Details of a Researcher - Uchida, Hiroyuki

Papers - Uchida, Hiroyuki

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Preparation and fuel cell performance of catalyst layers using sulfonated polyimide ionomers.

Omata T, Tanaka M, Miyatake K, Uchida M, Uchida H, Watanabe M

ACS applied materials & interfaces 4 ( 2 ) 730 - 7 2012.02

ISSN 1944-8244

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Differential responses of primary auditory cortex in autistic spectrum disorder with auditory hypersensitivity.

Matsuzaki J, Kagitani-Shimono K, Goto T, Sanefuji W, Yamamoto T, Sakai S, Uchida H, Hirata M, Mohri I, Yorifuji S, Taniike M

Neuroreport 23 ( 2 ) 113 - 8 2012.01

ISSN 0959-4965

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Age and sex impact clozapine plasma concentrations in inpatients and outpatients with schizophrenia

Ismail Zahinoor, Wessels Alette M., Uchida Hiroyuki, Ng Wenzie, Mamo David C., Rajji Tarek K., Pollock Bruce G., Mulsant Benoit H., Bies Robert R.

American Journal of Geriatric Psychiatry (American Journal of Geriatric Psychiatry) 20 ( 1 ) 53 - 60 2012.01

ISSN 1064-7481

BACKGROUND: Although clozapine is primarily used in a younger to mid-life population of patients with psychosis, there are limited data on the clinical pharmacology of clozapine later in life. The objective of this study was to assess the magnitude and variability of plasma concentrations of clozapine and norclozapine across the lifespan in a real-world clinical setting. DESIGN: A population pharmacokinetic study using nonlinear mixed effect modeling (NONMEM). Age, sex, height, weight, and dosage formulation were covariates. SETTING: Inpatients and outpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007. PARTICIPANTS: Patients ranging in ages from 11 to 79 with schizophrenia spectrum disorders and prescribed clozapine (Clozaril). MEASUREMENTS: A total of 1142 plasma clozapine and norclozapine concentrations (2,284 concentration measurements) from 391 patients with schizophrenia spectrum disorder. RESULTS: A one-compartment model with first-order absorption and elimination best described the data. The population predicted clearance of clozapine for females was 27.1 L/h (SE 11.1%) and 36.7 L/h (SE 9.7%) for males. For norclozapine, clearance in females was 48.6 L/h (SE 10.8%) and 63.1 L/h (SE 9.3%) in males. The only covariates with a significant effect on clearance were age and sex: clearance for both parent and metabolite decreased exponentially with age at least 39 years. CONCLUSIONS: Decreased clearance of clozapine and norclozapine with age results in increased blood concentrations and, hence, the potential for adverse drug reactions. These findings have particular clinical relevance for the dosing and safety monitoring of clozapine in older adults, highlighting a need for increased vigilance.

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How psychotropic polypharmacy in schizophrenia begins

Shinfuku M., Uchida H., Tsutsumi C., Suzuki T., Watanabe K., Kimura Y., Tsutsumi Y., Ishii K., Imasaka Y., Mimura M., Kapur S.

Pharmacopsychiatry 45 ( 4 ) 133 - 137 2012

ISSN 0176-3679

Introduction: While patients with schizophrenia are often treated with psychotropic polypharmacy, how and when polypharmacy begins is not well documented. Methods: A systematic chart review of 300 patients, 100 of whom were psychotropic-free prior to their first visit, was conducted to examine 2-year longitudinal prescription patterns of concomitant psychotropics, in addition to a primary antipsychotic. Results: Overall polypharmacy occurred in 79% patients, with 2-year rates of the use of hypnotics, benzodiazepine derivative anxiolytics, anticholinergic drugs, antidepressants, and mood stabilizers were 56.7, 49.7, 38.3, 21.3, and 14.0%, respectively. Once polypharmacy had started, it was continued until their final visit in >70% of the patients. In a subgroup of 100 psychotropic-free patients, mood stabilizers, antidepressants, anticholinergic antiparkinsonian drugs, anxiolytics, and hypnotics were initiated after 2.3, 2.3, 2.1, 1.6, and 1.5 antipsychotics had been prescribed, respectively (mean duration before the introduction of a concomitant drug in days: 17.7, 121.6, 86.4, 32.1, and, 57.7, respectively). Conclusion: Routine practice deviates significantly from algorithms - with polypharmacy often being initiated early, often a without trial of other options, and once started commonly stays.

