Efficacy Of Clozapine Research Articles

Predictors of clozapine efficacy in treatment-resistant schizophrenia: A cross-sectional analysis of sociodemographic, clinical, biochemical, and electrophysiological EEG changes

Abstract Context: Although neuroleptics are available for treating schizophrenia, patient compliance with treatment remains a major hurdle. Such patients turn into treatment-resistant schizophrenia (TRS) where clozapine can be prescribed, but it causes severe side effects. Many markers can predict favorable responses to clozapine therapy. Aims: To assess sociodemographic, clinical, electrophysiological, and biochemical parameters among TRS patients and to evaluate the difference between TRS patients with and without response to clozapine. Settings and Design: A prospective observational study was carried out for a period of 2 years from October 31, 2020, to November 1, 2022, in the Psychiatry Department of a Tertiary Care Hospital in Eastern Odisha. Materials and Methods: All patients visiting the Psychiatry Department of a tertiary care hospital, diagnosed with International Classification of Diseases schizophrenia were screened for TRS as per modified Kane’s criteria. The assessed parameters were compared using the Brief Psychiatry Rating Scale, the Positive and Negative Syndrome Scale of Schizophrenia, and Clinical Global Impressions scale. Statistical Analysis Used: Data were compiled and analyzed using IBM corporation’s Statistical Package for the Social Sciences (SPSS) software version 27. Results: Thirty-one eligible patients consented to the study, with 21 (67.7%) females and 10 (32.3%) males. Maximum, 17 (54.8%), belonged to 18–35 years of age. The biochemical parameters, fasting blood sugar (FBS), and triglycerides (TGs) had mean values of 94.56 (±6.6) mg/dL and 157 (±9.8) mg/dL, respectively. Gross electroencephalogram abnormalities were seen in 3 (10%) cases. Conclusions: The female gender, higher education, and a shorter duration of untreated psychosis predicted a better outcome. The patients showing good responses had higher trends in FBS and TGs at follow-up. Clozapine was associated with increased electrophysiological intra- and interhemispheric asymmetry.

Clozapine treatment and astrocyte activity in treatment resistant schizophrenia: A proton magnetic resonance spectroscopy study

Clozapine is the only antipsychotic approved for treating treatment-resistant schizophrenia (TRS), characterized by persistent positive symptoms despite adequate antipsychotic treatment. Unfortunately, clozapine demonstrates clinical efficacy in only ~30–60 % of patients with TRS (clozapine-responders; ClzR+), while the remaining ~40–70 % are left with no pharmacological recourse for improvement (clozapine-resistant; ClzR−). Mechanism(s) underlying clozapine's superior efficacy remain unclear. However, in vitro evidence suggests clozapine may mitigate glutamatergic dysregulations observed in TRS, by modulating astrocyte activity in ClzR+, but not ClzR−. A factor that if proven correct, may help the assessment of treatment response and development of more effective antipsychotics. To explore the presence of clozapine-astrocyte interaction and clinical improvement, we used 3 T proton-magnetic resonance spectroscopy to quantify levels of myo-Inositol, surrogate biomarker of astrocyte activity, in regions related to schizophrenia neurobiology: Dorsal-anterior-cingulate-cortex (dACC), left-dorsolateral-prefrontal-cortex (left-DLPFC), and left-striatum (left-striatum) of 157 participants (ClzR− = 30; ClzR+ = 37; responders = 38; controls = 52). Clozapine treatment was assessed using clozapine to norclozapine plasma levels, 11–12 h after last clozapine dose. Measures for symptom severity (i.e., Positive and Negative Symptoms Scale) and cognition (i.e., Mini-Mental State Examination) were also recorded. Higher levels of myo-Inositol were observed in TRS groups versus responders and controls (dACC (p < 0.001); left-striatum (p = 0.036); left-DLPFC (p = 0.023)). In ClzR+, but not ClzR−, clozapine to norclozapine ratios were positively associated with myo-Inositol levels (dACC (p = 0.004); left-DLPFC (p < 0.001)), and lower positive symptom severity (p < 0.001). Our results support growing in vitro evidence of clozapine-astrocyte interaction in clozapine-responders. Further research may determine the viability of clozapine-astrocyte interactions as an early marker of clozapine response.

