S1-4
Perospirone ? clinical comparison with risperidone

Gaku Okugawa

Department of Neuropsychiatry, Kansai Medical University

Perospirone is one of the second-generation antipsychotic agents for the treatment of schizophrenia. Perospirone binds with high affinity to serotonin 5-HT2A receptors and dopamine D2 receptors. There was no report of clinical comparison of perospirone and riaperidone in the literature. We compared clinical efficacy and adverse events between perospirone and risperidone in a randomized clinical multi-center trial. Sixty-seven schizophrenic patients were enrolled the trials for 12 weeks. PANSS scores and DIEPS scores were investigated at time of 0, 4, 8 and 12 weeks. A 12-week course of perospirone and risperidone displayed efficacy in the most patients with schizophrenia. Perospirone was effective against positive, negative and general symptoms in patients with schizophrenia. There was no significant difference of PANSS and DIEPS scores at the time of 0, 4, 8 and 12 weeks between perospirone and risperidone. The number of dropped out patients was larger perospirone than risperidone. In conclusion, perospirone and risperidone have similar efficacies in patients with schizophrenia. Perospirone is more useful neuroleptics due to less adverse events.

S1-5
Current position of aripiprazole and its future prospects

Seiya Miyamoto

Department of Neuropsychiatry, St. Marianna University School of Medicine, Kawasaki, Japan.

Aripiprazole is the first dopamine D2 receptor partial agonist approved as an antipsychotic and called a dopamine system stabilizer. Several short-term randomized double-blind trials of aripiprazole demonstrated its efficacy similar to haloperidol, olanzapine, and risperidone against positive symptoms, and greater than haloperidol against negative and depressive symptoms in patients with acute exacerbations of schizophrenia. Two long-term double-blind studies showed that aripiprazole is superior to placebo and haloperidol in maintaining antipsychotic response and relapse prevention. All of these studies have shown that aripiprazole has a favorable safety and tolerability profile, with low liability for extrapyramidal symptoms, tardive dyskinesia, weight gain, sedation, hyperprolactinemia, or QTc prolongation. Thus, aripiprazole has been listed as a first-line agent for the treatment of schizophrenia in the majority of international guidelines and algorisms. However, the agent exhibits a lack of predictable dose-response relationship for efficacy and adverse events. To date, three naturalistic effectiveness studies of aripiprazole have demonstrated better effectiveness than other available atypical antipsychotics in a real-world practice setting. Long-term practical effectiveness studies are necessary, particularly those examining relative effects of aripiprazole and different atypicals on cognitive function, relapse prevention, subjective well-being, treatment adherence, disease progression, function, quality of life, cost, and use of health services.

Takashi Okada

Division of Child and Adolescent Psychiatry, Department of Neuropsychiatry, Faculty of Medicine, Kyoto University

Recently, newly developed psychotropic drugs are suggested to be well-tolerated and significantly effective for comorbid symptoms of pervasive developmental disorders (PDDs) in both randomized controlled and open trials. Methylphenidate is medicated for hyperactivity/impulsivity or inattention; selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine and fluvoxamine, are often effective for repetitive or compulsive behaviors; alpha-2 agonist, clonidine and guanfacine are used for hyperarousal and hyperactivity; novel antipsychotics, such as risperidone and olanzapine, are medicated for irritability, tantrum and aggressiveness. However, it should be noted that children and adolescents with PDD may experience adverse events; for example insomnia, appetite loss, agitation, irritability, worsening of tics, social withdrawal in methylphenidate medication; agitation, sleep disturbance and nausea in SSRI medication; hypotension and sedation in alpha-2 agonist medication; obesity and sedation in neuroleptic medication. In general, pharmacotherapy is not effective for core symptoms of PDD, reactive behaviors to environments and maladaptive behaviors. At first, target symptoms for pharmacotherapy should be made clear. In addition, the risk-benefit balance and limitations of medications should be considered. Lastly, it should be emphasized that comprehensive treatments, combining pharmacotherapy and psychosocial approaches, are essential in treatments for individuals with PDD.

