Optimal Dosing of Risperidone and Olanzapine in the Maintenance Treatment for Patients With Schizophrenia and Related Psychotic Disorders: A Retrospective Multicenter Study.

OBJECTIVES: This study aims to determine the optimal tolerability dose ranges of risperidone (RIS) and olanzapine (OLZ) administered during schizophrenia maintenance phase. METHODS: Two-year continuation rates of prescription at discharge were examined using a retrospective cohort study method. Adult patients with schizophrenia and related psychotic disorders, receiving antipsychotic monotherapy with RIS or OLZ at discharge, were included. The primary outcome measures were the time to treatment discontinuation and 2-year continuation rates at 4 modal dose ranges of each drug. We estimated the optimal tolerability dose ranges by comparing the continuation rates at various modal doses. RESULTS: Of 648 patients, 344 received RIS and 304 received OLZ. The RIS 2-year continuation rates at 4 daily modal dose ranges were significantly different (0.5-2.5 mg: 46.0%, 3.0-5.0 mg: 40.0%, 5.5-7.5 mg: 30.0%, and 8.0-10.0 mg: 28.0%), with the difference favoring RIS at lower doses (0.5-5.0 mg) more than higher doses (5.5-10.0 mg). In contrast, there were no significant differences among OLZ 4 modal dose ranges (2.5-7.5 mg: 49.1%, 10.0-15.0 mg: 42.6%, 17.5-22.5 mg: 40.9%, and 25.0-30.0 mg: 39.0%). The time to treatment discontinuation significantly favored OLZ over RIS. However, it did not significantly differ between RIS and OLZ at lower doses. CONCLUSIONS: It is suggested that the optimal tolerability dose range during maintenance treatment is 0.5 to 5.0 mg/d for RIS and 2.5 to 30 mg/d for OLZ, and that RIS at lower doses is comparable with OLZ at lower doses.

Anti-NMDA Receptor Antibody Positivity and Presentations Without Seizure, Involuntary Movement, Hypoventilation, or Tumor: A Systematic Review of the Literature.

Patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may remain undiagnosed and untreated with immunotherapy. To investigate specific features and responses to immunotherapy of atypical anti-NMDAR antibody positivity patients, the authors reviewed and evaluated previous case reports/series including patients without seizure, involuntary movement, hypoventilation, or tumor. Of 22 patients identified, 21 responded to immunotherapy. Two patients had neurological/motor symptoms with few/no psychiatric/cognitive symptoms, and eight had both. Twelve patients presented with psychiatric/cognitive symptoms with few/no neurological/motor symptoms, and ≥1 had memory impairment, catatonia, abnormal MRI or electroencephalogram results. The authors recommend lumbar puncture and examination of anti-NMDAR antibodies for patients with these features.

Course of insight, depression and suicidality in inpatients with first-episode schizophrenia who received group psychoeducation.

AIM: We aimed to investigate whether gaining insight through psychoeducation for first-episode schizophrenia is associated with increased suicidality. METHODS: We conducted a secondary analysis of a prospective cohort study that included inpatients with first-episode schizophrenia who attended a group psychoeducation program during their admission. The group psychoeducation program consisted of four weekly sessions provided by a multidisciplinary team. The primary outcome was the correlation between changes in insight and suicidality. We also examined whether change in insight was associated with changes in hopelessness and depression. We measured insight using the Birchwood Insight Scale. Suicidality, hopelessness and depression were measured using the Calgary Depression Rating Scale for Schizophrenia. RESULTS: A total of 125 people participated in the educational program. The Spearman's correlation coefficient between changes in insight and suicidality was -0.14 (95% confidence interval, -0.31 to 0.04; p = .12). Similarly, gain in insight did not significantly correlate with change in depression (0.01, 95% confidence interval, -0.17 to 0.18; p = .93) and change in hopelessness (0.01, 95% confidence interval, -0.16 to 0.19; p = .88). CONCLUSIONS: We observed almost no association between gaining insight and suicidality after a group psychoeducation program in inpatients with first-episode schizophrenia.

Switching strategies for antipsychotic monotherapy in schizophrenia: a multi-center cohort study of aripiprazole.

