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Antipsychotic-induced weight gain is an extremely common problem in people with schizophrenia and is associated with increased morbidity and mortality. Adjunctive pharmacological interventions may be necessary to help manage antipsychotic-induced weight gain. This review splits and updates a previous Cochrane Review that focused on both pharmacological and behavioural approaches to this problem.To determine the effectiveness of pharmacological interventions for preventing antipsychotic-induced weight gain in people with schizophrenia.The Cochrane Schizophrenia Information Specialist searched Cochrane Schizophrenia's Register of Trials on 10 February 2021. There are no language, date, document type, or publication status limitations for inclusion of records in the register.We included all randomised controlled trials (RCTs) that examined any adjunctive pharmacological intervention for preventing weight gain in people with schizophrenia or schizophrenia-like illnesses who use antipsychotic medications.At least two review authors independently extracted data and assessed the quality of included studies. For continuous outcomes, we combined mean differences (MD) in endpoint and change data in the analysis. For dichotomous outcomes, we calculated risk ratios (RR). We assessed risk of bias for included studies and used GRADE to judge certainty of evidence and create summary of findings tables. The primary outcomes for this review were clinically important change in weight, clinically important change in body mass index (BMI), leaving the study early, compliance with treatment, and frequency of nausea. The included studies rarely reported these outcomes, so, post hoc, we added two new outcomes, average endpoint/change in weight and average endpoint/change in BMI.Seventeen RCTs, with a total of 1388 participants, met the inclusion criteria for the review. Five studies investigated metformin, three topiramate, three H2 antagonists, three monoamine modulators, and one each investigated monoamine modulators plus betahistine, melatonin and samidorphan. The comparator in all studies was placebo or no treatment (i.e. standard care alone). We synthesised all studies in a quantitative meta-analysis. Most studies inadequately reported their methods of allocation concealment and blinding of participants and personnel. The resulting risk of bias and often small sample sizes limited the overall certainty of the evidence. Only one reboxetine study reported the primary outcome, number of participants with clinically important change in weight. Fewer people in the treatment condition experienced weight gains of more than 5% and more than 7% of their bodyweight than those in the placebo group (5% weight gain RR 0.27, 95% confidence interval (CI) 0.11 to 0.65; 1 study, 43 participants;7% weight gain RR 0.24, 95% CI 0.07 to 0.83; 1 study, 43 participants; very low-certainty evidence). No studies reported the primary outcomes, 'clinically important change in BMI', or 'compliance with treatment'. However, several studies reported 'average endpoint/change in body weight' or 'average endpoint/change in BMI'. Metformin may be effective in preventing weight gain (MD -4.03 kg, 95% CI -5.78 to -2.28; 4 studies, 131 participants; low-certainty evidence); and BMI increase (MD -1.63 kg/m2, 95% CI -2.96 to -0.29; 5 studies, 227 participants; low-certainty evidence). Other agents that may be slightly effective in preventing weight gain include H2 antagonists such as nizatidine, famotidine and ranitidine (MD -1.32 kg, 95% CI -2.09 to -0.56; 3 studies, 248 participants; low-certainty evidence) and monoamine modulators such as reboxetine and fluoxetine (weight: MD -1.89 kg, 95% CI -3.31 to -0.47; 3 studies, 103 participants; low-certainty evidence; BMI: MD -0.66 kg/m2, 95% CI -1.05 to -0.26; 3 studies, 103 participants; low-certainty evidence). Topiramate did not appear effective in preventing weight gain (MD -4.82 kg, 95% CI -9.99 to 0.35; 3 studies, 168 participants; very low-certainty evidence). For all agents, there was no difference between groups in terms of individuals leaving the study or reports of nausea. However, the results of these outcomes are uncertain given the very low-certainty evidence.There is low-certainty evidence to suggest that metformin may be effective in preventing weight gain. Interpretation of this result and those for other agents, is limited by the small number of studies, small sample size, and short study duration. In future, we need studies that are adequately powered and with longer treatment durations to further evaluate the efficacy and safety of interventions for managing weight gain.

