Taishiro Kishimoto

Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies.

OBJECTIVE Recent, large, randomized controlled trials (RCTs) showed no benefit of long-acting injectable (LAI) antipsychotics over oral antipsychotics in preventing relapse in schizophrenia, nor did a recent meta-analysis incorporating these studies. However, RCTs might enroll a disproportionate number of patients with better treatment adherence and lower illness severity. Mirror-image studies, which compare periods of oral antipsychotic versus LAI treatment in the same patients, might therefore better reflect the real-world impact of LAIs. DATA SOURCES A systematic literature search without language restriction was conducted using MEDLINE/PubMed, Cochrane Library, Web of Science, PsycINFO, and CINAHL until May 31, 2012. Search terms included synonyms of (1) antipsychotic(s) AND (2) schizophrenia and related disorders AND (3) depot, (long-acting) injection(s), microsphere, decanoate, palmitate, enanthate. STUDY SELECTION Of 5,483 identified citations, 607 articles were fully inspected, and 582 were ineligible. Finally, 25 mirror-image studies from 28 countries that followed 5,940 patients with schizophrenia for ≥ 12 months (≥ 6 months each on oral antipsychotic and LAI treatment) met the inclusion criteria and were analyzed. DATA EXTRACTION Coprimary outcomes were hospitalization risk and number of hospitalizations. Secondary outcomes included hospitalization days and length of stay. DATA SYNTHESIS LAIs showed strong superiority over oral antipsychotics in preventing hospitalization (16 studies, N = 4,066; risk ratio = 0.43; 95% CI, 0.35-0.53; P < .001) and in decreasing the number of hospitalizations (15 studies, 6,342 person-years; rate ratio = 0.38; 95% CI, 0.28-0.51; P < .001). This strong advantage was also observed for secondary outcomes and in multiple clinically relevant subpopulations and treatment groups. CONCLUSIONS Results from mirror-image studies in patients eligible for clinical use of LAIs showed strong superiority of LAIs compared to oral antipsychotics in preventing hospitalization. The results were in contrast to the recent meta-analysis of RCTs, which showed no superiority of LAIs. Given the possible biases in mirror-image studies, such as expectation bias, natural illness course, and time effect, a cautious interpretation is required. Nevertheless, the population in mirror-image studies better reflects the population receiving LAIs in clinical practice.

Non-adherence to medication in patients with psychotic disorders: epidemiology, contributing factors and management strategies

Although non‐adherence is common across all branches of medicine, psychotic disorders pose additional challenges that increase its risk. Despite the importance of non‐adherence, clinicians generally spend too little time on assessing and addressing adherence attitudes and behaviors. Importantly, how adherence is measured significantly impacts the findings, and the most frequently employed methods of asking patients or judging adherence indirectly based on efficacy or tolerability information have poor validity. Novel technologies are being developed that directly assess adherence and that can also be used to both provide real‐time feedback to clinicians and serve as an intervention with patients. Several treatments are available that can positively impact adherence. Among psychosocial interventions, those combining multiple approaches and involving multiple domains seem to be most effective. Although long‐acting injectable antipsychotics are theoretically a very powerful tool to assure adherence and signal non‐adherence, recent results from randomized controlled trials failed to show superiority compared to oral antipsychotics. These data are in contrast to nationwide cohort studies and mirror‐image studies, which arguably include more representative patients receiving long‐acting antipsychotics in clinical practice. This disconnect suggests that traditional randomized controlled trials are not necessarily the best way to study interventions that are thought to work via reducing non‐adherence. Clearly, non‐adherence is likely to remain a major public health problem despite treatment advances. However, increasing knowledge about factors affecting adherence and leveraging novel technologies can enhance its early assessment and adequate management, particularly in patients with psychotic disorders.

Relapse prevention in schizophrenia: a systematic review and meta-analysis of second-generation antipsychotics versus first-generation antipsychotics