RATIONALE: Changing antipsychotics of patients with chronic schizophrenia involves several risks. Switching to aripiprazole is especially difficult. We investigated switching methods and related factors for successful switching patients with chronic schizophrenia to aripiprazole. OBJECTIVES: This study was a multi-center historical cohort study and approved by the research ethics committee of Okayama University Hospital and Okayama Psychiatric Medical Center. We compared survival proportions of 178 chronic schizophrenia patients who continued aripiprazole monotherapy for 6 months after non-direct switching (add-on switching (n = 45), cross switching (n = 62)) or direct switching (n = 71). We adjusted possible confounders using a Cox proportional hazards model. RESULTS: Of patients with chronic schizophrenia, 56.7% (101/178) were switched to aripiprazole monotherapy, and 55.0% (98/178) showed improvement in symptoms as demonstrated by the Clinical Global Impression Severity score. Kaplan-Meier survival curves showed that non-direct switching had a higher survival proportion than direct switching (log-rank test, p = 0.012). Even after adjusting for several variables using a Cox proportional hazards model, add-on switching had a significantly lower hazard at 6 months than direct switching (hazard ratio 0.42, 95% confidence interval 0.21-0.82, P = 0.01). In cases of switching to aripiprazole for psychiatric symptoms, non-direct switching had a lower hazard than direct switching (hazard ratio 0.41, 95% confidence interval 0.21-0.81, P = 0.01) but was not significant for adverse reaction. When aripiprazole was switched from olanzapine, add-on switch showed the lowest hazard ratio for continuation (hazard ratio 0.29, 95% confidence interval 0.07-1.11, P = 0.07). CONCLUSIONS: Flexibility in strategies when switching to aripiprazole may induce a better outcome for patients with chronic schizophrenia.

Algorithm-based pharmacotherapy for first-episode schizophrenia involuntarily hospitalized: A retrospective analysis of real-world practice.

BACKGROUND: Little is known about the clinical outcomes of severely ill patients with first-episode schizophrenia spectrum disorders (FES) who are considered to lack the capacity to consent to clinical trials. We investigated the feasibility of an algorithm-based pharmacotherapy (ABP) and clinical outcomes of patients with FES involuntarily hospitalized and treated with ABP. METHODS: We conducted a retrospective chart review of 160 patients admitted involuntarily between October 2012 and October 2015. Our algorithm aimed to delay olanzapine, standardize medications and suggest initiation of clozapine after failure (non-response or intolerability) of third-line antipsychotic treatment. The duration of each adequate antipsychotic treatment at optimal dosage was 4 weeks or more. RESULTS: The physician adherence rate to ABP was 95%. Response and remission rates were 76.0% and 48.6% in the first adequate antipsychotic trial (Phase I, n = 146), 62.5% and 25.0% in the second adequate antipsychotic trial (Phase II, n = 32), and 16.7% and 0% in the third adequate antipsychotic trial (Phase III, n = 6). Response and remission rates in the clozapine trial (n = 9) increased to nearly the level of Phase I (66.7% and 44.4%). The treatment-resistance rate was 8.4% to 10.3%. CONCLUSIONS: These findings suggested the validity of ABP and initiation of clozapine for treatment-resistant psychotic symptoms for even severely ill involuntarily hospitalized patients with FES.

Predictors of remission during acute treatment of first-episode schizophrenia patients involuntarily hospitalized and treated with algorithm-based pharmacotherapy: Secondary analysis of an observational study.

AIM: Early clinical response predicts symptomatic remission and recovery in the maintenance treatment phase of first-episode schizophrenia (FES). However, little is known about predictors of symptomatic remission during acute treatment of severely ill patients with FES. Here, we conducted a secondary analysis of our retrospective observational study, which examined response, remission and treatment-resistance rates in seriously ill patients with FES spectrum disorders involuntarily hospitalized and treated with algorithm-based pharmacotherapy. METHODS: We performed a retrospective chart review of 131 involuntarily admitted patients with schizophrenia or schizoaffective disorder. Our algorithm aimed to delay olanzapine treatment, standardize medications and suggest initiation of clozapine after failure of third-line antipsychotic treatment. The duration of each adequate antipsychotic treatment at an optimal dosage was 4 weeks or more. Remission was defined using the symptom-severity component of consensus remission criteria. A logistic regression model was applied to identify significant predictors of remission at discharge. RESULTS: Overall, 74 patients (56%) were in remission at discharge. Non-remitters were hampered from becoming remitters mainly by the presence of negative symptoms. There were no differences in first-line antipsychotics, dosage of antipsychotics at time of response and adherence rates to algorithm-based pharmacotherapy between remitters and non-remitters. Shorter duration of untreated psychosis, favourable early response and less negative symptoms at baseline were identified as independent predictors of remission at discharge. CONCLUSIONS: The importance of early intervention and specific and adequate treatments of negative symptoms is highlighted.

Incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia treated with aripiprazole or risperidone: secondary analysis of an observational study.

RATIONALE: In the antipsychotic treatment of schizophrenia with little medication history, especially in drug-naïve cases, predictors of side effects are important. However, predictors of antipsychotic-induced akathisia remain unclear. OBJECTIVES: This study aimed to investigate the incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia spectrum disorders (FES). METHODS: This is a secondary analysis of our retrospective observational study. Data were obtained from 129 consecutive patients with FES involuntarily hospitalized in a tertiary psychiatric public hospital and treated with aripiprazole or risperidone. The primary outcome was the presence of acute akathisia during the first 1 month. A Cox proportional hazard model was used to examine significant predictors of the onset of akathisia. RESULTS: Acute akathisia was diagnosed in 54 patients (42%). Neither antipsychotics (aripiprazole or risperidone), duration of untreated psychosis, iron deficiency, sex, age nor baseline symptomatic severity was identified as an independent predictor of akathisia. Rapid risperidone initiation significantly increased the onset of akathisia (adjusted hazard ratio [HR], 6.47; 95%; 95% confidence interval [CI], 1.94-21.65; p = 0.002), but rapid aripiprazole initiation did not (adjusted HR, 1.08; 95% CI, 0.50-2.31; p = 0.84). A significant interaction was found between rapid antipsychotic initiation and the risk of akathisia with aripiprazole versus risperidone (p = 0.027). CONCLUSIONS: Severely ill patients with FES initiating aripiprazole or risperidone could have a high risk for akathisia. Rapid risperidone initiation should be avoided because of the risk for akathisia, and careful monitoring of akathisia may be necessary for all patients initiating aripiprazole.

Anti-NMDA-receptor antibody in initial diagnosis of mood disorder.

Anti-NMDAR encephalitis is increasingly recognized as one etiology of psychiatric symptoms, but there is not enough evidence on patients with mood disorder. We assayed anti-NR1/NR2B IgG antibodies in serum and/or cerebrospinal fluid of 62 patients initially diagnosed with mood disorder by a cell-based assay. We also investigated the specific patient characteristics and psychotic symptoms. At first admission, the patients showed only psychiatric symptoms without typical neurological signs or abnormal examination findings. Four of the 62 patients had anti-NR1/NR2B IgG antibodies. The anti-NR1/NR2B IgG antibody-positive patients showed more super- or abnormal sensitivity (P = 0.00088), catatonia (P = 0.049), and more conceptual disorganization (P < 0.0001), hostility (P = 0.0010), suspiciousness (P < 0.0001), and less emotional withdrawal (P < 0.0001) and motor retardation (P < 0.0001) on the Brief Psychiatric Rating Scale than the antibody-negative patients. During the clinical course, anti-NR1/NR2B IgG antibody-positive patients showed more catatonia (P = 0.0042) and met Graus's criteria for diagnosis of anti-NMDAR encephalitis, but negative patients did not. Immunotherapy was effective for anti-NR1/NR2B IgG antibody-positive patients, and there was the weak relationship (R²â€¯= 0.318) between the anti-NR1/NR2B IgG antibody titer in the cerebrospinal fluid and the Brief Psychiatric Rating Scale score.

Mother-infant separation among mothers with mental illness: An exploratory observational study in Japan.

Mother-infant separation may influence child development and behavior problems. We reviewed charts for 3639 female patients to investigate rates, reasons, and predictors for mothers with mental illness being separated from their infants during the first year after childbirth in Japan. Of 77 patients with childbirth, 26 cases (34%) presented with maternal separation. The most common reason was psychiatric hospitalization. Diagnoses of schizophrenia spectrum disorders or mood disorders were independent contributors for maternal separation. Clinicians should pay particular attention to relapse or onset of psychotic or mood disorders during the perinatal period.