S2-4
Pharmacotherapy of children with Attention-Deficit/Hyperactivity Disorder

Junzo Iida MD.,PhD.1)　Hideki Negoro MD.,PhD.2)

１）Nara Medical University Faculty of Nursing
２）Nara Medical University Department of Psychiatry

Attention-Deficit/Hyperactivity Disorder(AD/HD) is a syndrome of childhood onset that is characterized by symptoms of inattention, hyperactivity, and impulsiveness. At present the pharmacological treatment is one of the most established and scientifically validated treatment in medicine. Recently, the NIMH Collaborative Multisite Multimodal Treatment Study of Children With AD/HD(MTA)randomized more than 500
children with AD/HD to four groups: community treatment, medication management, behavioral management, and combined medication management and behavioral management. After 14 months of treatment, those patients receiving expert medication management had superior outcomes to those treated in the community and behavioral management.
The Texas Children’s Medication Algorithm recommended a stimulant as the first stage of treatment. Stimulants improve the core symptoms of AD/HD that consists of inattention, impulsivity, and hyperactivity. But they also improve concomitant symptoms, that include oppositionalism and noncompliance, aggressivity, social interactions, and academic productivity and academic accuracy. Recent studies indicate that both behavior and cognitive performance improve with stimulant treatment in a dose-dependent fashion.
The stimulants bind to the dopamine transporter on presynaptic axons, blocking reuptake, thus leading to an increase in synaptic dopamine. The stimulant-related reduction in psychomotor activity has been thought to be mediated by dopamine stimulation of striatal structures and secondary effects on prefrontal areas.

S3-2
Early Investigational New Drug for CNS using Positron Emission Tomography

Tetsuya Suhara, MD, PhD

Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.

Positron emission tomography (PET) techniques have enabled the visualization of target molecules of various psychotropic drugs, such as receptors and transporters in the living human brain. The concept of occupancy has been used as a reliable index for therapeutic drug monitoring at specific binding sites. Previous PET studies on antipsychotics have suggested that 70%-80% of central dopamine D2 receptor occupancy provides the desired therapeutic effects without any extrapyramidal symptom. Our PET study indicated that some of the first-generation antipsychotics such as sultopride, have been fixed in overdose. With regard to the time course, we demonstrated a discrepancy between the half-life of serum concentration and that of receptor occupancy. We also suggested that receptor occupancies could be predicted by the plasma concentrations of drugs from a simulation study. Regarding the antidepressant therapy, serotonin transporter occupancy is also used as one of the indices for the evaluation of antidepressants such as selective serotonin reuptake inhibitors. Clinical doses of clomipramine and fluvoxamine occupied about 80% of serotonin transporter, and dose escalation would have minimal effect on serotonin transporter blockade. Recent studies have elucidated that drug efflux transporters, which act at the blood-brain barrier, play a critical role in the penetration of drugs into the brain. In particular, significant attention has been paid to P-glycoprotein, one of the drug efflux transporters, because variety of drugs including psychotropics reported to be its substrates. The application of PET method on drug evaluation can provide us useful information about the characteristics of psychotropics, including an optimal clinical dose and the kinetic profile at the sites of action as well as their ability to penetrate into the brain.

Takano A, Suhara T, Ikoma Y, Yasuno F, Maeda J et al.: Estimation of the time-course of dopamine D2 receptor occupancy in living human brain from plasma pharmacokinetics of antipsychotics. Int J Neuropsychopharmacol 7: 19-26, 2004
Takano A, Suhara T, Yasuno F, Suzuki K, Takahashi H et al.: The antipsychotic sultopride is overdosed - a PET study of drug-induced receptor occupancy in comparison with sulpiride. Int J Neuropsychopharmacol 1-7, 2005
Takano A, Suzuki K, Kosaka J, Ota M, Nozaki S et al.: A dose-finding study of duloxetine based on serotonin transporter occupancy. Psychopharmacology (Berl) 185: 395-399, 2006
Takano A, Kusuhara H, Suhara T, Ieiri I, Morimoto T et al.: Evaluation of In Vivo P-Glycoprotein Function at the Blood-Brain Barrier Among MDR1 Gene Polymorphisms by Using 11C-Verapamil. J Nucl Med 47: 1427-1433, 2006