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Asymptomatic deep vein thrombosis in a patient with major depressive disorder.

Ishida T, Katagiri T, Uchida H, Suzuki T, Watanabe K, Mimura M

Case reports in psychiatry 2012 261251 2012

ISSN 2090-682X

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How psychotropic polypharmacy in schizophrenia begins: A longitudinal perspective

Shinfuku M., Uchida H., Tsutsumi C., Suzuki T., Watanabe K., Kimura Y., Tsutsumi Y., Ishii K., Imasaka Y., Mimura M., Kapur S.

Pharmacopsychiatry (Pharmacopsychiatry) 45 ( 4 ) 133 - 137 2012

ISSN 01763679

Introduction: While patients with schizophrenia are often treated with psychotropic polypharmacy, how and when polypharmacy begins is not well documented. Methods: A systematic chart review of 300 patients, 100 of whom were psychotropic-free prior to their first visit, was conducted to examine 2-year longitudinal prescription patterns of concomitant psychotropics, in addition to a primary antipsychotic. Results: Overall polypharmacy occurred in 79% patients, with 2-year rates of the use of hypnotics, benzodiazepine derivative anxiolytics, anticholinergic drugs, antidepressants, and mood stabilizers were 56.7, 49.7, 38.3, 21.3, and 14.0%, respectively. Once polypharmacy had started, it was continued until their final visit in >70% of the patients. In a subgroup of 100 psychotropic-free patients, mood stabilizers, antidepressants, anticholinergic antiparkinsonian drugs, anxiolytics, and hypnotics were initiated after 2.3, 2.3, 2.1, 1.6, and 1.5 antipsychotics had been prescribed, respectively (mean duration before the introduction of a concomitant drug in days: 17.7, 121.6, 86.4, 32.1, and, 57.7, respectively). Conclusion: Routine practice deviates significantly from algorithms - with polypharmacy often being initiated early, often a without trial of other options, and once started commonly stays. © Georg Thieme Verlag KG Stuttgart · New York.

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Management of schizophrenia in late life with antipsychotic medications: A qualitative review

Suzuki T., Remington G., Uchida H., Rajji T., Graff-Guerrero A., Mamo D.

Drugs and Aging (Drugs and Aging) 28 ( 12 ) 961 - 980 2011.12

ISSN 1170229X

Although patients with schizophrenia are reported to have excess mortality compared with the general population, many affected patients will nonetheless survive and continue to have the disorder in later life. Consequently, geriatric schizophrenia will be a significant public health concern in the years to come, and evidence-based treatment of schizophrenia in older patients is becoming an urgent issue. However, there has been a paucity of comparative data to guide selection of antipsychotics for schizophrenia in late life.The primary aim of this review was to synthesize the available evidence on management of late-life schizophrenia with antipsychotic medications; a secondary aim was to evaluate treatment resistance in this population. Accordingly, PubMed and EMBASE were searched using the keywords 'antipsychotics', 'age' and 'schizophrenia' to identify psychopharmacological studies of antipsychotics in late-life schizophrenia (last search 30 April 2011). The literature search identified 23 prospective studies of use of antipsychotics for schizophrenia in older patients (generally age ≥65 years), including eight double-blind trials. The sample size was smaller than 40 patients for 52 of the studies. Two of the double-blind studies were post hoc analyses and one was a placebo-controlled trial. In the largest double-blind study, olanzapine (n88, median dose 10mgday) and risperidone (n87, median dose 2mgday) were compared in patients not resistant to these therapies, with similar effects. There have also been several open-label trials of these two agents that have shown efficacy and tolerability in non-resistant patients. Evidence on other antipsychotics has been scarce and less robust.The gold standard for treatment-resistant schizophrenia is clozapine. However, almost all of the studies of clozapine to date have effectively excluded older patients with schizophrenia. Only one small study has evaluated clozapine (n24, mean dose 300mgday) in comparison with chlorpromazine (n18, mean dose 600mgday) in a difficult-to-treat older population; the investigators reported that both treatments were similarly efficacious. Furthermore, there has been little compelling evidence in favour of or against augmentation of antipsychotics with other psychotropic medications in the older age group.Treatment of non-resistant, late-life schizophrenia with olanzapine and risperidone appears to be supported by the available evidence. However, data on geriatric patients with schizophrenia are generally scarce, particularly for treatment-resistant subpopulations, underscoring the need for more research in this important area. © 2011 Adis Data Information BV. All rights reserved.