Few controlled trials compared second-generation antipsychotics (SGAs) with first-generation antipsychotics (FGAs) regarding relapse prevention in schizophrenia. We conducted a systematic review/meta-analysis of randomized trials, lasting ⩾6 months comparing SGAs with FGAs in schizophrenia. Primary outcome was study-defined relapse; secondary outcomes included relapse at 3, 6 and 12 months; treatment failure; hospitalization; and dropout owing to any cause, non-adherence and intolerability. Pooled relative risk (RR) (±95% confidence intervals (CIs)) was calculated using random-effects model, with numbers-needed-to-treat (NNT) calculations where appropriate. Across 23 studies (n=4504, mean duration=61.9±22.4 weeks), none of the individual SGAs outperformed FGAs (mainly haloperidol) regarding study-defined relapse, except for isolated, single trial-based superiority, and except for risperidones superiority at 3 and 6 months when requiring ≥3 trials. Grouped together, however, SGAs prevented relapse more than FGAs (29.0 versus 37.5%, RR=0.80, CI: 0.70–0.91, P=0.0007, I2=37%; NNT=17, CI: 10–50, P=0.003). SGAs were also superior regarding relapse at 3, 6 and 12 months (P=0.04, P<0.0001, P=0.0001), treatment failure (P=0.003) and hospitalization (P=0.004). SGAs showed trend-level superiority for dropout owing to intolerability (P=0.05). Superiority of SGAs regarding relapse was modest (NNT=17), but confirmed in double-blind trials, first- and multi-episode patients, using preferentially or exclusively raw or estimated relapse rates, and for different haloperidol equivalent comparator doses. There was no significant heterogeneity or publication bias. The relevance of the somewhat greater efficacy of SGAs over FGAs on several key outcomes depends on whether SGAs form a meaningful group and whether mid- or low-potency FGAs differ from haloperidol. Regardless, treatment selection needs to be individualized considering patient- and medication-related factors.

Osteoporosis and fracture risk in people with schizophrenia.

Purpose of review Excessive bone mineral density (BMD) loss has been associated with schizophrenia, but its mechanisms and clinical implications are less clear. The aim of this review was to summarize the risk of osteoporosis and bone fractures in schizophrenia patients. Moreover, we aimed to examine the impact of antipsychotic-induced hyperprolactinemia on bone metabolism. Recent findings Fifteen of 16 studies (93.8%) reported lower BMD or higher prevalence of osteoporosis in at least one region, or in at least one subgroup of schizophrenia patients compared with controls, but results were inconsistent across measured areas. Higher fracture risk was associated with schizophrenia in 2/2 studies (independently: n = 1), and 3/4 studies with antipsychotics. Reasons for this difference include insufficient exercise, poor nutrition, smoking, alcohol use, and low vitamin D levels. Altogether, 9/15 (60.0%) studies examining the relationship between antipsychotic-induced hyperprolactinemia and BMD loss found some effects of hyperprolactinemia. However, results were mixed, samples and effects were small, and only two studies were prospective. Summary Schizophrenia is associated with reduced BMD and fracture risk. Prevention, early detection, and intervention are required. The relative contributions of antipsychotic-related hyperprolactinemia and unhealthy lifestyle behaviors remain unclear, needing to be assessed in well designed, prospective studies, including bone turnover markers as intermediary endpoints.

The Bipolar Prodrome Symptom Interview and Scale–Prospective (BPSS‐P): description and validation in a psychiatric sample and healthy controls

The aim of the present study was to investigate the psychometric properties of the Bipolar Prodrome Symptom Interview and Scale–Prospective (BPSS‐P), the first specific interview for emerging bipolar disorder (BD) symptoms.

The impact of prolactin-raising antipsychotics on bone mineral density in patients with schizophrenia: findings from a longitudinal observational cohort.

To examine the effect of prolactin-raising antipsychotics on bone mineral density (BMD), data of 164 schizophrenia patients who received ≥2 dual-energy x-ray absorptiometry scans were analyzed (49.3% men; mean ± SD age: 58.5 ± 11.0 years; duration of treatment: 26.7 ± 13.8 years). Patients were divided into a prolactin-raising antipsychotic (n=141) or prolactin-sparing (n=23) group, and time x group interaction was examined using mixed effect model. Although the BMD difference did not reach significance over 3.4 ± 1.6 years, a significant antipsychotic-class vs. time interaction was found (p=0.011), indicating a negative impact of prolactin-raising antipsychotics on BMD. Large-scale, randomized-controlled data are required to replicate and extend these findings.