This retrospective cohort study aimed to investigate the longitudinal changes in clozapine dose over a 5-year period in patients with treatment-resistant schizophrenia (TRS). Patients with TRS who were administered clozapine at a hospital between April 2012 and December 2016 and continued treatment with clozapine for at least 1 year were included. Clozapine doses were compared at the dose-fixation point, defined as when the same regimen of clozapine had been continued for 8 weeks or longer, and the post-dose-fixation phase, at 12, 36 and 60 months after clozapine initiation. We included 103 patients and found no significant differences in clozapine dose between the dose-fixation point and post-dose-fixation phase. Approximately half of the patients were categorized into an unchanged group at 12 months after clozapine initiation, whereas approximately 40% of patients were categorized into either the decreased or increased group at 60 months. Multivariable regression analysis revealed that the change in clozapine dose between the dose-fixation point and 60 months after clozapine initiation was negatively associated with clozapine dose at the dose-fixation point. On average, the clozapine dose was unchanged during long-term treatment in patients with TRS, although the dose was decreased or increased in approximately 40% of the patients.

Introduction This study investigated combined prescriptions of drugs for mood disorders and physical comorbidities that need special attention in the light of frequent physical comorbidities in patients with mood disorders. Methods We used the claims sampling data of 581,990 outpatients in January 2015 from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Fisher’s exact test was performed to compare the prescription rates of non-steroidal anti-inflammatory drugs (NSAIDs), loop/thiazide diuretics, angiotensin-converting enzyme inhibitors, and/or angiotensin II receptor blockers between lithium users and age- and sex-matched non-lithium users; NSAIDs, antiplatelet drugs, and/or anticoagulants between selective serotonin reuptake inhibitor (SSRI)/serotonin-noradrenaline reuptake inhibitor (SNRI) users and non-users; warfarin between mirtazapine users and non-users; and the proportions of patients in the two groups with a diagnosis of somatic conditions for which these medications were indicated and actually received them. A Bonferroni corrected p-value of Results Prescriptions of the above-mentioned medications were less frequent in lithium and mirtazapine users and comparable in SSRI/SNRI users, compared to non-users (18.3 vs. 31.9%, p=7.6×10−10; 0.78 vs. 1.65%, p=0.01; 23.1 vs. 24.1%, p=0.044). In a subgroup of patients with somatic diseases for which these medications were indicated, the prescription rates were comparable in lithium and mirtazapine users and higher in SSRI/SNRI users compared to non-users (28.0 vs. 29.4%, p=0.73; 4.7 vs. 7.4%, p=0.28; 35.6 vs. 33.4%, p=0.0026). Discussion Pharmacotherapy with drugs for mood disorders and physical comorbidities that require attention was commonly observed in clinical practice.

Clozapine is generally recommended to be prescribed in a divided dosing regimen based on its relatively short plasma half-life. However, there has been little evidence to support the superiority of divided dosing of clozapine over once-daily dosing. To our knowledge, there have been no studies examining differences in actual plasma concentrations or adverse effects between the 2 dosing strategies of clozapine. We aimed to compare actual plasma concentrations of clozapine between once-daily and divided dosing regimens, and to examine the relationships of these regimens with psychiatric symptoms and adverse effects of clozapine.We analyzed data from 108 participants of a previous study conducted in 2 hospitals in Japan. A population pharmacokinetic model was used to estimate the peak and trough plasma concentrations of clozapine based on actual plasma concentrations. We evaluated psychiatric symptoms with the Brief Evaluation of Psychosis Symptom Domains and adverse effects of clozapine with the Glasgow Antipsychotic Side-effects Scale for Clozapine.The estimated peak and trough plasma concentrations of clozapine did not differ significantly between once-daily and divided dosing regimens. There were no significant differences in psychiatric symptoms except for depression/anxiety or subjective adverse effects of clozapine between the 2 dosing strategies.Our findings tentatively support the feasibility and clinical utility of once-daily dosing of clozapine in clinical practice. Further studies are needed to replicate these findings and determine causality between dosing strategies and clinical outcomes.