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Is switching antidepressants following early nonresponse more beneficial in acute-phase treatment of depression?

Nakajima Shinichiro, Uchida Hiroyuki, Suzuki Takefumi, Watanabe Koichiro, Hirano Jinichi, Yagihashi Tatsuhiko, Takeuchi Hiroyoshi, Abe Takayuki, Kashima Haruo, Mimura Masaru

Progress in Neuro-Psychopharmacology and Biological Psychiatry 35 ( 8 ) 1983 - 1989 2011.12

ISSN 0278-5846

Rationale: Treatment guidelines for major depressive disorder (MDD) recommend a continuous use of antidepressants for several weeks, while recent meta-analyses indicate that antidepressant efficacy starts to appear within 2. weeks and early treatment nonresponse is a predictor of subsequent nonresponse. Objectives: We prospectively compared 8-week outcomes between switching antidepressants and maintaining the same antidepressant in early nonresponders, to generate a hypothesis on possible benefits of early switching strategy. Method: Patients with MDD without any treatment history for the current episode were included. When subjects failed to show an early response (i.e., ≥ 20% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS)) to the initial treatment with sertraline 50. mg at week 2, they were randomly divided into two groups; in the Continuing group, sertraline was titrated at 50-100. mg, whereas sertraline was switched to paroxetine 20-40. mg in the Switching group. A primary outcome measure was a response rate (i.e., ≥ 50% improvement in the MADRS) at week 8. Results: Among 132 subjects, 41 subjects showed early nonresponse. The Switching group (n = 20) showed a higher rate of responders than the Continuing group (n = 21) (75% vs. 19%: p = 0.002). Further, the Switching group was also superior in the rate of remitters (total score of ≤ 10 in the MADRS) (60% vs. 14%: p = 0.004) and continuous changes in the MADRS (19.0 vs. 7.5: p < 0.001). Conclusions: Our preliminary findings suggest that patients with MDD who fail to show early response to an initial antidepressant may derive benefits from the early switching antidepressants in the acute-phase treatment of depression.

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Is switching antidepressants following early nonresponse more beneficial in acute-phase treatment of depression?: A randomized open-label trial

Nakajima S., Uchida H., Suzuki T., Watanabe K., Hirano J., Yagihashi T., Takeuchi H., Abe T., Kashima H., Mimura M.

Progress in Neuro-Psychopharmacology and Biological Psychiatry (Progress in Neuro-Psychopharmacology and Biological Psychiatry) 35 ( 8 ) 1983 - 1989 2011.12