Efficacy of clozapine versus standard treatment in adult individuals with intellectual disability and treatment-resistant psychosis (CLOZAID): study protocol of a multicenter randomized clinical trial.

Intellectual disability (ID) affects approximately 1% of the worldwide population and individuals with ID have a higher comorbidity with mental illness, and specifically psychotic disorders. Unfortunately, among individuals with ID, limited research has been conducted since ID individuals are usually excluded from mental illness epidemiological studies and clinical trials. Here we perform a clinical trial to investigate the effectiveness of clozapine in the treatment of resistant psychosis in individuals with ID. The article highlights the complexity of diagnosing and treating psychopathological alterations associated with ID and advocates for more rigorous research in this field. A Phase IIB, open-label, randomized, multicenter clinical trial (NCT04529226) is currently ongoing to assess the efficacy of oral clozapine in individuals diagnosed with ID and suffering from treatment-resistant psychosis. We aim to recruit one-hundred and fourteen individuals (N=114) with ID and resistant psychosis, who will be randomized to TAU (treatment as usual) and treatment-with-clozapine conditions. As secondary outcomes, changes in other clinical scales (PANSS and SANS) and the improvement in functionality, assessed through changes in the Euro-QoL-5D-5L were assessed. The main outcome variables will be analyzed using generalized linear mixed models (GLMM), assessing the effects of status variable (TAU vs. Clozapine), time, and the interaction between them. The treatment of resistant psychosis among ID individuals must be directed by empirically supported research. CLOZAID clinical trial may provide relevant information about clinical guidelines to optimally treat adults with ID and treatment-resistant psychosis and the benefits and risks of an early use of clozapine in this underrepresented population in clinical trials. Clinicaltrials.gov: NCT04529226. EudraCT: 2020-000091-37.

Clozapine Efficacy and Adverse Drug Reactions Among a Nationwide Study of 1021 Australians Prescribed Clozapine: The ClozaGene Study.

The ClozaGene Study is a nationwide cohort of adults who have been treated with clozapine. While clozapine is indicated in the management of treatment-resistant schizophrenia, it is associated with a considerable adverse drug reaction (ADR) burden, and not all patients achieve adequate symptomatic response. The current study focuses on self-reported experiences of clozapine use and response, clozapine-associated ADRs, and mental health comorbidity. A total of 1021 participants (41.0% female; aged 46.2 ± 10.6 years [range 18-66]) were recruited via a mail-out based on prescriptions for clozapine. Participants completed a self-report questionnaire. Most participants (90.1%, n = 912) were living with schizophrenia while 41.5% reported a lifetime diagnosis of depression, 15.6% bipolar disorder, and 8.1% schizoaffective disorder. Clozapine was currently prescribed to 944 (92.5%) participants and 37.8% of these participants self-reported currently taking additional antipsychotic medication. Nearly 3 quarters of participants living with schizophrenia reported that clozapine helped control their schizophrenia symptoms moderately to very well. The most commonly reported ADRs were sialorrhea (80.3%), weight gain (71.0%), constipation (56.9%), and sedation (52.8%). The prevalence of clozapine cessation due to clozapine-induced myocarditis and neutropenia was 1% and 0.4%, respectively. Our findings highlight the high rate of psychotic and metabolic symptoms and ADRs among adults prescribed clozapine in the general Australian population. Future genomic analyses will focus on identifying genetic variants influencing clozapine treatment response and side effects.

