriptyline, 4 h post-dose, significantly impaired road-tracking and car-following related driving performance and reduced driver vigilance. Paroxetine impaired neither driving performance nor cognitive function.
Conclusions: Acute doses of amitriptyline significantly impaired driving performance, based on real situations of traffic accidents and reduced vigilance in healthy male subjects, while those of paroxetine did not affect these driving or cognitive performances. The results suggest that the choice of antidepressants, in view of social reintegration, is important in terms of the safety of a motorized society.

Ken Wada ¹⁾, Takuji Fukumoto ¹⁾, Makiko Kishimoto ¹⁾, Takafumi Yamori ¹⁾, Takashi Iwamoto ¹⁾, Takanobu Sasaki ²⁾, Hiroaki Jitsuiki ³⁾,

１）Department of Psychiatry, Hiroshima City Hospital,
２）Sasaki Mental Clinic, ３）Department of Psychiatry, Hiroshima University Hospital

Objective: To investigate two-year outcome of unipolar depression patients with manic or hypomanic switch during acute antidepressant treatment.
Method: Review of the medical records revealed 37 consecutive patients who were admitted to our Department from 1997 to 2002. Their clinical course was followed for 2 years after discharge. Results: Study subjects were composed of 23 men and 14 women, whose average age was 48.8+/-12.3 years. Of the 37 patients, 30 (81.1%) patients were followed for 2 years after discharge. None developed a manic episode, 10 developed a hypomanic episode and 16 had a depressive episode, including 1 patient who lost to follow-up. Two patients developed hypomania during acute antidepressant treatment for recurrent depressive episode. Bipolar conversion occurred in 6 patients, including 1 patient with rapid cycling, during 1 year and in another 2 patients over the subsequent 1 year after discharge. Of the 30 patients, 26 continuously received maintenance treatment with mood stabilizers for 2 years after discharge.
Conclusion: During the 2-year follow-up period after discharge, bipolar conversion occurred in a few unipolar depression patients with antidepressant-induced manic or hypomanic switch in the previous depressive episode. Maintenance treatment with mood stabilizers might prevent both spontaneous and antidepressant-induced mania or hypomania.

Ayumu Miyamoto, Sunao Ochiai, Masamichi Motonishi　and Yuji Yanagi

Koujyukai Medical Corporation Mihara Hospital

In the present when selective serotonin reuptake inhibitor or serotonin noradrenalin reuptake inhibitor is the first line antidepressant for the treatment of major depressive disorder, amoxapine is a tricyclic antidepressant possessing dopamine-blocking activity, and its prescription frequency is still high. A case of neuroleptic malignant syndrome caused by amoxapine was reported. A 44-year-old married man had suffered from major depressive episodes for two years since his mother died. Hypnotic abuse was seen from October. He lied down all day, and refused to take a meal in November. Therefore he was admitted to our hospital in December. On his first hospital day only intravenous fluid was used in treatment due to gait disturbance caused by hypnotic overdoses. On hospital day 3 gait disturbance was ameliorated, and amoxapine 75mg/day, brotizolam 0.5mg/day and zolpidem 10mg/day were initiated. Although insomnia and psychomotor retardation remained, depressive mood and decreased appetite tended to be improved. On day 11 he developed akinetic mutism concomitant with hyperpyrexia, muscular rigidity, tremor, sialorrhea, and dysphagia. Then amoxapine was discontinued, and infusion was begun under the diagnosis of neuroleptic malignant syndrome (NMS). On day 12 dantrolene sodium was administrated, but symptoms of NMS were aggravated accompanied by seizures and dyspnea. Therefore he was immediately transferred to the acute critical care center and treated with mechanical ventilation, whole body cooling, dantrolene sodium, bromocriptine and phenytoin. He recovered from NMS five days after admission to the center.