S3-4
Source localizations of EEG oscillatory activity in association with plasma concentrations of antiepileptic drugs

Ryouhei Ishii, Leonides Canuet , Ryu Kurimoto, Koji Ikezawa, Michiyo Azechi, Hidetoshi Takahashi, Takayuki Nakahachi, Masao Iwase, Masatoshi Takeda

Department of Psychiatry, Osaka University, Osaka, Japan

The overall effects of antiepileptic drugs (AEDS) on EEG power spectrum have been explored by a number of studies, on the basis of neurophysiological and neuropsychological measures. However, few neuroimaging studies have addressed the source localizations of brain oscillatory activity changes induced by AEDs. It has been reported that several AEDs are related to EEG background slowing pattern. Since EEG slowing is generally considered as indicator of central nervous system dysfunction, specifically neuronal biochemical disturbance, the localization of EEG changes associated to chronic AED therapy might help in the recognition of drug-related neurotoxicity. In this paper we report on source localizations of resting, awake EEG related to chronic carbamazepine and valproic acid monotherapy in patients with cryptogenic localization-related epilepsy. By using standardized Low-Resolution Electromagnetic Tomography (sLORETA) we evaluated the correlation of plasma concentrations of AEDs with EEG sources of brain oscillatory activity in the conventional frequency bands (Delta, theta, alpha1, alpha2, beta1, beta2, beta3). The presence of significant EEG slowing in these patients that was particularly distributed over the frontal regions in association with increased plasma levels of AEDs, is consistent with reports of mental abnormalities involving frontal network in patients with long-term epilepsy. EEG oscillatory activity changes might be clinically useful as a measure of AED-related neurotoxicity.

S4-1
Pharmacologic Profile of Fluvoxamine and its Implication in the Treatment of Depression and Anxiety Disorders

Osamu Tajima, MD, PhD,

Department of Mental Health, Kyorin University School of Health Sciences

Fluvaximine is the first SSRI launched in Japan and widely used for the treatment of depression and anxiety disorders, particularly obsessive-compulsive disorder and social anxiety disorder. Compared with other SSRIs such as fluoxetine, citalopram, paroxetine and sertraline, prescription of fluvoxamine is very low in other countries mainly because of somewhat higher incidence of gastrointestinal side effects especially nausea due to higher starting dose, 100mg/day. Contrary to the impression among clinicians that fluvoxamine has lower tolerability and efficacy, fluvoxamine has lower affinity for muscarinic and histaminergic receptors compared to paroxetine, sertraline and citalopram and highest affinity for sigma-1 receptors among SSRIs now available and has comparable efficacy and tolerability. Fluvoxamine may have fewer effects on sexual function, sleep pattern and behavioral arousal. Although the clinical significance of binding to sigma-1 receptors remains uncertain, it has been suggested that the sigma-1 receptors in the brain might be involved in the pathophysiology of anxiety, depression and psychosis. The place of fluvoxamine in the pharmacotherapy of depression and anxiety disorders, especially its potential usefulness for psychotic depression was discussed.