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.

Background To summarize the current state of knowledge on antipsychotic treatment strategies for the acute phase and treatment resistance in schizophrenia, we conducted a systematic review of guidelines and algorithms. Methods We conducted a systematic literature search to identify clinical guidelines and algorithms on this topic using MEDLINE and Embase. We extracted information on recommendations for antipsychotic treatment strategies, including those for non-response (i.e., increasing antipsychotic dose and switching to another antipsychotic) and treatment resistance. Results We identified a total of 17 guidelines/algorithms in various countries that were published after 2011. With respect to antipsychotic dose, most of the guidelines (N = 10/11) agreed starting with a low dose or the lowest licensed/effective dose and then titrating the dose upwards. Regarding antipsychotic treatment strategies for non-response, all of the guidelines (N = 9/9) recommended increasing antipsychotic dose towards the upper end of its approved dose range. Five guidelines suggested for increasing beyond the therapeutic dose range in exceptional cases, while overall 10 guidelines including them were negative about such strategy. The vast majority of guidelines (N = 16/17) recommended switching to another antipsychotic for non-response; however, some guidelines mentioned the lack of evidence for these strategies other than the use of clozapine. All the guidelines (N = 17/17) endorsed initiating clozapine after failure to respond to 2 different antipsychotics. Four guidelines endorsed an early use of clozapine, yet as the third antipsychotic. Conclusion The currently available guidelines and algorithms recommended increasing antipsychotic dose and switching to another antipsychotic, particularly clozapine for treatment-resistant schizophrenia, during the acute phase of schizophrenia for non-response.

Although antipsychotics are commonly used for delirium, their adverse effects are a serious concern in light of extrapyramidal symptoms and cardiovascular disturbances. In clinical practice, sedative antidepressants are frequently used as an alternative treatment for delirium; however, there is scarce evidence. Thus, we conducted a retrospective chart review to examine the use and effectiveness of trazodone and mianserin for delirium.Patients who were admitted to a university hospital during 4 years and received either trazodone or mianserin on a regular schedule as monotherapy for the treatment of delirium were included. The rates of and times to the improvement of delirium were compared.Among 3971 patients who developed delirium, 379 (9.5%) and 341 (8.6%) patients received trazodone and mianserin on a regular schedule; 52 and 46 patients met the eligibility criteria (ie, monotherapy) for trazodone and mianserin, respectively. The percentages of patients 65 years or older were 86.5% (n = 45) for trazodone and 89.1% (n = 41) for mianserin. The rates of the improvement of delirium were 63.5% for trazodone and 50.0% for mianserin. Times to the improvement of delirium were 5.3 days (95% confidence interval, 3.2-7.4 days) for trazodone and 9.3 days (95% confidence interval, 5.3-13.3 days) for mianserin. There were no significant differences in the primary outcomes between the 2 groups ( P = 0.17 and P = 0.13, respectively).Considering potentially serious, sometimes lethal, adverse effects of antipsychotics, sedative antidepressants such as trazodone and mianserin may be a treatment option for delirium, especially in the elderly.

