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Background Although long-acting injectable antipsychotics (LAI-APs) have been considered as a monotherapeutic option in the maintenance treatment of schizophrenia, it has been recently reported that the combination therapy of LAI-APs and oral antipsychotics (OAPs) is common. Methods We conducted a retrospective chart review to examine the situation of the combination therapy of LAI second-generation antipsychotics (LAI-SGAs) and OAPs, and a questionnaire survey to investigate prescribers' attitudes toward the combination therapy. We included patients who received any LAI-SGAs for 1 month or longer and classified them into monotherapy and combination therapy groups. We collected information on age, sex, primary psychiatric diagnosis, and concomitant psychotropic medications. Results Of the 132 patients, 39 (29.5%) received the combination therapy of LAI-SGAs and OAPs. Long-acting injectable risperidone was significantly associated with receiving the combination therapy compared with LAI aripiprazole. Olanzapine was the most common OAP in combination with LAI-SGAs. Only 8 patients (20.5%) concurrently received the same type of OAPs as LAI-SGAs. More than 60% of the patients received OAP polypharmacy before the initiation of LAI-SGAs. The psychiatrists in charge prescribed LAI-SGAs mainly because of a concern about adherence, and OAPs mainly because of insufficient dose of LAI-SGAs, to patients in the combination therapy group. They estimated that adherence to OAPs in two thirds of the patients in the combination therapy group was 80% or higher. Conclusions The present study showed that the combination therapy of LAI-SGAs and OAPs is often conducted in real-world clinical practice. Considering the reason for the introduction of LAI-APs, clinicians should carefully monitor patients' adherence to OAPs concurrently used with LAI-APs.

Long-acting injectable antipsychotics (LAI-APs) remain underutilized. One reason is the concern that LAI-APs might cause serious adverse events such as neuroleptic malignant syndrome (NMS) and lead to prolonged symptoms compared with oral treatment. Because the risk of NMS associated with LAI second-generation antipsychotics (LAI-SGAs) remains unclear, we compared reporting frequency, time to onset, and mortality of NMS between LAI- and oral SGAs using data from a Japanese spontaneous adverse event reporting database between April 2004 and September 2019. Of 5791 patients reporting adverse events due to LAI-SGAs or the equivalent oral SGAs, 768 (13%) developed NMS. LAI aripiprazole and LAI paliperidone were associated with a significantly lower reporting frequency of NMS than the equivalent oral SGAs (adjusted reporting odds ratio [95% confidence interval]: 0.35 [0.19–0.63] and 0.40 [0.27–0.59], respectively). Between 42% and 62% of the NMS associated with LAI- and oral SGAs other than LAI risperidone occurred within 30 days after initiation. The proportion of mortality due to NMS associated with oral aripiprazole was 13.1% and no deaths occurred in patients with NMS associated with LAI aripiprazole. The proportions of mortality due to NMS associated with oral risperidone/paliperidone, LAI risperidone, and LAI paliperidone were 8.8%, 4.2%, and 3.4%, respectively. Our findings showed that LAI-SGAs were not associated with a higher reporting frequency and mortality of NMS compared with oral SGAs, although clinicians need to closely monitor the occurrence of NMS not only during oral SGA treatment, but also, and in particular, in the early stage of LAI-SGA treatment.

Introduction Clozapine is the gold standard of treatment for patients with treatment-resistant schizophrenia. However, approximately 60% of those patients do not respond to clozapine; moreover, clinical outcomes after clozapine discontinuation are unclear so far. Therefore, we conducted a systematic review to clarify the outcomes after clozapine discontinuation. Methods A systematic literature search was conducted, using MEDLINE and Embase with the following keywords: (clozapine AND (cessation* OR cease* OR withdraw* OR discontinu* OR halt* OR stop* OR switch*) AND (schizophreni* OR schizoaffective)). Results A total of 28 clinical studies from 27 articles were identified and included in this systematic review. Three randomized controlled trials reported worsening of psychiatric symptoms. In 10 single-arm studies, the results of worsening and improving psychiatric symptoms were inconsistent. In one large retrospective cohort study, clozapine rechallenge, olanzapine, and antipsychotic polypharmacy had lower rehospitalization rates compared to no medication after clozapine discontinuation. In the other 14 retrospective studies, the vast majority showed worsening of clinical status after clozapine discontinuation. Among five studies on clinical outcomes after clozapine rechallenge, four reported improvements in clinical status in more than half of patients who rechallenged clozapine. The remaining study reported that the clozapine discontinuation-rechallenge group had a worse remission assessment score than the clozapine discontinuation-no rechallenge group. Discussion Clinical outcomes generally worsen after clozapine discontinuation. Clozapine rechallenge and olanzapine may be considered following clozapine discontinuation. The outcomes after clozapine discontinuation in clozapine non-responders remain inconclusive; therefore, well-designed studies are warranted.