ISSN 02785846

Rationale: Treatment guidelines for major depressive disorder (MDD) recommend a continuous use of antidepressants for several weeks, while recent meta-analyses indicate that antidepressant efficacy starts to appear within 2. weeks and early treatment nonresponse is a predictor of subsequent nonresponse. Objectives: We prospectively compared 8-week outcomes between switching antidepressants and maintaining the same antidepressant in early nonresponders, to generate a hypothesis on possible benefits of early switching strategy. Method: Patients with MDD without any treatment history for the current episode were included. When subjects failed to show an early response (i.e., ≥ 20% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS)) to the initial treatment with sertraline 50. mg at week 2, they were randomly divided into two groups; in the Continuing group, sertraline was titrated at 50-100. mg, whereas sertraline was switched to paroxetine 20-40. mg in the Switching group. A primary outcome measure was a response rate (i.e., ≥ 50% improvement in the MADRS) at week 8. Results: Among 132 subjects, 41 subjects showed early nonresponse. The Switching group (n = 20) showed a higher rate of responders than the Continuing group (n = 21) (75% vs. 19%: p = 0.002). Further, the Switching group was also superior in the rate of remitters (total score of ≤ 10 in the MADRS) (60% vs. 14%: p = 0.004) and continuous changes in the MADRS (19.0 vs. 7.5: p < 0.001). Conclusions: Our preliminary findings suggest that patients with MDD who fail to show early response to an initial antidepressant may derive benefits from the early switching antidepressants in the acute-phase treatment of depression. © 2011 Elsevier Inc.

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Treatment resistant schizophrenia and response to antipsychotics

Suzuki Takefumi, Remington Gary, Mulsant Benoit H., Rajji Tarek K., Uchida Hiroyuki, Graff-Guerrero Ariel, Mamo David C.

Schizophrenia Research 133 ( 1-3 ) 54 - 62 2011.12

ISSN 0920-9964

Background: There remains a lack of agreement regarding criteria for treatment-resistant schizophrenia (TRS) and definition of response. Method: A literature search was conducted to identify clinical studies of antipsychotics in TRS using PubMed, EMBASE and PsycINFO (last search 31 July 2011). Psychopharmacological studies with the number of participants of ≥ 40 were evaluated in terms of definitions for TRS and subsequent treatment response. Results: Thirty-three studies of antipsychotics in TRS were reviewed. TRS has been defined mainly by severity in symptoms. Many studies based TRS with at least 2 failed adequate antipsychotic trials (at chlorpromazine equivalent doses of ≥ 1000. mg/day for ≥ 6. weeks), but some studies adopted prospective treatment arm to be certain of sample refractoriness. Treatment response has been defined by a relative change in the representative scales (most commonly ≥ 20% decrease in the Positive and Negative Syndrome Scale), but it sometimes included the absolute criteria such as post-treatment score of ≤ 35 in the Brief Psychiatric Rating Scale or Clinical Global Impression-severity score of ≤ 3 (mild or less severe). Social functioning has not been a primary outcome measure in past pivotal trials, and other important domains of the illness such as cognition and subjective perspectives have not been incorporated into definitions of treatment resistance or response. However, adopting various assessment scales can be time-consuming and complicated, with an additional possibility of disagreement among raters. Conclusion: Defining outcomes in schizophrenia is a challenging task. It is imperative that the field agrees on how this population is better defined and what constitutes treatment response.

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Effects of aging on 5-HT _2AR binding

Uchida Hiroyuki, Chow Tiffany W., Mamo David C., Kapur Shitij, Mulsant Benoit H., Houle Sylvain, Pollock Bruce G., Graff-Guerrero Ariel

International Journal of Geriatric Psychiatry 26 ( 12 ) 1300 - 1308 2011.12

ISSN 0885-6230

Objective We explored whether prior findings of reduction in serotonin 2A receptor (5-HT _2AR) binding with age could be replicated and whether high resolution research tomography (HRRT) for positron emission tomography could compensate for partial volume effects in the presence of age-related brain atrophy, which has been a traditional concern for radioligand PET studies in the elderly. Methods We derived 5-HT _2AR nondisplaceable binding potentials (BP _ND) in frontal, temporal, anterior-cingulate, insula, caudate and putamen volumes of interest (VOIs) for 28 healthy subjects (mean ± SD age = 43.9 ± 17.0 years, range: 19-78 years) using HRRT. Partial volume correction (PVC) was performed in the VOI analysis. Results The 5-HT _2AR BP _NDs decreased with age, a relationship best described by an exponential-decay regression. The BP _NDs were found to be consistent before and after PVC, with an intra-class correlation coefficient of 0.84 and 95% confidence interval = 0.78-0.88. Conclusions These new findings update current knowledge, in that the aging process is not always uniform across the life span and suggest that PVC may not be necessary with HRRT in healthy subjects.