This study aimed to examine symptom changes during short-term discontinuation of antipsychotics and address whether antipsychotic withdrawal can induce a rapid symptom exacerbation (i.e., rebound psychosis). The data from three double-blind, randomized, controlled trials comparing lurasidone versus placebo in patients with acute exacerbation of schizophrenia were pooled and analyzed. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) total and the Clinical Global Impression–Severity scale (CGI-S) scores. The scores before and after the antipsychotic discontinuation phase were compared. Factors associated with score changes were also explored. Among 2,154 patients participating in the trials, 600 who received antipsychotic monotherapy and completed the antipsychotic discontinuation phase were included in the analysis. No patients received clozapine. The mean ± standard deviation of the duration of the discontinuation phase was 5.9 ± 2.5 days. The PANSS total and CGI-S scores statistically significantly changed from 94.0 ± 9.5 to 95.4 ± 10.5 and from 4.9 ± 0.6 to 4.9 ± 0.7, respectively, during this phase; however, the absolute difference was minimal. The score changes were not associated with the type or dose of prior antipsychotics, or the duration or strategy (abrupt versus gradual) of antipsychotic discontinuation. Symptoms did not worsen to a clinically meaningful degree after a short-term discontinuation of non-clozapine antipsychotics in patients with acute exacerbation of schizophrenia, suggesting that the efficacy of antipsychotics persists at least several days after discontinuation. This finding casts doubt on the existence of rebound psychosis.

Purpose: Patients with schizophrenia have a higher mortality risk than the general population. However, no recent studies have investigated mortality in people with schizophrenia in Japan. Therefore, we conducted a retrospective study to evaluate excess mortalityand risk factors for mortality in patients with schizophrenia in Japan. Methods: We included patients diagnosed with schizophrenia or schizoaffective disorder at Yamanashi Prefectural Kita Hospital between January 1, 2013, and December 31, 2017. Standardized mortality ratios were used to compare mortality rates between patients with schizophrenia and the general population. Logistic regression analysis was performed to estimate risk factors associated with mortality. Results: Of the 1,699 patients with schizophrenia (893 men and 806 women), 104 (55 men and 49 women) died during the study period. The all-cause standardized mortality ratio (95% confidential interval [CI]) was 2.25 (1.81–2.68); the natural- and unnatural-cause standardized mortality ratios were 2.09 (1.64–2.54) and 4.68 (2.63–6.74), respectively. Male sex (odds ratio [OR] = 2.24, 95% CI = 1.10–4.56), age (OR = 1.12, 95% CI = 1.09–1.16), and barbiturate use (OR = 8.17, 95% CI = 2.07–32.32) were associated with a high risk of mortality. Conclusion: The mortality rate remains high in patients with schizophrenia in Japan. Further studies are needed to evaluate mortality trends in this population.

No clinical guidelines currently recommend antipsychotic monotherapy (APM) for major depressive disorder (MDD). Although several randomized controlled trials (RCTs) have compared the effectiveness, efficacy, and safety of APM versus placebo in patients with MDD, no meta-analysis has examined this topic. We conducted a systematic literature search using MEDLINE and Embase to identify relevant RCTs and performed a meta-analysis to compare the following outcomes between APM and placebo: study discontinuation due to all causes, lack of efficacy, and adverse events, changes in total scores on depression severity scales (e.g., Hamilton Depression Rating Scale and Montgomery Åsberg Depression Rating Scale) and in the Clinical Global Impression - Severity scale (CGI-S) score, and individual adverse event rates. A total of 13 identified studies with 14 comparisons involving 3,197 participants that met the eligibility criteria were included in the meta-analysis. No significant difference was found in study discontinuation due to all causes between the APM and placebo groups. However, there were significant differences in study discontinuation due to lack of efficacy in favor of the APM group and study discontinuation due to adverse events in favor of the placebo group. Compared with the placebo group, the APM group was significantly superior in relation to score reduction on the depression severity scales and CGI-S and inferior in relation to 8 of 23 individual adverse events. APM could be a useful treatment option for the acute phase of MDD, although clinicians should be aware of an increased risk of some adverse events.