Effects of the antipsychotics haloperidol, clozapine, and aripiprazole on the dendritic spine.

Three types of antipsychotics, typical (e.g. haloperidol), atypical (e.g. clozapine), and dopamine partial agonist (e.g. aripiprazole), are administered for treatment of schizophrenia. These antipsychotics have different efficacy and side-effect profiles. We investigated whether aripiprazole, clozapine, and haloperidol differentially regulate the dendritic spine through the AKT-GSK-3 beta cascade. Dissociated cortical neurons from Sprague-Dawley rats were prepared and cultured for 28 days. Aripiprazole, clozapine, or haloperidol was administered to the rat cortical neurons. The levels of PSD95 protein and AKT-GSK-3 beta cascade-related proteins were investigated by Western blot. The number of spines and PSD95 puncta were investigated by immunofluorescence cell staining. Aripiprazole (1 µM or 10 µM) and clozapine (1 µM) increased the levels of PSD95 protein, the number of spines, phosphorylated Akt Thr308 and Ser473, and phosphorylated GSK-3 beta Ser9. On the other hand, haloperidol (1 µM or 10 µM) or an inappropriate concentration of clozapine (10 µM) decreased them. A GSK inhibitor also increased the levels of PSD-95 protein and caused the same morphology. Aripiprazole, clozapine, and haloperidol differentially regulate the dendritic spine, and this effect may occur through the AKT-GSK-3 beta cascade. Selection and appropriate dose of these antipsychotics may be important for the protection of dendritic spines in patients with schizophrenia.

Two-year effectiveness of risperidone and aripiprazole in the maintenance treatment of patients with recent-onset or chronic schizophrenia and related psychotic disorders: a retrospective multicenter study.

This study aimed to assess the comparative effectiveness of risperidone (RIS) versus aripiprazole (ARP) in patients with recent-onset or chronic schizophrenia during maintenance treatment and to examine the interaction between illness duration and the effectiveness of the treatment. All adult patients with schizophrenia and related disorders discharged from four psychiatric hospitals between 2006 and 2012 were screened and the 2-year continuation rates of monotherapy using RIS or ARP after discharge were examined retrospectively. The treatment continuation of the two drugs in patients with recent-onset (illness duration <5 years) or chronic schizophrenia (illness duration ≥5 years) and the moderator effect of illness duration on the effectiveness of the treatment were analyzed. Of 328 patients, 233 received RIS and 95 received ARP. No significant difference was found between the two drugs in the treatment continuation for the entire sample. However, there was a significant difference favoring ARP in the recent-onset subgroup mainly because of differences in tolerability, whereas RIS tended to present better outcomes in patients with chronic illness. Furthermore, there was a significant variation in the effectiveness of the treatment between recent-onset and chronic schizophrenia. Our results suggest that illness duration is an important moderator in terms of the long-term effectiveness of the two drugs.

Predictive factors for hyperglycaemic progression in patients with schizophrenia or bipolar disorder.