Differential impact of intermittent versus continuous treatment with clozapine on fatty acid metabolism in the brain of an MK-801-induced mouse model of schizophrenia

Continuous antipsychotic treatment is often recommended to prevent relapse in schizophrenia. However, the efficacy of antipsychotic treatment appears to diminish in patients with relapsed schizophrenia and the underlying mechanisms are still unknown. Moreover, though the findings are inconclusive, several recent studies suggest that intermittent versus continuous treatment may not significantly differ in recurrence risk and therapeutic efficacy but potentially reduce the drug dose and side effects. Notably, disturbances in fatty acid (FA) metabolism are linked to the onset/relapse of schizophrenia, and patients with multi-episode schizophrenia have been reported to have reduced FA biosynthesis. We thus utilized an MK-801-induced animal model of schizophrenia to evaluate whether two treatment strategies of clozapine would affect drug response and FA metabolism differently in the brain. Schizophrenia-related behaviors were assessed through open field test (OFT) and prepulse inhibition (PPI) test, and FA profiles of prefrontal cortex (PFC) and hippocampus were analyzed by gas chromatography–mass spectrometry. Additionally, we measured gene expression levels of enzymes involved in FA synthesis. Both intermittent and continuous clozapine treatment reversed hypermotion and deficits in PPI in mice. Continuous treatment decreased total polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs) and FAs in the PFC, whereas the intermittent administration increased n-6 PUFAs, SFAs and FAs compared to continuous administration. Meanwhile, continuous treatment reduced the expression of Fads1 and Elovl2, while intermittent treatment significantly upregulated them. This study discloses the novel findings that there was no significant difference in clozapine efficacy between continuous and intermittent administration, but intermittent treatment showed certain protective effects on phospholipid metabolism in the PFC.

Multiple serum anti-glutamate receptor antibody levels in clozapine-treated/naïve patients with treatment-resistant schizophrenia

BackgroundGlutamatergic function abnormalities have been implicated in the etiology of treatment-resistant schizophrenia (TRS), and the efficacy of clozapine may be attributed to its impact on the glutamate system. Recently, evidence has emerged suggesting the involvement of immune processes and increased prevalence of antineuronal antibodies in TRS. This current study aimed to investigate the levels of multiple anti-glutamate receptor antibodies in TRS and explore the effects of clozapine on these antibody levels.MethodsEnzyme linked immunosorbent assay (ELISA) was used to measure and compare the levels of anti-glutamate receptor antibodies (NMDAR, AMPAR, mGlur3, mGluR5) in clozapine-treated TRS patients (TRS-C, n = 37), clozapine-naïve TRS patients (TRS-NC, n = 39), and non-TRS patients (nTRS, n = 35). Clinical symptom severity was assessed using the Positive and Negative Symptom Scale (PANSS), while cognitive function was evaluated using the MATRICS Consensus Cognitive Battery (MCCB).ResultThe levels of all four glutamate receptor antibodies in TRS-NC were significantly higher than those in nTRS (p < 0.001) and in TRS-C (p < 0.001), and the antibody levels in TRS-C were comparable to those in nTRS. However, no significant associations were observed between antibody levels and symptom severity or cognitive function across all three groups after FDR correction.ConclusionOur findings suggest that TRS may related to increased anti-glutamate receptor antibody levels and provide further evidence that glutamatergic dysfunction and immune processes may contribute to the pathogenesis of TRS. The impact of clozapine on anti-glutamate receptor antibody levels may be a pharmacological mechanism underlying its therapeutic effects.

Rethinking Clozapine: Lights and Shadows of a Revolutionary Drug.

The current literature globally highlights the efficacy of Clozapine in several psychiatric disorders all over the world, with an FDA indication for reducing the risk of repeated suicidal behavior in patients with schizophrenia or schizoaffective disorder. A growing field of research is also stressing a possible broader beneficial effect of Clozapine in promoting neuroprotection and neurotrophism. However, this drug is linked to several life-threatening side effects, such as agranulocytosis, myocarditis and seizures, that limit its use in daily clinical practice. For this work, a search was performed on PubMed using the terms "Clozapine indications", "Clozapine adverse effects", "Clozapine regenerative effects", and "Clozapine neuroplasticity" with the aim of reviewing the scientific literature on Clozapine's treatment indications, adverse effects and potential regenerative role. The results confirmed the efficacy of clozapine in clinical practice, although limited by its adverse effects. It appears crucial to raise awareness among clinicians about the potential benefits of using Clozapine, as well educating medical personnel about its risks and the early identification of possible adverse effects and their management.