No studies have compared clinical outcomes after discontinuation of clozapine between patients who responded to clozapine and those who did not. Therefore, we examined 1-year clinical outcomes after clozapine discontinuation in responders and nonresponders. We reviewed data on patients who discontinued clozapine and retrospectively followed them for 1 year. Clinical information was collected from medical records starting at the initiation of clozapine administration, at discontinuation and at 1 year after discontinuation. In addition, clinical status was assessed using the Clinical Global Impression - Severity (CGI-S) and Clinical Global Impression - Improvement (CGI-I) scales. We classified the patients into clozapine responder and nonresponder groups according to the CGI-I score. Thirty-nine patients were enrolled in this study. Olanzapine was the most common antipsychotic prescribed after clozapine discontinuation in both the responder and nonresponder groups. The mean CGI-S score significantly increased 1 year after clozapine discontinuation in the responder group and significantly decreased in the nonresponder group; there was a significant difference in changes in the CGI-S scores between the groups. The difference remained significant after controlling for clozapine dose and duration of treatment. The findings suggest that clinicians may consider continuing and discontinuing clozapine treatment for patients who responded to clozapine and those who did not, respectively.

Although striatal dopamine neurotransmission is believed to be functionally linked to the formation of the corticostriatal network, there has been little evidence for this regulatory process in the human brain and its disruptions in neuropsychiatric disorders. Here, we aimed to investigate associations of striatal dopamine transporter (DAT) and D2 receptor availabilities with gray matter (GM) volumes in healthy humans. Positron emission tomography images of D2 receptor (n = 34) and DAT (n = 17) captured with the specific radioligands [11C]raclopride and [18F]FE‐PE2I, respectively, were acquired along with T1‐weighted magnetic resonance imaging data in our previous studies, and were re‐analyzed in this work. We quantified the binding potentials (BP ND) of these radioligands in the limbic, executive, and sensorimotor functional subregions of the striatum. Correlations between the radioligand BP ND and regional GM volume were then examined by voxel‐based morphometry. In line with the functional and anatomical connectivity, [11C]raclopride BP ND in the limbic striatum was positively correlated with volumes of the uncal/parahippocampal gyrus and adjacent temporal areas. Similarly, we found positive correlations between the BP ND of this radioligand in the executive striatum and volumes of the prefrontal cortices and their adjacent areas as well as between the BP ND in the sensorimotor striatum and volumes of the somatosensory and supplementary motor areas. By contrast, no significant correlation was found between [18F]FE‐PE2I BP ND and regional GM volumes. Our results suggest unique structural and functional corticostriatal associations involving D2 receptor in healthy humans, which might be partially independent of the nigrostriatal pathway reflected by striatal DAT., This is the first study to investigate the relationship between regional gray matter volumes and availabilities of both dopamine D2 receptor and transporter in the striatum of healthy adults, by using our previous magnetic resonance imaging and positron emission tomography datasets. We have demonstrated positive correlations between dopamine D2/3 receptor radioligand BP ND in the functional subregions of the striatum and the gray matter (GM) volumes of regions that could be functionally and anatomically connected to each of these striatal subdomains. Meanwhile, no marked correlations were observed between dopamine transporter radioligand BP ND and regional GM volumes.

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.

Introduction There has been no consensus on whether and how long add-on drugs for augmentation therapy should be continued in the treatment of depression. Methods Double-blind randomized controlled trials that examined the effects of discontinuation of drugs used for augmentation on treatment outcomes in patients with depression were identified. Meta-analyses were performed to compare rates of study withdrawal due to any reason, study-defined relapse, and adverse events between patients who continued augmentation therapy and those who discontinued it. Results Seven studies were included (n=841 for continuing augmentation therapy; n=831 for discontinuing augmentation therapy). The rate of study withdrawal due to any reason was not significantly different between the 2 groups (risk ratio [RR]=0.86, 95% confidence interval [CI]=0.69–1.08, p=0.20). Study withdrawal due to relapse was less frequent in the continuation group than in the discontinuation group (RR=0.61, 95% CI=0.40–0.92, p=0.02); however, this statistical significance disappeared when one study using esketamine as augmentation was excluded. Analysis of the data from 5 studies that included a stabilization period before randomization found less frequent relapse in the continuation group than in the discontinuation group (RR=0.47, 95% CI=0.36–0.60, p Discussion No firm conclusions could be drawn in light of the small number of studies included. Currently available evidence suggests that add-on drugs, other than esketamine, used for augmentation therapy for depression may be discontinued. This may not be the case for patients who are maintained with augmentation therapy after remission.