BACKGROUND: Patients with schizophrenia or bipolar disorder have a high risk of developing type 2 diabetes. AIMS: To identify predictive factors for hyperglycaemic progression in individuals with schizophrenia or bipolar disorder and to determine whether hyperglycaemic progression rates differ among antipsychotics in regular clinical practice. METHOD: We recruited 1166 patients who initially had normal or prediabetic glucose levels for a nationwide, multisite, l-year prospective cohort study to determine predictive factors for hyperglycaemic progression. We also examined whether hyperglycaemic progression varied among patients receiving monotherapy with the six most frequently used antipsychotics. RESULTS: High baseline serum triglycerides and coexisting hypertension significantly predicted hyperglycaemic progression. The six most frequently used antipsychotics did not significantly differ in their associated hyperglycaemic progression rates over the 1-year observation period. CONCLUSIONS: Clinicians should carefully evaluate baseline serum triglycerides and coexisting hypertension and perform strict longitudinal monitoring irrespective of the antipsychotic used. DECLARATION OF INTEREST: The authors report no financial or other relationship that is relevant to the subject of this article. Relevant financial activities outside the submitted work are as follows. I.K. has received honoraria from Astellas, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Nippon Chemiphar, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Tanabe Mitsubishi Pharma, Shionogi and Yoshitomiyakuhin; has received research/grant support from AbbVie GK, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Takeda Pharmaceutical, Tanabe Mitsubishi Pharma, Shionogi and Yoshitomiyakuhin; and is a member of the advisory boards of Dainippon Sumitomo Pharma and Tanabe Mitsubishi Pharma. Y.T. has received speaker's honoraria from Dainippon-Sumitomo Pharma, Otsuka, Meiji-Seika Pharma, Janssen Pharmaceutical, Daiichi-Sankyo Company, UCB Japan and Ono Pharmaceutical. K.U. has received honoraria from Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Takeda Pharmaceutical, Hisamitsu Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Tanabe Mitsubishi Pharma, Shionogi and Yoshitomiyakuhin. B.Y. has received speaker's honoraria from Otsuka Pharmaceutical and Janssen Pharmaceutical. J. I. has received honoraria from Dainippon Sumitomo Pharma, Eli Lilly, Janssen Pharmaceutical, Meiji Seika Pharma, MSD, Novartis Pharma, Otsuka Pharmaceutical and Mochida Pharma.

The critical treatment window of clozapine in treatment-resistant schizophrenia: Secondary analysis of an observational study.

Previous studies have suggested that a delay in initiating clozapine is one of the predictors of outcomes in treatment-resistant schizophrenia (TRS). However, whether there is a critical treatment window of clozapine in TRS and the duration of that window remain unclear. We conducted a secondary analysis of a previously published observational study using a retrospective chart review of 105 patients with TRS who were treated with clozapine. We included 90 patients who remained on clozapine for at least 3 months. The delay in initiating clozapine was an independent contributor to symptomatic improvement based on treatment with clozapine by multiple linear regression analysis. A receiver operating characteristic curve analysis (area under the curve: 0.78) confirmed 2.8 years was the best predictive cut-off value of delay in initiating clozapine for responses in patients treated with clozapine (sensitivity: 0.66, specificity: 0.84). In patients with a delay in initiating clozapine of ≤2.8 years and a delay in initiating clozapine of >2.8 years, the response rates were 81.6% and 30.8% (risk ratio=2.65; 95% confidence interval, 1.80, 3.63), respectively. Clinicians should reduce the delay in initiating clozapine to less than 3 years to improve symptomatic outcomes in TRS and to prevent clozapine-resistant schizophrenia.

Is quetiapine suitable for treatment of acute schizophrenia with catatonic stupor? A case series of 39 patients.

PURPOSE: We aimed to determine which antipsychotic is most effective for the treatment of acute schizophrenia with catatonic stupor. PATIENTS AND METHODS: Data were obtained from the medical records of 450 patients with the diagnosis of schizophrenia, who had received acute psychiatric inpatient treatment between January 2008 and December 2010 at our hospital. Among them, 39 patients (8.7%) met the definition of catatonic stupor during hospitalization. The diagnoses of schizophrenia in all 39 patients were reconfirmed during the maintenance phase. We retrospectively reviewed the medical records of these 39 patients to investigate which antipsychotics were chosen for treatment during the period from admission to recovery from catatonia, at the time of discharge, and 12 and 30 months after discharge. RESULTS: As compared to other antipsychotics, it was found out that use of quetiapine had better outcomes and hence was used more often. A total of 61.5% of patients were on quetiapine at the time of recovery from catatonia and 51.3% of patients were on quetiapine at the time of discharge as compared to only 17.9% of patients on quetiapine on admission. However, at 12 and 30 months after discharge, the rates had decreased to 38.4% and 25.6%. Similarly, of 29 patients who were not administered electroconvulsive therapy, quetiapine was used at significantly higher rates at the time of recovery from catatonia (48.3%) than at the time of admission (17.2%). All 39 patients had received an antipsychotic as the first-line treatment and some antipsychotics might have contributed to the development of catatonia. CONCLUSION: This study suggests that quetiapine is a promising agent for the treatment of schizophrenia with catatonic stupor during the acute phase.