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Impact of feedback from pharmacists in reducing antipsychotic polypharmacy in schizophrenia

Hazra Monica, Uchida Hiroyuki, Sproule Beth, Remington Gary, Suzuki Takefumi, Mamo David C.

Psychiatry and Clinical Neurosciences (Psychiatry and Clinical Neurosciences) 65 ( 7 ) 676 - 678 2011.12

ISSN 1323-1316

The objective was to examine effects of active interventions on physician's prescribing of antipsychotic polypharmacy. Prescriptions for patients with schizophrenia at the Centre for Addiction and Mental Health, Canada were collected in 2006 (n = 648) and 2008 (n = 778). During the intervening period, a pharmacist monitored prescriptions with antipsychotic polypharmacy and contacted corresponding prescribers to provide education on risks of polypharmacy. Moreover, educational sessions on polypharmacy were presented to inpatient and outpatient teams. A three-fold decrease in the prevalence of antipsychotic polypharmacy was observed between 2006 (18.3%) and 2008 (6.6%). Thus, active monitoring of prescriptions with educational interventions could reduce antipsychotic polypharmacy.

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Patient's trust in their psychiatrist

Minamisawa Atsumi, Suzuki Takefumi, Watanabe Koichiro, Imasaka Yasushi, Kimura Yoshie, Takeuchi Hiroyoshi, Nakajima Shinichiro, Kashima Haruo, Uchida Hiroyuki

European Archives of Psychiatry and Clinical Neuroscience 261 ( 8 ) 603 - 608 2011.12

ISSN 0940-1334

Investigating and characterizing the degree and correlates of patient's trust in their treating psychiatrists across a range of psychiatric disorders is of a great clinical relevance to enhance our therapeutic alliance, which has not been addressed in the literature. In this study, outpatients who visited one of the participating psychiatric clinics in Tokyo, Japan between October and November, 2010 were asked to complete the Trust in Physician Scale (TPS), an 11-item self-report questionnaire. A univariate general linear model was used to examine the effects of the following variables on the TPS total score: age, sex, diagnosis, Global Assessment of Functioning score, educational background, physician's years of practice as a psychiatrist, duration of treatment with their current psychiatrists, sex concordance between patients and their psychiatrists, and whether patients were older than their psychiatrists. Five hundred and four patients were enrolled (mean ± SD age = 42.8 ± 13.6 years; 176 men; Psychiatric diagnoses (ICD-10): F0 [N = 8], F2 [N = 72], F3 [N = 252], F4 [N = 147], F6 [N = 22]). A duration of treatment with their current psychiatrist of ≥1 year and a duration of their physician's clinical expertise as a psychiatrist for ≥10 years were associated with a greater degree of patient's trust in their psychiatrist. Furthermore, patients with a F3 diagnosis showed a significantly higher TPS total score than those with F4. These findings underscore an importance of paying close attention to patients who are relatively new and are not treated by well-experienced psychiatrists in terms of subjective trust. Furthermore, this likely holds more true for patients with neurotic disorders.

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Subjective recognition of adverse events with antidepressant in people with depression

Kikuchi Toshiaki, Suzuki Takefumi, Uchida Hiroyuki, Watanabe Koichiro, Kashima Haruo