BACKGROUND To date, there have been no studies evaluating adherence to clozapine with electronic adherence monitoring (EAM) such as the Medication Event Monitoring System (MEMS® ). METHODS In outpatients with schizophrenia, we conducted a 3-month prospective study investigating antipsychotic adherence with EAM (eCAP® ). Participants were treated with different oral antipsychotics, including clozapine, and blind to EAM monitoring; all were on antipsychotic monotherapy administered once daily. Outcome measures included adherence rate, missed dose, and medication gap. Adherence trajectory patterns were also analyzed for clozapine vs. other antipsychotics collectively. RESULTS A total of 111 patients were included in the study; 33 and 78 patients received clozapine or other antipsychotics, respectively. Adherence rates, defined as proportion of days that the subject took the medication at the prescribed time ± 3 h and proportion of subjects with ≥80% adherence, were numerically higher in patients receiving clozapine vs. other antipsychotics (72.0% vs. 65.1%, P = 0.10; 49.5% vs. 35.7%, P = 0.11, respectively). Along similar lines, some of the missed dose and medication gap outcomes were significantly better in patients receiving clozapine vs. other antipsychotics. Three adherence trajectory patterns were identified for both clozapine and other antipsychotics, with two shared by both groups (i.e., low adherence with a slight decrease over time; high and stable adherence). CONCLUSION Findings suggest that in patients with schizophrenia clozapine adherence is at least comparable, if not slightly better, compared with other antipsychotics.

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.

Background We updated our previous systematic review regarding clinical guidelines and algorithms on antipsychotic treatment in the maintenance phase of schizophrenia (doi: 10.1016/j.schres.2011.11.021) to incorporate and synthesize more recent findings to guide clinical practice. Methods We conducted a systematic literature search to identify clinical guidelines and algorithms describing antipsychotic treatment in the maintenance phase of schizophrenia using MEDLINE and Embase. We assessed overall quality of the guidelines/algorithms according to the AGREE II instrument and extracted information on treatment recommendations. Results We identified 20 guidelines/algorithms from various regions, including 11 updated or newly launched ones after the previous systematic review in 2012. All of the guidelines/algorithms satisfied a certain level of quality. Where mentioned, endorsements were sorted into “recommended”, “partially recommended”, or “not recommended”. As for antipsychotic discontinuation strategy, a majority of guidelines/algorithms that mentioned this strategy did not recommend it for multiple-episode schizophrenia (N = 5/6). On the other hand, the guidelines/algorithms tended to shift from “not recommended” to “partially recommended” both for schizophrenia in general (N = 7/13, N = 7/8 for those published after 2013) and first-episode schizophrenia (N = 10/11, N = 7/7 for those published after 2013) regarding this strategy. All guidelines/algorithms (N = 9/9) converged to discourage antipsychotic intermittent/targeted strategy. Similar to antipsychotic discontinuation strategy, all of the updated or new guidelines/algorithms (N = 6/6) endorsed antipsychotic dose reduction/lower dose strategy. Conclusion Recent clinical guidelines and algorithms on antipsychotic maintenance treatment in schizophrenia shifted more toward a possibility of antipsychotic discontinuation and dose reduction/lower dose strategies. Nonetheless, clinicians need to contemplate on the risk-benefit balance of these strategies for individual patients.