Takeshi Inoue, Yuji Kitaichi, Tsukasa Koyama

Hokkaido University Graduate School of Medicine, Department of Psychiatry

Sertraline, a selective serotonin reuptake inhibitor (SSRI), has some unique characteristics and more clinical information of treatment strategy compared with other SSRIs. First, the antidepressant efficacy of sertraline for non-responders to other SSRIs or tricyclic antidepressants has been confirmed in large-scale clinical trials such as STAR*D. On the other hand, the treatment options for sertraline non-responders have also been studied: a switch to imipramine is effective and extended duration of treatment is preferable to dose increase and mianserin augmentation. Second, sertraline has a lower potential for drug interactions than other SSRIs. Third, sertraline produces a relatively weak dopamine reuptake inhibition in vitro, but this effect is not negligible in vivo. Our recent study using in vivo microdialysis method showed that sertraline increased extracellular dopamine in the nucleus accumbens of rats but not medial prefrontal cortex at a dose of 20 mg/kg

, which is comparable to clinical doses in human, but other SSRIs paroxetine and fluvoxamine failed. We suggest that dopamine increased by sertraline is clinically meaningful action and may explain why sertraline is effective for non-responders to other SSRIs or imipramine.

S4-4
Proper Use of New Antidepressants
- Focusing upon Differentiation between Milnacipran and SSRIs -

Kaoru Sakamoto

Department of Psychiatry, Tokyo Women’s Medical University

Milnacipran, a serotonin-noradrenaline reuptake inhibitor (SNRI) is now used as a first-line treatment for depression in Japan.
Overseas studies have described the antidepressant effect of milnacipran as superior to that of SSRIs, yet further accumulation of relevant data is needed.
In assessing clinical responses to certain drugs, needless to mention, their relation to dosage levels should be taken into account. Published data have corroborated a higher remission rate associated with an increased dose of milnacipran from the usual 100 mg daily to 150 mg or 200mg daily.
Milnacipran is recommended as a first-line therapy for depression in elderly subjects in virtue of its advantages including fewer drug interactions, and no adverse effect upon cognitive function. Cautious use of milnacipran with successful dosage increase up to 150 mg daily has been experienced in many cases of elderly patients at this department, with the results demonstrating usefulness and safety of the regimens.
It has become re-emphasized in recent years that treatment of depression must aim at remission of the disease rather than response to treatment. As for disease remission, nonetheless, it has also been pointed out that there is a disparity between symptomatic remission and social remission in that, even if a symptomatic remission is achieved, it does not necessarily lead directly to social rehabilitation.
It has recently been suggested that milnacipran is likely to be associated with a higher social remission rate, as compared with SSRIs, based on assessments using the social adaptation self-evaluation scale (SASS).
Increasing reports from other clinical specialties have recently shown that milnacipran is effective for pain-related disorders such as postherpetic neuralgia, glossodynia and low back pain, and a U.S. phase III clinical trial data demonstrated significant usefulness of the drug in the treatment of fibromyalgia as compared with placebo.
From the viewpoint of the safety profile, nausea and queasiness have been reported slightly lower in incidence with the use of milnacipran, compared to SSRIs, and the occurrence rate of discontinuation syndrome appears also to be lower with milnacipran than with SSRIs. Meanwhile, regard may have to be paid to noradrenaline-related adverse reactions such as dysuria, tachycardia and blood pressure elevation.

S5-4
Consideration of clinical trial with placebo: double-blind placebo-controlled trial for Schizophrenia

Mari HONDA

Chuo University, lecturer

This report aims to consider ethical legal issues on double-blind placebo-controlled trial.
The Declaration of Helsinki provides consent of subject should be obtained. In Japan, departmental regulations on Good Clinical Practice (1997) provide informed consent in writing, and when it’s difficult to get consent, consent of legal representative. Understanding of subject between explanation and consent is necessary, and it’s important to get social consent to new medical practice.
For protection of the vulnerable, it should be noted whether they distinguish consent to hospitalization, medical treatment and clinical trial. At present, as to inpatient, they should be able to seek consent to clinical trial, only in case of hospitalization with consent. Assent of legal representative should also be obtained, considering ability of decision-making is unbalance. Measures of rescue in aggravation are indispensable. Necessity of research is subjected to ethical review.
In France, to adapt European directive, the concept of “direct individual benefit” is replaced by the “benefit/risk” balance. The law justifies risk of inpatient without consent, taking into account benefit of group with the same attribute. In the US, it’s pointed out that many mental disorders are familial, and wish to help others is an important determinant of research participation.