Making sense of norclozapine levels: 3 clinical axioms

Laboratories commonly provide norclozapine concentrations when a plasma clozapine level is requested, but the appropriate use of this information for the treatment of individuals with schizophrenia is not always clear. Particularly vexing is the fact that norclozapine possesses pharmacological properties that are distinct from its parent compound and which contribute to clozapine's efficacy signal, yet the literature focuses primarily on the association of clozapine levels with symptomatic improvement. The purpose of this brief article is to highlight findings with respect to the need to track norclozapine levels, or the ratio of clozapine/norclozapine plasma levels, to optimize efficacy among inadequate responders to clozapine treatment. In addition, there will be a discussion of the specific type of information provided by the clozapine/norclozapine ratio on clozapine's clearance, and how this ratio is sometimes misinterpreted. There is clinical value from to be derived from norclozapine levels and the clozapine/norclozapine ratio for schizophrenia management, and the principles governing use of this information will be distilled into 3 succinct axioms to aid clinicians in managing their clozapine-treated patients with schizophrenia.

Efficacy of clozapine compared with other second-generation antipsychotic drugs in patients with treatment-resistant schizophrenia: protocol for a systematic review and individual patient data meta-analysis of randomised controlled trials

IntroductionGuidelines recommend clozapine for treatment-resistant schizophrenia. However, meta-analysis of aggregate data (AD) did not demonstrate higher efficacy of clozapine compared with other second-generation antipsychotics but found substantial heterogeneity between trials...

Efficacy of Clozapine in Patients with Schizophrenia – A 3-Month follow-up Study from North India

Abstract Background: Treatment-resistant schizophrenia (TRS) is one of the most disabling forms of schizophrenia. The Indian population being different in its sociodemographic factors, clinical profiles, and family structures, the experience of the efficacy of clozapine here is insufficient. Aim: The aim of the study is to explore the efficacy of clozapine in TRS over 3 months of drug use. Materials and Methods: It was an open-label interventional 12-week follow-up study, with 30 consenting adults with TRS determined as per modified Conley and Kelly’s criteria of treatment resistance. The patient’s sociodemographic and clinical details were recorded. Oral clozapine was initiated with gradual up-titration after preclozapine workup. The Positive and Negative Syndrome Scale (PANSS) score was assessed at baseline and reviewed at 4 weekly intervals. Results: By the end of 12 weeks, on an average dose of 494 ± 113.83 mg/day, 36.67% of patients reported 25%–50% improvement in PANSS score. The maximum improvement was seen in the positive symptoms subscale followed by the general and negative symptoms subscale. Conclusion: This study enlightens the dosage differences and efficacy of clozapine in the management of TRS in the Indian population.

Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia.

Despite its enduring relevance as the single most effective and important evidence-based treatment for schizophrenia, underutilization of clozapine remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to offer clozapine due to its relatively large side-effect burden and the complexity of its use. This underscores the necessity for continued education regarding both the vital nature and the intricacies of clozapine treatment. This narrative review summarizes all clinically relevant areas of evidence, which support clozapine's wide-ranging superior efficacy - for treatment-resistant schizophrenia (TRS) and beyond - and make its safe use eminently feasible. Converging evidence indicates that TRS constitutes a distinct albeit heterogeneous subgroup of schizophrenias primarily responsive to clozapine. Most importantly, the predominantly early onset of treatment resistance and the considerable decline in response rates associated with its delayed initiation make clozapine an essential treatment option throughout the course of illness, beginning with the first psychotic episode. To maximize patients' benefits, systematic early recognition efforts based on stringent use of TRS criteria, a timely offer of clozapine, thorough side-effect screening and management as well as consistent use of therapeutic drug monitoring and established augmentation strategies for suboptimal responders are crucial. To minimize permanent all-cause discontinuation, re-challenges after neutropenia or myocarditis should be considered. Owing to clozapine's unique efficacy, comorbid conditions including substance use and most somatic disorders should not dissuade but rather encourage clinicians to consider clozapine. Moreover, treatment decisions need to be informed by the late onset of clozapine's full effects, which for reduced suicidality and mortality rates may not even be readily apparent. Overall, the singular extent of its efficacy combined with the high level of patient satisfaction continues to distinguish clozapine from all other available antipsychotics.