Journal of Affective Disorders 135 ( 1-3 ) 347 - 353 2011.12

ISSN 0165-0327

Background: While it has been reported that physicians may under-recognize adverse effects of antidepressants thoroughly in clinical settings, subjective bias in recognition of adverse effects (AEs) with antidepressants has not been specifically investigated. Methods: Four-hundred ninety-three participants with depressive disorders (ICD-10) were assessed for the severity of 20 common AEs and their inferred causal relationship with antidepressants, together with the Quick Inventory for Depressive Symptoms (QIDS). These assessments occurred twice at the 1st visit (when they were antidepressant free) and 2nd visit (10 days after the initiation of antidepressants). 'Possible AEs' and 'under-recognized AEs' were defined as 'events with exacerbation in the severity' and 'events with negative causal attribution to antidepressants' at the time of the 2nd visit, respectively. Results: Three-hundred sixty-three participants (73.6%) experienced ≥1 under-recognized AEs. Flu like symptoms (96.5% of participants who experienced possible AEs), sexual dysfunction (94.2%), blurred vision (93.4%), anxiety/tension (91.1%) and sweating (89.2%) were found to be prevalent as under-recognized AEs. Participants with under-recognized AEs had less improvement in the QIDS than those without (27.1% vs. 11.1% decrease, p < 0.001). Limitations: It is intrinsically challenging to exactly differentiate between antidepressant AEs and symptoms of depression. And the severity of depression, that of AEs and causal relationship between AEs and antidepressants were assessed not by objective but subjective scales. Conclusions: An overall trend to under-recognize AEs of antidepressants was found and people with a lesser degree of early improvement tend to understate the causality, which has an implication in interpreting voluntarily expression of AEs.

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Effects of aging on 5-HT <inf>2A</inf>R binding: A HRRT PET study with and without partial volume corrections

Uchida H., Chow T., Mamo D., Kapur S., Mulsant B., Houle S., Pollock B., Graff-Guerrero A.

International Journal of Geriatric Psychiatry (International Journal of Geriatric Psychiatry) 26 ( 12 ) 1300 - 1308 2011.12

ISSN 08856230

Objective We explored whether prior findings of reduction in serotonin 2A receptor (5-HT 2AR) binding with age could be replicated and whether high resolution research tomography (HRRT) for positron emission tomography could compensate for partial volume effects in the presence of age-related brain atrophy, which has been a traditional concern for radioligand PET studies in the elderly. Methods We derived 5-HT 2AR nondisplaceable binding potentials (BP ND) in frontal, temporal, anterior-cingulate, insula, caudate and putamen volumes of interest (VOIs) for 28 healthy subjects (mean ± SD age = 43.9 ± 17.0 years, range: 19-78 years) using HRRT. Partial volume correction (PVC) was performed in the VOI analysis. Results The 5-HT 2AR BP NDs decreased with age, a relationship best described by an exponential-decay regression. The BP NDs were found to be consistent before and after PVC, with an intra-class correlation coefficient of 0.84 and 95% confidence interval = 0.78-0.88. Conclusions These new findings update current knowledge, in that the aging process is not always uniform across the life span and suggest that PVC may not be necessary with HRRT in healthy subjects. Copyright © 2011 John Wiley & Sons, Ltd.

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Patient's trust in their psychiatrist: A cross-sectional survey

Minamisawa A., Suzuki T., Watanabe K., Imasaka Y., Kimura Y., Takeuchi H., Nakajima S., Kashima H., Uchida H.

European Archives of Psychiatry and Clinical Neuroscience (European Archives of Psychiatry and Clinical Neuroscience) 261 ( 8 ) 603 - 608 2011.12

ISSN 09401334

Investigating and characterizing the degree and correlates of patient's trust in their treating psychiatrists across a range of psychiatric disorders is of a great clinical relevance to enhance our therapeutic alliance, which has not been addressed in the literature. In this study, outpatients who visited one of the participating psychiatric clinics in Tokyo, Japan between October and November, 2010 were asked to complete the Trust in Physician Scale (TPS), an 11-item self-report questionnaire. A univariate general linear model was used to examine the effects of the following variables on the TPS total score: age, sex, diagnosis, Global Assessment of Functioning score, educational background, physician's years of practice as a psychiatrist, duration of treatment with their current psychiatrists, sex concordance between patients and their psychiatrists, and whether patients were older than their psychiatrists. Five hundred and four patients were enrolled (mean ± SD age = 42.8 ± 13.6 years; 176 men; Psychiatric diagnoses (ICD-10): F0 [N = 8], F2 [N = 72], F3 [N = 252], F4 [N = 147], F6 [N = 22]). A duration of treatment with their current psychiatrist of ≥1 year and a duration of their physician's clinical expertise as a psychiatrist for ≥10 years were associated with a greater degree of patient's trust in their psychiatrist. Furthermore, patients with a F3 diagnosis showed a significantly higher TPS total score than those with F4. These findings underscore an importance of paying close attention to patients who are relatively new and are not treated by well-experienced psychiatrists in terms of subjective trust. Furthermore, this likely holds more true for patients with neurotic disorders. © 2011 Springer-Verlag.

