Published papers

Objective: While 65%-80% occupancy of dopamine D2 receptors with antipsychotics has been proposed to achieve optimal therapeutic response during acute treatment of schizophrenia, it remains unclear as to whether it is also necessary to maintain D2 receptor occupancy within this "safe" window for ongoing maintenance treatment. The data are especially scarce for long-acting antipsychotic formulations. Method: Clinically stable patients with schizophrenia (DSM-IV) receiving a stable dose of risperidone long-acting injectable (LAI) as antipsychotic monotherapy for at least 3 months and free of any psychiatric hospitalization over the past 6 months were included. Dopamine D2 receptor occupancy levels at trough were estimated from plasma concentrations of risperidone plus 9-hydroxyrisperidone immediately before the intramuscular injection of risperidone LAI, using a 1-site binding model derived from our previous positron emission tomography data. This study was conducted from October to December 2011. Results: 36 patients were included in this study (mean ± SD age, 49.3 ± 14.0 years; mean ± SD dose and interval of injections, 38.2 ± 11.6 mg and 16.5 ± 14.0 days, respectively). Mean ± SD D2 receptor occupancy was 62.1% ± 15.4%; 52.8% of the subjects (n = 19) did not demonstrate an occupancy of ≥ 65%. On the other hand, 13.9% (n = 5) showed a D2 occupancy as high as over 80% at the estimated trough. Conclusions: More than half of patients taking risperidone LAI maintained clinical stability without achieving continuous blockade of dopamine D2 receptors ≥ 65% in real-world clinical settings. Results suggest that sustained dopamine D2 receptor occupancy levels of ? 65% may not be necessary for maintenance treatment with risperidone LAI in schizophrenia. © Copyright 2012 Physicians Postgraduate Press, Inc.

Although recent treatment guidelines for schizophrenia recommend that the prior antipsychotic agent should remain stable for at least 2 weeks when aripiprazole is introduced, there is no trial-based evidence to support this strategy. This study was designed to compare this strategy with another conventional one in patients with schizophrenia. We conducted a randomized, 14-week, open-label trial to compare the following 2 switching strategies: (1) add-on of aripiprazole on a current regimen, wait for 4 weeks, and the tapering of prior antipsychotics and (2) add-on of aripiprazole and the simultaneous tapering of prior antipsychotics in patients with schizophrenia. Aripiprazole was initiated at 12 mg/d and then titrated between 12 and 30 mg. The previous antipsychotic medication was reduced biweekly by 25%. Assessments included the Clinical Global Impression Scale Schizophrenia version, the Drug-Induced Extrapyramidal Symptoms Scale, and the Subjective Well-being Under Neuroleptics, Short Version, Japanese Edition. Impressions toward their assigned strategy were also subjectively evaluated at baseline and end point. Fifty-three patients were enrolled, and 48 patients completed this trial. No significant differences were found in changes from the baseline in the total Clinical Global Impression Scale Schizophrenia version severity, Drug-Induced Extrapyramidal Symptoms Scale, and Subjective Well-being Under Neuroleptics, Short Version, Japanese Edition scores throughout the study period between the 2 strategies. Both strategies were judged by subjects to be tolerable and favorable without between-group differences. In conclusion, both strategies were found to be objectively safe and well tolerated. Taken together with similar results from subjective assessments, it would be reasonable to choose either of these 2 strategies in clinical practice based on a patients' preference. Copyright © 2008 by Lippincott Williams & Wilkins.

Studies were sought that evaluated the prevalence, effectiveness, and safety of pro re nata (p.r.n.) medications in psychiatric practice for which evidence has been scarce despite their wide application. To this end, a systematic literature search was performed using various search engines (last search: October 2012) with cross-referencing. A total of 34 studies were identified: 16 studies on epidemiological usage, 16 retrospective studies on effectiveness/safety as well as reasons, and only two prospective studies on the effectiveness/safety of p.r.n. medications. All the patients studied were inpatients, and the reasons for p.r.n. were acute behavioral dyscontrol in 29 studies. Psychiatric diagnoses and outcome measures to assess effectiveness/safety varied and were described in 27 and 20 studies, respectively. Medications under study included antipsychotics (mainly chlorpromazine, haloperidol, olanzapine, risperidone, or quetiapine), benzodiazepines (mainly diazepam and lorazepam), and antihistamines (mainly diphenhydramine). Altogether, 17 studies reported that p.r.n. medications were effective in psychiatric inpatients. Those two prospective studies targeted solely a child/adolescent population with small sample sizes. Currently available data are limited in number, quality, and scope; there has been only equivocal evidence to guide the choice of p.r.n. medications for psychiatric patients, hence there is a need for more investigations on this important clinical topic. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Background: No study has examined dopamine D2/3 receptor (D2/3R) availability in antipsychotic-free older patients with schizophrenia. Methods: We included patients with schizophrenia 50years or older who were antipsychotic-free for at least 3months. We compared non-displaceable binding potential (BPND) of [11C]-raclopride in the caudate, putamen, ventral striatum, and globus pallidus between patients and age- and sex-matched healthy controls. Results: Ten patients participated (antipsychotic-naive=4). No differences in BPND were found between patients and controls in any ROIs (F(1, 72)=42, p=52). Conclusion: The preliminary results suggest no differences in D2/3R availability between antipsychotic-free older patients with schizophrenia and controls.