Iranian psychiatrists’ attitude towards clozapine use for patients with treatment-resistant schizophrenia: a nationwide survey

BackgroundClozapine has the greatest efficacy for treatment-resistant schizophrenia (TRS), even though its underutilization is not uncommon across different countries. This study aimed to investigate the knowledge and attitude of Iranian psychiatrists toward clozapine use.MethodIn this cross-sectional study, a questionnaire was distributed among psychiatrists registered with the Iranian Psychiatrists Association (including its provincial branches) to assess their knowledge and attitude towards clozapine use. A total of 282 psychiatrists completed the questionnaire. Descriptive analysis was used to describe demographic information, and Chi-square tests were conducted to determine if there is an association between academic position and work experience. All statistical analyses were performed using SPSS® version 25.0 for Windows, and a significance level of 0.05 was used.ResultsMost respondents (93%) acknowledged that they prescribed clozapine for their patients, and 74% believed that clozapine was more effective than other antipsychotic drugs. However, 43.3% of the respondents said they did not believe in the safety of clozapine. Difficulty initiating and having no firsthand experience in the superiority of clozapine were reported by 81.2 and 80% of the respondents, respectively. Our results also showed an association between having an academic position and access to appropriate facilities for the control and management of patients treated with clozapine and believing in the safety of clozapine (p < 0.05). Longer work experience (more than 15 years) was associated with a higher prescription of clozapine, belief in greater effectiveness of clozapine, and its safety (p < 0.0001).ConclusionIranian psychiatrists had a good self-perception of knowledge about the efficacy of clozapine for patients with TRS, but concerns about serious side effects are common. Psychiatrists with longer work experience and academic positions were more optimistic towards clozapine use than the younger ones with no academic position. Considering the results in planning the strategies to decrease concerns about clozapine use is recommended.

Evidence of pharmacogenetics-based fluvoxamine use as an add-on to clozapine treatment in psychiatry.

Pharmacological treatments used for psychiatric disorders, such as clozapine, demonstrate large interindividual variability in terms of possible adverse effects and therapeutic benefit. This variability can be explained by multiple factors, including pharmacogenetic factors. Clozapine efficacy can be impacted by CYP polymorphisms. A growing body of literature on pharmacogenetics suggests the clinical benefit of concomitant use of clozapine and fluvoxamine to improve global pharmacotherapeutic management. This article reviews and discusses available clinical and pharmacological data and limitations of clozapine augmentation with fluvoxamine based on pharmacogenetic rationale and clinical experience. The aim is to provide an updated approach on how to use the pharmacological and pharmacogenetic profile to improve clozapine efficacy and tolerance in severely ill patients.

Combination of clozapine, cariprazine and fluoxetine in treatment-resistant schizophrenia patient with prominent negative symptoms: A Case report

IntroductionDespite pharmacological advances in the treatment of schizophrenia, significant number of patients are still treatment-resistant. Clozapine is recommended as first-line treatment for treatment-resistant schizophrenia (TRS) in guidelines. Despite the greater efficacy of clozapine over other antipsychotics in the management of TRS, a significant number of patients fail to attain adequate response or develop adverse effects, and more interventions are needed.ObjectivesTo describe a clinical case of treatment-resistant schizophrenia patient with prominent negative symptoms treated with combination of clozapine, cariprazine and fluoxetine, and to review the literature.MethodsClinical case presentation through review of the clinical file and non-systematic review on PubMed and ResearchGate.ResultsA 41 year old female patient presented to inpatient clinic with low mood, occasional commanding and commenting verbal hallucinations, occasional suicidal thoughts, blunted affect, anhedonia, asociality, she was apathetic, lacked motivation to get up from bed, had night’s sleep disturbance. Patient was diagnosed with Schizophrenia in 2009, she has been hospitalized in Psychiatric wards for 16 times. She has received treatment with combinations of several antipsychotic drugs and antidepressants, had side-effects and have not reached full remission. During treatment with clozapine (up to 175mg per day) in combination with cariprazine (up to 4.5mg per day) and fluoxetine (up to 20mg per day), gradually negative symptoms decreased, patient became more active, showed interest in daily and rehabilitation activities, night’s sleep improved.Conclusions Patient with treatment-resistant schizophrenia benefited from combination of clozapine, cariprazine and fluoxetine. Further research is necessary on treatment combination strategies for TRS.DisclosureNo significant relationships.