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Subjective recognition of adverse events with antidepressant in people with depression: A prospective study

Kikuchi T., Suzuki T., Uchida H., Watanabe K., Kashima H.

Journal of Affective Disorders (Journal of Affective Disorders) 135 ( 1-3 ) 347 - 353 2011.12

ISSN 01650327

Background: While it has been reported that physicians may under-recognize adverse effects of antidepressants thoroughly in clinical settings, subjective bias in recognition of adverse effects (AEs) with antidepressants has not been specifically investigated. Methods: Four-hundred ninety-three participants with depressive disorders (ICD-10) were assessed for the severity of 20 common AEs and their inferred causal relationship with antidepressants, together with the Quick Inventory for Depressive Symptoms (QIDS). These assessments occurred twice at the 1st visit (when they were antidepressant free) and 2nd visit (10 days after the initiation of antidepressants). 'Possible AEs' and 'under-recognized AEs' were defined as 'events with exacerbation in the severity' and 'events with negative causal attribution to antidepressants' at the time of the 2nd visit, respectively. Results: Three-hundred sixty-three participants (73.6%) experienced ≥1 under-recognized AEs. Flu like symptoms (96.5% of participants who experienced possible AEs), sexual dysfunction (94.2%), blurred vision (93.4%), anxiety/tension (91.1%) and sweating (89.2%) were found to be prevalent as under-recognized AEs. Participants with under-recognized AEs had less improvement in the QIDS than those without (27.1% vs. 11.1% decrease, p < 0.001). Limitations: It is intrinsically challenging to exactly differentiate between antidepressant AEs and symptoms of depression. And the severity of depression, that of AEs and causal relationship between AEs and antidepressants were assessed not by objective but subjective scales. Conclusions: An overall trend to under-recognize AEs of antidepressants was found and people with a lesser degree of early improvement tend to understate the causality, which has an implication in interpreting voluntarily expression of AEs. © 2011 Elsevier B.V. All rights reserved.

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Treatment resistant schizophrenia and response to antipsychotics: A review

Suzuki T., Remington G., Mulsant B., Rajji T., Uchida H., Graff-Guerrero A., Mamo D.

Schizophrenia Research (Schizophrenia Research) 133 ( 1-3 ) 54 - 62 2011.12

ISSN 09209964

Background: There remains a lack of agreement regarding criteria for treatment-resistant schizophrenia (TRS) and definition of response. Method: A literature search was conducted to identify clinical studies of antipsychotics in TRS using PubMed, EMBASE and PsycINFO (last search 31 July 2011). Psychopharmacological studies with the number of participants of ≥ 40 were evaluated in terms of definitions for TRS and subsequent treatment response. Results: Thirty-three studies of antipsychotics in TRS were reviewed. TRS has been defined mainly by severity in symptoms. Many studies based TRS with at least 2 failed adequate antipsychotic trials (at chlorpromazine equivalent doses of ≥ 1000. mg/day for ≥ 6. weeks), but some studies adopted prospective treatment arm to be certain of sample refractoriness. Treatment response has been defined by a relative change in the representative scales (most commonly ≥ 20% decrease in the Positive and Negative Syndrome Scale), but it sometimes included the absolute criteria such as post-treatment score of ≤ 35 in the Brief Psychiatric Rating Scale or Clinical Global Impression-severity score of ≤ 3 (mild or less severe). Social functioning has not been a primary outcome measure in past pivotal trials, and other important domains of the illness such as cognition and subjective perspectives have not been incorporated into definitions of treatment resistance or response. However, adopting various assessment scales can be time-consuming and complicated, with an additional possibility of disagreement among raters. Conclusion: Defining outcomes in schizophrenia is a challenging task. It is imperative that the field agrees on how this population is better defined and what constitutes treatment response. © 2011 Elsevier B.V.