Hiroshi Naitoh, Nakao Iwata

Department of Psychiatry, Fujita Health University, Toyoake, Japan

Idiosyncratic drug reactions may be defined as adverse effects that cannot be explained by the known mechanisms of action of the offending agent, do not occur at any dose in most patients, and develop mostly unpredictably in susceptible individuals only. Sodium valproate (VPA) has been in clinical use for the treatment of epilepsy since 1975 and bipolar disorder since 2002 in Japan. We report the case induced by VPA, mood stabilizer for adolescents with bipolar disorder. A 35-year-old man was treated with VPA for 6 weeks. He suddenly developed a fatigue, appetite loss, fever and agitation with hypereosinophilia and altered liver function. The syndrome resolved with the discontinuation of VPA. The time-course and assessment of drug induced liver injury by the diagnostic scale of the international consensus meeting establish the diagnosis. Drug-induced hypersensitivity is rarely induced by VPA. Although levels of hepatic enzymes may be elevated during an early reversible stage of VPA toxicity, by the time clinical symptoms develop, hepatic failure may be irreversible. The authors suggest that strict clinical monitoring for 3 months after administration of VPA is more important than laboratory monitoring.

Masayuki Sawada ¹⁾, Hideki Negoro ¹⁾, Takako Onishi ²⁾, Junzo Iida ³⁾, Toshifumi Kishimoto ¹⁾

１）Department of Psychiatry, Nara Medical University School of Medicine
840, shijo-cho, kashihara-shi, Nara, 634-8522, Japan
２）Kyo Mental Clinic
1-14-13, gakuenkita, nara-shi, Nara, 631-0036, Japan
３）Nara Medical University Faculty of Nursing
840, shijo-cho, kashihara-shi, Nara, 634-8522, Japan
４）Department of Psychiatry, Nara Medical University School of Medicine
840, shijo-cho, kashihara-shi, Nara, 634-8522, Japan

In medical treatment of obsessive-compulsive disorder (OCD), we have experienced some cases that their OCD symptoms are not adequately improved with one kind of medicine clinically. In such cases, there are a few cases where combination therapy more than a kind of medicine are effective. In a treatment of OCD, there are some reports which some cases of adult patients with OCD are effectively treated by fluvoxamine and olanzapine. However, in OCD patients less than 18 years old, any reports of combination therapy of fluvoxamine and olanzapine was not found when we had examined it. In this case report, we experienced a case of adolescent patient with OCD effectively treated by fluvoxamine and olanzapine. Therefore, in adolescent patients with OCD as well as adult patients with OCD, our case report indicated that it might be necessary to consider using combination therapy more than two kinds of medicines if their OCD symptoms were not adequately improved with one kind of medicine.

Yosuke Kokubo ¹⁾,Osamu Takashio ¹⁾,Tempei Otsubo ²⁾,Hiroaki Tanaka ¹⁾, Ryou Akita ¹⁾,
Genshin Minegishi ¹⁾,Bun Yamagata ¹⁾,Kenji Sanada ¹⁾,Hiroki Yamada ¹⁾,Koichi Ichimura ¹⁾,
Shigeo Torii ¹⁾, Yuka Okajima ¹⁾,Natuko Hirasima ¹⁾,Masaru Mimura ¹⁾, Nobumasa Katou ²⁾

１）Department of Psychiatry, Showa University East Hospital
１）Department of Psychiatry, School of Medicine, Showa University

[Object] Changes in drug treatments of panic disorder in this decade was surveyed.
[Method] Among outpatients who visited Showa University Higashi Hospital clinical psychiatry at the initial visit and were diagnosed with panic disorder by DSM-IV, 102 patients (male : 48, female :54 , average age 34.4 ± 11.1) of 1994-1996’s group、 and 211 patients (male :81, female :130, average age 35.8±13.2) of 2004-2006’s group were surveyed. Medical records on drug treatment of panic disorder during one month from first medical examination were retrospectively surveyed. Species and the prescribed daily dose of benzodiazepine (BZ) antianxiety agents were primarily investigated.
[Result] While in 94-96’s group, the tricyclic or tetracyclic antidepressant (TCA) was applied to 15 patients (14.7%), in 04-06’s group, the selective serotonin reuptake inhibitor (SSRI) was used for 137 patients (64.9%). Mean doses of BZ antianxiety agents (diazepam equivalent) by each patient of 94-96’s group and 04-06’s group were 7.4 ± 4.9 mg/day and 5.1 ± 3.7 mg/day, respectively, and the mean dose of 04-06’s group was significantly reduced(p<0.0001). While in 04-06’s group, ｍean doses of BZ antianxiety agents of the group not taking SSRI was 6.7 ± 4.5mg/day, ｍean doses of BZ antianxiety agents of the group taking SSRI was 4.9 ± 3.8mg/day, and the mean dose of the group taking SSRI was significantly high(p<0.01).
[Conclusion ] Drug treatments of panic disorder of 94-96’s group was compared with that of 04-06’s group, and consequently, mean dose of BZ by each patient was reduced.It was believed that in this decade, SSRI was firmly-established as a first choice for treatment of panic disorder,and tendency to refrain from BZ having problem of addiction at recommended dose was exhibited.