Only a few studies have investigated changes in the dose of long-acting injectable second-generation antipsychotics (LAI-SGAs) over the long term in the maintenance treatment of schizophrenia. In this retrospective cohort study, we examined longitudinal changes in antipsychotic dose over a 3-year period in patients with schizophrenia who had been taking LAI-SGAs for at least 1 year. We compared the total daily chlorpromazine equivalent dose of antipsychotics at 12, 24 and 36 months with the baseline dose at 3 months after initiation of LAI-SGAs. We also performed multiple regression analysis to explore factors associated with change in total daily dose 12 months after treatment initiation. A total of 154 patients fulfilled the inclusion criteria. There was no significant difference in total daily antipsychotic dose between 3 months and 12, 24 or 36 months after treatment initiation. Total daily dose was increased in 43 (27.9%), 31 (34.8%) and 22 patients (36.7%) at 12, 24 and 36 months, respectively. Age and total antipsychotic dose at 3 months were significantly negatively associated with change in total daily dose. Antipsychotic dose was basically unchanged during long-term treatment in patients treated with LAI-SGAs in the maintenance phase, although there was an increase in some patients.

Purpose/background Although high-dose olanzapine might be a treatment option in patients with treatment-resistant schizophrenia, it can be reduced to the standard dose after symptoms are stabilized. We examined the rate of olanzapine reduction from high to standard dose and whether this change was successful. Methods/procedures We included patients who received high-dose olanzapine (>20 mg/d) for 4 weeks or longer at our hospital. First, we retrospectively followed the patients for 6 years and estimated the percentage of those whose olanzapine was reduced from high to standard dose. Second, we followed patients who received olanzapine reduction for 1 year and estimated the rate of success based on the study-defined criteria for unsuccessful reduction. We also explored factors associated with the dose reduction and successful results. Findings/results Among 110 patients who received high-dose olanzapine treatment, 72 had their olanzapine dose reduced to the standard dose for 6 years; the duration of high-dose olanzapine treatment was significantly and negatively associated with a reduction in olanzapine (hazard ratio, 0.98; 95% confidence interval, 0.98-0.99). Among the patients whose olanzapine was reduced, 50 achieved successful reduction for 1 year. Among the reasons for the reduction, an unknown reason was significantly associated with successful reduction (hazard ratio, 4.93; 95% confidence interval, 1.55-22.8). Implications/conclusions The findings suggest that high-dose olanzapine can be reduced to the standard dose after stabilization of symptoms in most patients with schizophrenia.

OBJECTIVE Neuroleptic malignant syndrome (NMS) is a potentially fatal, idiosyncratic reaction to antipsychotics. Due to low incidence of NMS, research on risk factors of mortality associated with NMS is limited. METHODS Two authors independently searched Medline/Embase/Cochrane/CINAHL/PsychINFO databases for case reports with author-defined NMS published in English until 05/30/2020. Demographic, clinical, treatment, and outcome data were independently extracted following PRISMA guidelines. NMS severity was rated using the Francis-Yacoub scale. Mortality risk factors were identified using a multivariable regression analysis including all characteristics that were significantly different between NMS cases resulting vs. not resulting in death. RESULTS 683 cases with NMS were analyzed (median age = 36 years, males = 62.1%). In a multivariable model, independent predictors of NMS mortality were lack of antipsychotic discontinuation (odds ratio (OR) = 4.39 95% confidence interval (CI) = 2.14-8.99; p < 0.0001), respiratory problems (OR = 3.54 95%CI = 1.71-7.32; p = 0.0004), severity of hyperthermia (Unit-OR = 1.30, 95%CI = 1.16-1.46; p < 0.0001), and older age (Unit-OR = 1.05, 95%CI = 1.02-1.07; p = 0.0014). Even in univariate, patient-level analyses, antipsychotic formulation was not related to death (oral antipsychotic (OAP): n = 39/554 (7.0%) vs. long-acting injectable (LAI): n = 13/129 (10.1%); p = 0.2413). Similarly, death with NMS was not related to antipsychotic class (first-generation antipsychotic: n = 38/433 (8.8%) vs. second-generation antipsychotic: n = 8/180 (4.4%); p = 0.0638). Non-antipsychotic co-treatments were not associated with NMS mortality. CONCLUSION Despite reliance on case reports, these findings indicate that presence of respiratory alterations, severity of hyperthermia, and older age should alert clinicians to a higher NMS mortality risk, and that antipsychotics should be stopped to reduce mortality, yet when NMS arises on LAIs, mortality is not increased vs. OAPs.