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Factors associated with response to clozapine in schizophrenia: A review

Suzuki T., Uchida H., Watanabe K., Kashima H.

Psychopharmacology Bulletin (Psychopharmacology Bulletin) 44 ( 1 ) 32 - 60 2011.11

ISSN 00485764

Background: Clozapine has been serving as the gold standard medication for patients with treatment-resistant schizophrenia who failed to respond to other antipsychotics. However, factors affecting response to this medication have not been comprehensively reviewed recently. Methods: In order to find factors associated with response to clozapine in schizophrenia, a literature search was conducted using PubMed through January 2011 with keywords of clozapine, response, and schizophrenia. Cross-referencing of relevant articles was also performed. Factors were arbitrarily classified into the following: demographic/clinical, oral dosage/pharmacokinetic, biochemical, (electro)physiological, genetic, imaging, and combinations. Results: A synthesis from 280 articles indicated that demographic and clinical variables such as high baseline symptoms and low premorbid functioning have not been particularly useful in predicting response to clozapine. Pharmacokinetic evidence points to a threshold clozapine level of 350 ng/ml but in a context of significant inter- as well as intra-individual variability. Pharmacokinetic perspectives appear to have more implication in special situations including poor response, suspected toxicity and nonadherence. A number of laboratory-based studies have reported on many potential candidates for response prediction to clozapine, however, reproducibility, specificity, robustness of the findings, as well as clinical feasibility and cost-effectiveness all pose a significant practical challenge, in relation with the fact that pathophysiological bases of treatment resistance in schizophrenia largely remain to be elucidated. Conclusions: No unequivocal factors to clozapine response were found despite a relatively rich body of the literature, which calls for more works on this important topic. Clozapine level of 350 ng/ml appears to be useful in case of nonresponse.

Time course of improvement with antipsychotic medication in treatment-resistant schizophrenia

Suzuki Takefumi, Remington Gary, Arenovich Tamara, Uchida Hiroyuki, Agid Ofer, Graff-Guerrero Ariel, Mamo David C.

British Journal of Psychiatry (British Journal of Psychiatry) 199 ( 4 ) 275 - 280 2011.10

ISSN 0007-1250

Background: Improvements are greatest in the earlier weeks of antipsychotic treatment of patients with non-resistant schizophrenia. Aims: To address the early time-line for improvement with antipsychotics in treatment-resistant schizophrenia. Method: Randomised double-blind trials of antipsychotic medication in adult patients with treatment-resistant schizophrenia were investigated (last search June 2010). A series of metaregression analyses were carried out to examine the effect of time on the average item scores in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) at three or more distinct time points within the first 6 weeks of treatment. Results: Study duration varied from 4 weeks to 1 year and the definitions of treatment resistance as well as of treatment response were not necessarily consistent across 19 identified studies, resulting in highly variable rates of response (0-76%). The mean standardised baseline item score in the PANSS or BPRS was 3.4 (s.e. = 0.06) in the five studies included in the meta-regression analysis, with the average baseline Clinical Global Impression - Severity score being 5.2 (marked illness). For the pooled population treated with a range of antipsychotics (n = 1019), significant reductions in the mean item scores occurred during the first 4 weeks; improvements observed in later weeks were smaller and non-significant. In contrast, weekly improvement with clozapine was significant throughout (n = 356). Conclusions: Our findings provide preliminary evidence that the majority of improvement with antipsychotics may occur relatively early. More consistent improvements with clozapine may be associated with a gradual titration. To further elucidate response patterns, future studies are needed to provide data over regular intervals during earlier stages of treatment.

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