Bifidobacterium-Rich Fecal Donor May Be a Positive Predictor for Successful Fecal Microbiota Transplantation in Patients with Irritable Bowel Syndrome

Background/Aims: Dysbiosis is associated with various systemic disorders including irritable bowel syndrome (IBS). Fecal microbiota transplantation (FMT) might restore intestinal microbial balance. The study aimed to determine the safety and efficacy of FMT in IBS patients, as well as also positive predictors for FMT. Methods: This was a single-arm, open-label study. Eligible patients were diagnosed based on Rome III Diagnostic Criteria. Fecal materials were administered to the patient via colonoscopy. The primary end point was a change in the Bristol stool form scale at 4 weeks after FMT. Recovery to types 3-4 was considered a clinical response. The secondary end point was a change in intestinal microbiota and psychological status using the Hamilton Rating Scale. Results: Ten patients were enrolled. Six patients achieved a clinical response. The diversity of patients 4 weeks after FMT increased significantly compared with patients before FMT, and that of responding patients was significantly higher than non-responder patients. The abundance of Bifidobacterium in effective donors was significantly higher than in ineffective donors and patients. Psychological status of all patients was significantly improved after FMT. Conclusions: FMT for patients with IBS is safe, and relatively effective. Bifidobacterium-rich fecal donor may be a positive predictor for successful FMT. Key Summary: (1) Dysbiosis is associated with various gastrointestinal disorders including IBS. (2) FMT has potential to restore intestinal microbial balance. (3) We showed that FMT improved stool form and psychological status of IBS patients. (4) Bifidobacterium-rich donor efficiently induced symbiosis in IBS patients.

Safety and tolerability of long-acting injectable versus oral antipsychotics: A meta-analysis of randomized controlled studies comparing the same antipsychotics

OBJECTIVE We aimed to assess whether long-acting injectable antipsychotics (LAIs), which are initiated in a loading strategy or overlapping with oral antipsychotics (OAPs) and which cannot be stopped immediately, are associated with greater safety/tolerability issues than OAPs. METHOD Systematic review and meta-analysis of randomized controlled trials (RCTs) comparing LAIs and OAPs, including only LAI-OAP pairs of the same OAP (allowing oral risperidone and paliperidone as comparators for either risperidone or paliperidone LAI). Primary outcome was treatment discontinuation due to adverse events. Secondary outcomes included serious adverse events, death, ≥1 adverse event and individual adverse event rates. RESULTS Across 16 RCTs (n=4902, mean age=36.4years, males=65.8%, schizophrenia=99.1%) reporting on 119 adverse event outcomes, 55 (46.2%) adverse events were reported by ≥2 studies allowing a formal meta-analysis. Out of all 119 reported adverse events, LAIs and OAPs did not differ significantly regarding 115 (96.6%). LAIs were similar to OAPs regarding the frequency of treatment discontinuation due to adverse events, serious adverse events, all-cause death and death for reasons excluding accident or suicide. Compared to OAPs, LAIs were associated with significantly more akinesia, low-density lipoprotein cholesterol change and anxiety. Conversely, LAIs were associated with significantly lower prolactin change. CONCLUSION LAIs and OAPs did not differ on all serious and >90% of individual adverse events. However, more studies focusing on adverse event frequencies, severity and time course associated with LAI vs OAP formulations of the same antipsychotic are needed. Additionally, adverse events data for LAIs after stopping overlapping oral antipsychotic treatment are needed.

Sleep and mood disorders in dry eye disease and allied irritating ocular diseases.

The aim of the present study was to evaluate sleep and mood disorders in patients with irritating ocular diseases. The study design was a cross-sectional/case-control study conducted in six eye clinics. Out of 715 outpatients diagnosed with irritating ocular surface diseases and initially enrolled, 301 patients with dry eye disease (DED) and 202 age-matched control participants with other ocular surface diseases were analyzed. The mean Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS) scores were 6.4 ± 3.2 and 11.1 ± 5.7 for severe DED (n = 146), 5.5 ± 3.3 and 9.8 ± 4.0 for mild DED (n = 155), 5.5 ± 3.1 and 9.5 ± 6.6 for chronic conjunctivitis (n = 124), and 5.0 ± 3.3 and 8.9 ± 5.3 for allergic conjunctivitis (n = 78). There were significant differences among these diagnostic groups for PSQI (P < 0.05). Regression analysis of patients with DED revealed the PSQI and HADS scores were significantly correlated with the severity of DED (P < 0.05). Our results demonstrate that sleep quality in patients with DED is significantly worse than in patients with other irritating ocular surface diseases and it is correlated with the severity of DED.

The 2nd Schizophrenia International Research Society Conference, 10-14 April 2010, Florence, Italy: summaries of oral sessions.

The 2nd Schizophrenia International Research Society Conference, was held in Florence, Italy, April 10-15, 2010. Student travel awardees served as rapporteurs of each oral session and focused their summaries on the most significant findings that emerged from each session and the discussions that followed. The following report is a composite of these reviews. It is hoped that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.