European archives of psychiatry and clinical neuroscience (2022). doi:10.1007/s00406-022-01542-1, Published by Steinkopff, Darmstadt

Continuing antipsychotic treatment in patients with schizophrenia under clinical remission remains controversial. Even though the mainstream opinion declares an outweighed balance against medication discontinuation, recent reviews and critiques suggest that some patients may remain symptom free and well functioning after stopping antipsychotics, but few predictors can identify who can try medication discontinuation, whilst no guidelines exist for reducing medication to reach the lowest effective dose safely. Analyzing the findings from studies employing different methodologies, adopting evidence from pharmacodynamic research, and observing dose reduction in stable patients, as well as taking inspiration from the metaphor of the Cantor set in natural philosophy, we introduce an alternative solution and propose a guided dose-reduction algorithm that follows a set of clear precautions and instructions. The algorithm recommends only a fraction (no more than 25%) of the dosage to be reduced at a time, with at least a 6-month stabilization period required before reducing another 25% of the dose. Patients are empowered to actively participate in decision making when they are ready for further dose tapering, or should they retreat to a previous dosage if warning signs of a relapse re-emerge. An intermittent or irregular dosing schedule can be used to adapt this algorithm to real-world practice. Our preliminary findings suggest that patients with remitted psychosis can do well along this path. We anticipate that this approach can help optimize the risk-benefit ratio and instill a hope in patients with schizophrenia that they can maintain in stable remission under a lower antipsychotic dose without an increased risk of relapse.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

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 There are only a few treatment algorithms for first‐episode schizophrenia. Moreover, all the algorithms apply to acute treatment, but not maintenance treatment. Therefore, we aimed to develop acute and maintenance treatment algorithms for first‐episode schizophrenia. Methods The algorithm committee of the Japanese Society of Clinical Neuropsychopharmacology developed pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first‐episode schizophrenia. Results The acute treatment algorithm focuses on drug‐naïve patients with first‐episode schizophrenia who are not old or very agitated and recommends first‐line treatment with aripiprazole, second‐ or third‐line treatment with risperidone/paliperidone or olanzapine, and fourth‐line treatment with clozapine. Long‐acting injection of the current antipsychotic agent can be used for poor medication adherence or based on patient preference. The agitation treatment algorithm recommends first‐line treatment with lorazepam and second‐ or third‐line treatment with quetiapine or levomepromazine and clearly instructs that the medication used for agitation should be reduced and then discontinued after remission of agitation. The maintenance treatment algorithm recommends the gradual reduction of antipsychotics to the minimum effective dose after remission of positive symptoms. Conclusions We hope that our unique algorithms will be used broadly and will contribute to minimizing patients' burden related to antipsychotic treatment.

Objective Non-convulsive status epilepticus (NCSE) can manifest as catatonia, although it is unclear how frequently such cases have been reported. The common clinical features of these two conditions are also unclear. Methods Using the MEDLINE and Embase databases, we performed a systematic literature search to identify cases diagnosed with both catatonia, according to the Bush-Francis Catatonia Rating Scale, and NCSE, according to the Salzburg Consensus Criteria (last search: March 29, 2021). We extracted data on demographics, clinical features of catatonia, EEG findings, and treatments. Results A total of 66 patients with catatonic NSCE (men, 49%; mean age, 42.0 years) were identified from our search. Of the 66 cases described: 30 (46%) showed motor symptoms; 35 (38%) occurred in patients with preceding episodes of epileptic seizures; 19 (29%) showed subtle ictal clinical phenomena, such as minor twitching of the mouth, periorbital region, and extremities; 22 (33%) presented with psychiatric symptoms prior to the onset of catatonia; 17 (26%) had a history of psychiatric diseases; and in 10 cases (15%), NSCE was confirmed by intentional or non-intentional long-term EEG monitoring. Benzodiazepines were used as the initial treatment for NCSE in 30 cases (49%), of which 20 cases (73%) improved with monotherapy. Discussion A substantial number of cases included in the present review involved catatonia without any symptoms indicative of epilepsy, suggesting that NCSE may be misdiagnosed as a psychiatric disease, and highlighting the importance of the accurate diagnosis and treatment of NCSE in patients presenting with catatonia.