Takafumi Yoshida and Kenji Fukui

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

INTRODUCTION
Benzodiazepines are often administered for an extended period of time for anxiety disorder in Japan, leading to problems such as dependency. In contrast, tandospirone is not associated with drug dependence or withdrawal symptoms, and it is well-tolerated during long-term use. We herein report three cases of anxiety disorder that responded well to augmentation of selective serotonin reuptake inhibitors (SSRI) with tandospirone 60 mg.
CASE 1 　The patient was a 26-year-old woman diagnosed with obsessive-compulsive disorder. After making a mistake at work, she became obsessed with the thought that she might have injured someone, leading her to check over and over again. Her obsessive-compulsive symptoms improved slightly after treatment with fluvoxamine 50 mg, but she experienced pronounced dizziness. Therefore, the dose of fluvoxamine was lowered to 25 mg, but her obsessive-compulsive symptoms reappeared. Her obsessive-compulsive symptoms disappeared after addition of up to 60 mg of tandospirone.
CASE 2 　The patient was a 54-year-old woman diagnosed with generalized anxiety disorder. She was hospitalized for acute myocardial infarction. After discharge, she experienced chronic anxiety and frustration. Everything began to put her in a state of worry. It gradually became difficult for her to go outside alone, and she subsequently began to suffer from hypobulia and diminished interest. Her anxiety and frustration improved slightly with administration of paroxetine 20 mg, but she experienced pronounced generalized dullness. After lowering the dose of paroxetine to 10 mg and adding up to 60 mg of tandospirone, her anxiety resolved, and she was again able to enjoy hobbies and go outside alone.
CASE 3 　The patient was a 22-year-old man diagnosed with posttraumatic stress disorder. He was hospitalized for two weeks with a fracture of the left foot caused by a car accident. After discharge, he began to suffer from flashbacks and nightmares, chronic tension, loss of motivation and concentration, and panic attacks when he would start to get in a car. His fear and intrusive symptoms began to improve after taking paroxetine 40 mg and alprazolam 1.2 mg, but his tension and motivation/concentration did not improve, and drowsiness became more pronounced. After switching from alprazolam to tandospirone 60 mg, his tension and loss of motivation/concentration improved, and his drowsiness disappeared.

Kazumasa Shiozaki＊, Yoshio Hirayasu

Department of Psychiatry, School of Medicine, Yokohama City University
3-9 Fukuura, Kanazwa-Ku, Yokohama city 236-0004, Japan

[Introduction] Since the behavioral and psychological symptoms of dementia (BPSD) influence both the patient’s and family’s quality of life, appropriate treatment has to be provided. We report a case whose hallucinations and delusions improved as a result of treatment with donepezil.
[Case] A 77-year-old woman was examined because of memory disturbance and mental symptoms. Her MMSE score was 15 points.　A brain MRI examination revealed middle-class cerebral atrophy and multiple cerebral infarctions. When 50mg of quetiapine was prescribed, her auditory and visual hallucinations decreased. Afterwards, 8mg of perospirone was substituted for the quetiapine, and the patient went alone to a health resort in a neighboring prefecture without telling her family and returned in the next day. As a result of 100mg supplementation with cilostazol, her hallucinations and delusions seemed to be re-activated. These hallucinations and delusions disappeared after administration of donepezil. Her score on MMSE also improved slightly to 18 points.
[Discussion] This case was diagnosed as Alzheimer's disease with a vascular lesion.
Her hallucinations and delusions were not regarded as symptoms of delirium. This case suggests that choline substitution therapy using donepezil may be effective in the treatment of mental symptoms in patients with Alzheimer's disease.