Changes in corticostriatal connectivity and striatal tissue iron associated with efficacy of clozapine for treatment‑resistantschizophrenia.

RationaleThough numerous studies demonstrate the superiority of clozapine (CLZ) for treatment of persistent psychotic symptoms that are characteristic of treatment-refractory schizophrenia (TRS), what remains unknown are the neural and molecular mechanisms underlying CLZ’s efficacy. Recent work implicates increased corticostriatal functional connectivity as a marker of response to non-CLZ, dopamine (DA) D2-receptor blocking antipsychotic drugs. However, it is undetermined whether this connectivity finding also relates to CLZ’s unique efficacy, or if response to CLZ is associated with changes in striatal DA functioning.ObjectiveIn a cohort of 22 individuals with TRS, we examined response to CLZ in relation to the following: (1) change in corticostriatal functional connectivity; and (2) change in a magnetic resonance-based measure of striatal tissue iron (R2’), which demonstrates utility as a proxy measure for elements of DA functioning.MethodsParticipants underwent scanning while starting CLZ and after 12 weeks of CLZ treatment. We used both cortical and striatal regions of interest to examine changes in corticostriatal interactions and striatal R2’ in relation to CLZ response (% reduction of psychotic symptoms).ResultsWe first found that response to CLZ was associated with an increase in corticostriatal connectivity between the dorsal caudate and regions of the frontoparietal network (P < 0.05, corrected). Secondly, we observed no significant changes in striatal R2’ across CLZ treatment.ConclusionOverall, these results indicate that changes in corticostriatal networks without gross shifts in striatal DA functioning underlies CLZ response. Our results provide novel mechanistic insight into response to CLZ treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00213-022-06138-0.

Efficacy of clozapine for long-stay patients with treatment-resistant schizophrenia: 4-year observational study.

AimSupporting patients upon discharge following prolonged hospitalization in private psychiatric hospitals in Japan have long been an issue. This study evaluated the efficacy of clozapine in treating long‐stay patients with treatment‐resistant schizophrenia to reduce the frequency and duration of readmissions postdischarge.MethodsWe retrospectively examined the length and frequency of hospitalizations of long‐stay and non‐long‐stay patients with schizophrenia who were introduced to clozapine at our hospital.ResultsComparing participants’ medical records 2 years before and after the introduction of clozapine, we identified a significant decrease in both length and frequency of hospitalizations in all patients who were introduced to clozapine. In long‐stay patients, the length and frequency of hospitalization were significantly reduced. However, compared to non‐long‐stay patients, the period from introduction of clozapine to discharge was longer and the dose of clozapine was higher. Thus, it is necessary to take time to evaluate the therapeutic effects for long‐stay patients.ConclusionThe results showed that clozapine is helpful for patients with treatment‐resistant schizophrenia, who are considered difficult to treat and discharge in Japan.

Prolonged mannerism as an isolated, interesting, and old symptom in a schizophrenic patient with poor response to clozapine: a clinical image

The concept of catatonia was first described by a German psychiatrist, Kahlbaum, in 1874. Catatonia is a serious neurological disorder associated with a wide range of psychiatric, neurological, medical conditions, and drug-induced disorders. Nevertheless, there is no absolute guideline for treating catatonia patients in whom the cause of the disorder is unknown. Clozapine is the first atypical antipsychotic used for the treatment of catatonia. Our case was a 51-year-old single, right-handed man with schizophrenia and a specific symptom of catatonia. Despite previous studies findings revealing the efficacy of clozapine in relieving catatonia symptoms, our patient did not show a definite response to this medication. Hence, follow-up of these patients to evaluate other treatments and possible incidence or manifest of other catatonic features like waxy flexibility, echo phenomenon, and negativism are suggested.