Background Despite the clinical importance of antipsychotic long-acting injections (LAIs) in the treatment of schizophrenia, their use may be limited by patients' reluctance to accept the injections. No studies to date have investigated whether patients are more likely to withdraw their consent to treatment with LAIs than to treatment with oral antipsychotics (OAPs). Therefore, we performed a meta-analysis of randomized controlled trials (RCTs) to compare the risk of withdrawal of consent between the 2 routes of administration. Methods PubMed, the Cochrane Library, PsycINFO, and CINAHL were systematically searched. RCTs with open-label or rater-masked design that compared LAIs with OAPs were selected. Data on study discontinuation due to withdrawal of consent and/or loss to follow-up were extracted. Results A total of 16 studies (4815 patients) that met the study eligibility criteria were included in the meta-analysis. There was no significant difference between the LAI and OAP groups in the risk of cessation of treatment because of withdrawal of consent. Similarly, there was no significant difference in the risk of study discontinuation because of withdrawal of consent plus loss to follow-up. Conclusions These findings were unexpected and suggest that patients may not be more hesitant to continue LAIs than OAPs after consenting to or receiving treatment. Nevertheless, patients should be provided detailed explanations about the use of LAIs and a support system that encourages them to continue treatment.

The purpose of this study was to develop the Glasgow Antipsychotic Side effects Scale for Clozapine Japanese version (GASS-C-J) and examine its reliability to assess clozapine-related side effects. We developed the GASS-C-J using forward and backward translation. Semantic equivalence of the GASS-C-J to the GASS-C was confirmed by the original author. We then administered the GASS-C-J twice to 109 patients on clozapine treatment at two psychiatric hospitals in Japan. We assessed the internal consistency and test-retest reliability of the GASS-C-J using Cronbach's alpha and weighted kappa coefficient, respectively. We also examined if discrepancies in each GASS-C-J item score between the first and second rating were correlated with items of the Brief Evaluation of Psychosis Symptom Domains (BE-PSD). The Cronbach's alpha coefficient of the GASS-C-J at the first and second rating was 0.78 (95% CI: 0.72 to 0.84) and 0.82 (95% CI: 0.76 to 0.88), respectively. The weighted kappa coefficient of individual and total GASS-C-J item scores ranged from 0.45 to 0.88. Some symptom domains were correlated with discrepancies in specific items of the GASS-C-J: psychotic symptoms and nausea/vomiting (rs = 0.27), thirst (rs = 0.31), and appetite/weight gain (rs = 0.27); disorganized thinking and urinary incontinence (rs = 0.26); depression/anxiety and myoclonus (rs = 0.25), hypersalivation (rs = -0.27), and blurred vision (rs = -0.22). These findings demonstrate that the GASS-C-J can be used in clinical and research settings as a reliable scale to assess clozapine-related side effects.

Background Clozapine has been regarded as the gold standard for patients with treatment-resistant schizophrenia, but a recent network meta-analysis has questioned its relative superiority over other second-generation antipsychotics (SGAs) such as olanzapine and risperidone. Purpose We conducted a retrospective mirror-image study of clozapine vs other SGAs to evaluate real-world effectiveness of clozapine in terms of the duration of hospitalization and seclusion, both of which represent a critical outcome. Methods We included all patients who initiated clozapine at the Yamanashi Prefectural KITA Hospital and had continued to take any SGA(s) other than clozapine for at least 1 year before the initiation of clozapine. We obtained data on hospitalization and seclusion during 1 year of SGA treatment (SGA phase) and 1 year after the treatment was switched to clozapine (clozapine phase). Results The study included 35 patients (21 men, 31 with schizophrenia, 4 with schizoaffective disorder) with the average ± SD age of 37.3 ± 11.1 years. The results indicated that total hospitalization days did not differ significantly between SGA and clozapine treatment. However, total duration of seclusion was significantly shorter in the clozapine phase than in the SGA phase. Furthermore, the number of patients who were secluded at least once was significantly smaller in the clozapine phase than in the SGA phase. The results were essentially unchanged when outlier patients were excluded and only when patients taking olanzapine and/or risperidone during the SGA phase were considered. Conclusions Although the findings from this retrospective analysis need to be further tested in prospective trials, they endorse the relative effectiveness of clozapine over other SGAs in the real world.