Makiko Kishimoto ¹⁾ Ken Wada ¹⁾ Takuji Fukumoto ¹⁾ Takashi Iwamoto ¹⁾
Takafumi Yamori ¹⁾ Tomonobu Yano ¹⁾

１）Department of Psychiatry, Hiroshima City Hospital
２）Joge Yugaoka Hospital, Fuchu City

SSRI discontinuation syndrome has been frequently reported in the use of SSRI. We report a 34-year-old woman who experienced recurrent SSRI discontinuation syndrome with fasciculation and high CPK value. Since X - 3 years, she was treated with paroxetine at 40 mg/day at A hospital for her depression, but on May 6, X year, she discontinued to take this drug and on May 7 she developed fasciculation in her face and limbs with symptoms of anxiety and irritation. CPK value elevated to 4,167 IU/L. Under the diagnosis of SSRI discontinuation syndrome, administration of paroxetine at 40 mg/day was resumed and all the symptoms disappeared within 5 days. Thereafter, she was treated with paroxetine at 40 mg/day at A hospital, but on April 3, X + 1 year, she, feeling nauseated, ceased to take paroxetin. On April 4, she developed fasciculation in all her muscles with a slight elevation of CPK value. Administration of paroxetine was discontinued and electrolyte solutions were administered intravenously. All the symptoms disappeared within 3 days. Fasciculation does not generally appear by SSRI discontinuation syndrome and recurrence of this syndrome is rare. The present case is considered to have oversensitivity in the serotonin receptor system.

Go Endo ^{1) 2)}, Hirokazu Tachikawa ¹⁾, Takafumi Hori ³⁾, Nagafumi Doi ¹⁾,
Katuyoshi Mizukami ³⁾, Takashi Asada ³⁾

１）Ibaraki Prefectural Tomobe Hospital, Department of Psychiatry, Kasama, Japan
２）Division of Psychiatry, University of Tsukuba Hospital, Tsukuba, Japan
３）Department of Psychiatry, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

We report a patient who developed an acute mandibular dystonia possibly induced by concomitant administration of perospirone and clarithromycin. A case is 28 years old woman. At the age of 23, she was diagnosed as schizophrenia and treated with 8mg/day of perospirone. Two day before she consulted us, she caught a cold and clarithromycin 400 mg/day was prescribed by a family practitioner. The day after she took both of perospirone and clarithromycin, she felt difficulty in closing the mouth, and came to our hospital. She was diagnosed as acute mandibular dystonia and an intravenous injection of biperiden 5mg was administered, which resulted in relieving the difficulty in closing the mouth in several minutes. After she quit taking clarithromycin, dystonia was disappeared.
Perospirone is mainly metabolized by human cytochrome P450 3A4 (CYP3A4) to hydroxyperospirone. Hydroxyperospirone is reported to have less extrapyramidal symptoms compared with perospirone itself. In this case, taking clarithromycin, a CYP3A4 inhibitor, might have increased the blood concentration of perospirone resulting in dystonia. To our knowledge, there is no report that dystonia appeared after concomitant administration of perospirone and clarithromycin. We need to keep in mind that prescribing both of these might cause extrapyramidal symptoms.
Key words: Perospirone, dystonia, clarithromycin, side-effect, drug interactions

Yoshihiko Obara

Sapporo Kohsetu Hospital

Introduction: Improvement of sleep disturbance is reported recently by risperidone. There is nightmare as symptomatic one of the sleep disturbance. It is a phenomenon to usually awake from REM sleep immediately. We report the case who has improved nightmare by administering risperidone.
Case: 31 years old man with depression was controlled with an SSRI in ambulatory. There was a nightmare from November for X -1 year, and administration of clonazepam 6mg assumed that it was effective did not show improvement. A nightmare was improved by at bedtime administration of risperidone oral solution 1mg immediately in November in X year one year later.
Discussion: Adult sleep is divided into REM sleep and non-REM sleep. A nightmare occurs for the REM sleep period. In depression, REM latency shortens, and REM density increases, and orthosleep decreases. Therefore, it is thought that a nightmare is easy to come to develop. In the case, it is thought that a nightmare disappeared by improvement of hypnic quality such as increase of orthosleep, decrease of REM sleep and decrease of a halfway awakening by 5-HT2A receptor blockade of risperidone.