Objective: Blockade of dopamine D2 receptors with antipsychotics above 65% is associated with optimal chance of clinical response although recent data suggest a lower threshold for the maintenance treatment of schizophrenia. The objective of this study was to prospectively examine whether such continuous high blockade would be necessary for maintenance treatment. Method: In this single-blind, 52-week, randomized controlled trial, clinically stable patients with schizophrenia receiving risperidone or olanzapine were randomly assigned to the continuous D2 blockade (i.e. an estimated trough D2 blockade of >65%) or non-continuous blockade group (i.e. an estimated peak level of >65% with an estimated trough level of <65%). Oral doses corresponding to the assigned blockade levels were estimated from random plasma drug concentrations, using the models we developed; antipsychotic doses were then adjusted accordingly. Psychopathology and side effects were assessed at baseline and one year with the Positive and Negative Syndrome Scale (PANSS), Simpson-Angus Scale (SAS), and Abnormal Involuntary Movement Scale (AIMS). Results: Sixty-eight subjects (34 in each group) were enrolled. Twenty-six (76.5%) and thirty-one (91.2%) subjects completed the study in the continuous and non-continuous blockade groups, respectively, without any significant group difference. No significant differences were found on any of the assessment scales between the two groups. The degree of dosage change was small in both groups. Conclusion: These results offer support that the threshold for D2 receptor blockade in the maintenance treatment can be lower than 65%. However, these preliminary findings have to be confirmed through double-blind, larger scale trials with longer follow-up periods.

RESULTS: A total of 21 articles (10 clinical trials, 4 observational studies, and 7 case reports) met inclusion criteria. The clinical trials have shown that a combination treatment with risperidone or pimozide is not obviously related to an increase in QTc interval, whereas ziprasidone or sertindole combined with clozapine may prolong QTc interval. Among the 4 observational studies, antipsychotic polypharmacy was not clearly associated with QTc prolongation in 3 studies, each cross-sectional. In contrast, one prospective study showed a significant increase in QTc interval following antipsychotic coadministration. The case reports indicated an increased risk of QTc prolongation in at least some patients receiving antipsychotic polypharmacy.CONCLUSIONS: Currently available evidence fails to confirm that antipsychotic polypharmacy worsens QTc prolongation in general, although the evidence is scarce and inconsistent. Clinicians are advised to remain conservative in resorting to antipsychotic polypharmacy, as a combination of some QTc-prolongation liable antipsychotics may further prolong QTc interval, and efficacy supporting the clinical benefits of antipsychotic polypharmacy is equivocal, at best.OBJECTIVE: It remains unclear whether antipsychotic polypharmacy, a common clinical practice, is related to an increased risk of corrected time between start of Q wave and end of T wave (QTc) interval prolongation. We conducted a systematic review of the literature to address this important issue.METHOD: A systematic literature search was conducted in October 2014, using MEDLINE, Embase, and PsycINFO. Studies and case reports were included if they reported QTc intervals or QTc interval changes before and after antipsychotic polypharmacy or QTc intervals in both antipsychotic polypharmacy and monotherapy groups.

Steroid psychosis is a frequent complication of steroid treatment. Although perioperative steroid replacement therapy is generally administered in patients undergoing pituitary surgery, there are no previous reports concerning the development of steroid psychosis after perioperative steroid replacement therapy following pituitary surgery. We herein report a case of steroid psychosis induced by perioperative steroid replacement therapy for pituitary surgery. A 35-year-old man presented with a visual disturbance that had persisted for 1 year. A magnetic resonance imaging scan showed a large pituitary tumor, and a laboratory study revealed slight dysfunction of the hypothalamo-pituitary-adrenal axis. The patient was diagnosed with a non-functioning pituitary tumor and underwent tumor resection via the endoscopic endonasal approach. The initial dose of perioperative steroid replacement therapy was 200 mg of hydrocortisone administered immediately before the operation. The replacement dose was gradually tapered and discontinued over a 7-day period. On postoperative day 4, the patient exhibited an elated mood, grandiose delusions, anxiety, and agitation. We diagnosed these psychiatric symptoms as steroid psychosis induced by steroid replacement and we prescribed risperidone as a treatment. The symptoms gradually improved and did not recur. This case highlights the risk of steroid psychosis following treatment with perioperative steroid replacement therapy for pituitary adenoma and raises questions regarding the appropriateness of perioperative steroid replacement for pituitary adenoma.