Purpose Mirror-image studies, which compare equal periods of time before and after a new treatment is introduced, may reflect the real-world impact of that treatment. However, most mirror-image studies that have investigated the impact of long-acting injectable antipsychotics (LAIs) were unidirectional in design, for patients switching from oral antipsychotics (OAPs) to LAIs. Therefore, we conducted a bidirectional mirror-image study comparing LAIs and OAPs. Methods We included 126 schizophrenia or schizoaffective disorder patients' LAI treatment data from 3 psychiatric hospitals. Patients took OAPs for 6 months or more before initiating LAIs, or the reverse. We obtained data on the number of hospitalizations as a primary outcome, plus the total duration and mean duration of hospitalization as secondary outcomes during the 6 months of the patients' first treatment, and the 6 months after the patients started their second type of treatment. Results The results indicated that there was no significant difference in any outcomes between LAI and OAP treatment when going from LAIs to OAPs (n = 59). However, when patients started with OAPs and switched to LAIs (n = 67), they were hospitalized a significantly fewer number of times, and the duration of their stays was shorter in the LAI phase than in the OAP phase. When combined with bidirectional data, LAI superiority was still observed. Conclusions The findings endorse the relative effectiveness of LAIs over OAPs in the real world, although the inherent flaws of mirror-image studies such as expectation bias and having no parallel comparator should be considered.

Objective This systematic review aimed to elucidate the relationship between polydipsia and antipsychotics. Methods We systematically searched MEDLINE, Embase, and PsycINFO, and included clinical studies and case reports on polydipsia induced or improved by antipsychotics. Results We identified 61 articles: 1 double-blind randomized controlled trial (RCT), 4 single-arm trials, 1 cross-sectional study, 3 case series, and 52 case reports. The double-blind RCT demonstrated no significant difference in improvement in polydipsia between olanzapine and haloperidol. Two single-arm trials showed that polydipsia improved during clozapine treatment, whereas the other 2 showed that risperidone did not improve polydipsia. The cross-sectional study showed the prevalence of hyponatremia with first-generation antipsychotics (FGAs: 26.1%) and second-generation antipsychotics (SGAs: 4.9%). Two case series reported that clozapine improved polydipsia; the other one indicated that patients with polydipsia who were treated with FGAs had schizophrenia (70.4%) and mental retardation (25.9%). Of 90 cases in the case reports, 67 (75.3%) were diagnosed with schizophrenia. Of 83 cases in which antipsychotic treatment started before the onset of polydipsia, 75 (90.3%) received FGAs, particularly haloperidol (n = 24, 28.9%), and 11 (13.3%) received risperidone. Among 40 cases in which polydipsia was improved following antipsychotic treatment, 36 (90.0%) received SGAs, primarily clozapine (n = 14, 35.0%). Conclusions Although the causal relationship between polydipsia and antipsychotics remains unclear because of the paucity of high-quality studies, antipsychotics with high affinity to dopamine D2 receptors may be associated with an increased risk of polydipsia while clozapine may be effective for treating polydipsia.

Purpose The effectiveness of antipsychotic treatments in the acute phase of schizophrenia in actual clinical practice remains somewhat unclear. Therefore, the purpose of the present naturalistic, multi-center study conducted from 1 year starting in September 2017 was to examine the response rate to an initial or second antipsychotic in newly admitted patients with acute-phase schizophrenia, as well as the response rate and quality of augmentation with two antipsychotics in patients who failed to respond to both the initial and second antipsychotics. Results In total, there were 660 (42.8%) and 243 (15.7%) responders to an initial and a second antipsychotic, respectively; thus, 58.5% of all patients were responders to an initial or second antipsychotic. Among 581 nonresponders (37.7%), the initial antipsychotic or a third antipsychotic was added to the second antipsychotic. Among these patients, 89.8% showed a Clinical Global Impression-Improvement score ≤3 (from ‘minimally improved’ to ‘very much improved’). The rates of adverse events such as hyperglycemia, hyper-low-density lipoprotein cholesterolemia, hypertriglyceridemia, hyperprolactinemia, QTc prolongation, and extrapyramidal symptoms were not high in patients receiving augmentation with two antipsychotics compared with all patients, and no serious adverse events were reported. Conclusion Antipsychotic augmentation may be an option in acute-phase treatment for patients who do not respond to either an initial or a second antipsychotic.

Background: There have been scarce data on the distribution of clozapine concentrations in comparison with the recommended range (350–600 ng/ml) or their relationship with side effects among patients with treatment-resistant schizophrenia. Furthermore, no studies have assessed the association between side effects and overall exposure to the drug by calculating the 24-h area-under-curve (AUC). Methods: In- and outpatients with schizophrenia or schizoaffective disorder (ICD-10) who were receiving a stable dose of clozapine for ⩾2 weeks were included. Side effects were assessed using the Glasgow antipsychotic side-effects scale for clozapine (GASS-C). Using two collected plasma samples, plasma clozapine and norclozapine concentrations at peak and trough and their 24-h AUC were estimated using population pharmacokinetic models. Results: A total of 108 patients completed the study (mean ± SD age, 43.0 ± 10.1 years; clozapine dose, 357.5 ± 136.9 mg/day); 33 patients (30.6%) showed estimated trough concentrations of clozapine within the recommended range (350–600 ng/ml) whereas the concentrations were higher and lower than this range among 37 (43.5%) and 28 (25.9%) patients (%), respectively. There were no significant correlations between estimated peak or trough concentrations or 24-h AUC of both clozapine or norclozapine, and GASS-C total or individual scores. No significant differences were found between GASS-C total or individual item scores between the patients with estimated trough concentrations of clozapine of >600 ng/ml and the other subjects. Conclusion: The results suggest that clozapine or norclozapine concentrations are not linked directly to the extent of side effects experienced in clozapine-treated patients with treatment-resistant schizophrenia while the cross-sectional study design limits the interpretation of any causal relationships. These findings indicate that side effects associated with clozapine may occur at any dose or concentration.

Patients with schizophrenia are more likely than the general population to have metabolic syndrome and to live around 15 fewer years largely because of cardiovascular death. Recent studies have suggested that antipsychotic polypharmacy may be associated with metabolic disturbance including metabolic syndrome and the mortality related to it. Although antipsychotic polypharmacy is not recommended and there is limited evidence of its benefits, it is nevertheless becoming common in the treatment of schizophrenia. If it is indeed associated with a greater risk of metabolic syndrome, then more widespread use is a serious concern. In this chapter, we review the effects of antipsychotic polypharmacy on mortality, metabolic disturbance, and metabolic syndrome. The results of earlier studies indicate that antipsychotic polypharmacy might increase the risk of some metabolic disturbances and related mortality but not the risk of metabolic syndrome. The effects of antipsychotic polypharmacy on metabolic disturbance and metabolic syndrome may be unchanged in patients with schizophrenia even after changing unhealthy lifestyles. Further studies are still needed to clarify the association between antipsychotic polypharmacy and metabolic disturbance or metabolic syndrome. At present, in cases when antipsychotic polypharmacy is deemed necessary, it is recommended that testing for metabolic parameters should be undertaken more often in patients receiving polypharmacy than in those receiving monotherapy and stricter lifestyle interventions are needed.

Background Although the validity and safety of antipsychotic polypharmacy remains unclear, it is commonplace in the treatment of schizophrenia. This study aimed to investigate the degree that antipsychotic polypharmacy contributed to metabolic syndrome in outpatients with schizophrenia, after adjustment for the effects of lifestyle. Methods A cross-sectional survey was carried out between April 2007 and October 2007 at Yamanashi Prefectural KITA hospital in Japan. 334 patients consented to this cross-sectional study. We measured the components consisting metabolic syndrome, and interviewed the participants about their lifestyle. We classified metabolic syndrome into four groups according to the severity of metabolic disturbance: the metabolic syndrome; the pre-metabolic syndrome; the visceral fat obesity; and the normal group. We used multinomial logistic regression models to assess the association of metabolic syndrome with antipsychotic polypharmacy, adjusting for lifestyle. Results Seventy-four (22.2%) patients were in the metabolic syndrome group, 61 (18.3%) patients were in the pre-metabolic syndrome group, and 41 (12.3%) patients were in visceral fat obesity group. Antipsychotic polypharmacy was present in 167 (50.0%) patients. In multinomial logistic regression analyses, antipsychotic polypharmacy was significantly associated with the pre-metabolic syndrome group (adjusted odds ratio [AOR], 2.348; 95% confidence interval [CI], 1.181-4.668), but not with the metabolic syndrome group (AOR, 1.269; 95%CI, 0.679-2.371). Conclusions These results suggest that antipsychotic polypharmacy, compared with monotherapy, may be independently associated with an increased risk of having pre-metabolic syndrome, even after adjusting for patients' lifestyle characteristics. As metabolic syndrome is associated with an increased risk of cardiovascular mortality, further studies are needed to clarify the validity and safety of antipsychotic polypharmacy.