Clozapine induces metformin-resistant prediabetes/diabetes that is associated with poor clinical efficacy in patients with early treatment-resistant schizophrenia

BackgroundTwo distinct subtypes of treatment-resistant schizophrenia (TRS) have been recently reported, including early-treatment resistance (E-TR) and late-treatment resistance (L-TR). This study was to assess clozapine-induced metformin-resistant prediabetes/diabetes and its correlation with clinical efficacy in schizophrenia E-TR subtype. MethodsThis prospective cohort study enrolled 230 patients with schizophrenia E-TR subtype and they were treated with adequate doses of clozapine for 16 weeks, during which patients with prediabetes/diabetes were assigned to receive add-on metformin. The main outcomes and measures included incidence of clozapine-induced prediabetes/diabetes and metformin-resistant prediabetes/diabetes, and the efficacy of clozapine as assessed by the Positive and Negative Syndrome Scale (PANSS) score. ResultsClozapine-induced prediabetes/diabetes occurred in 76.52% of patients (170 prediabetes and 6 diabetes), of which the blood sugar of 43 (24.43%) patients was controlled with metformin. Despite add-on metformin, 47.06% (74/170) of prediabetes patients progressed to diabetes. In total, the incidence of clozapine-induced metformin-resistant prediabetes/diabetes was 75.57% (133/176). On completion of 16-week clozapine treatment, 16.52% (38/230) patients showed clinical improvement with PANSS scores of ≥50% declining. Furthermore, clozapine-induced prediabetes/diabetes was significantly correlated with the poor clinical efficacy of clozapine for schizophrenia E-TR subtype. ConclusionsThe incidence of clozapine-induced metformin-resistant prediabetes/diabetes was considerably high in the schizophrenia E-TR subtype. Clozapine-induced metformin-resistant prediabetes/diabetes represents an independent risk factor that adversely affects the clinical efficacy of clozapine for the schizophrenia E-TR subtype. This study provided new evidence for re-evaluating the use of clozapine for TRS, especially E-TR subtype, and the use of metformin for the glycemic control of clozapine-induced prediabetes/diabetes.

Use of olanzapine compared with clozapine for treatment-resistant schizophrenia in a real-world setting: nationwide register-based study.

Clozapine is generally considered as the treatment of choice for patients with treatment-resistant schizophrenia (TRS). However, its superiority has recently been questioned because olanzapine has been suggested as non-inferior to clozapine in its effectiveness. We aimed to investigate the current status of clozapine prescriptions to identify any disparity between clinical guidelines and real-world practices. In this study, we utilised the Health Insurance Review Agency database in the Republic of Korea to investigate the real-world effectiveness of clozapine for patients with TRS. We compared differences in patient variables before and after clozapine administration, and we also performed survival analyses for both psychiatric admissions and emergency room visits among patients who used clozapine or olanzapine. This study investigated an incident cohort of 64 442 patients, and 2338 patients have been prescribed clozapine. Of these, 998 patients had TRS. In survival analysis, clozapine showed a worse survival rate for psychiatric admissions than olanzapine (hazard ratio 0.615). We also identified that clinicians tended to try a number of antipsychotics, as recommended, before starting patients on clozapine. In conclusion, we found that olanzapine led to higher survival rates for psychiatric admissions than clozapine. Thus, considering the risk of serious adverse effects, clozapine may be used conservatively. Considering several studies advocating superior efficacy of clozapine, further studies with extensive data are recommended.

Interest of Fluvoxamine as an Add-On to Clozapine in Children With Severe Psychiatric Disorder According to CYP Polymorphisms: Experience From a Case Series.

Despite its drastic efficacy in resistant psychiatric disorders, clozapine remains rarely used in youth due to its side effects. Clozapine plasma level is determined through its metabolism involving several isoforms of cytochromes 450 (CYP450) family. Isoform CYP1A2 appears as a limiting enzyme involved in the metabolism of clozapine, while isoforms 2C19, 2D6, 3A4, and 3A5 also contribute in a minor way. Clozapine efficacy is limited by a significant inter-patient variability in exposure according to CYP's polymorphisms. Clozapine plasma levels may be increased with CYP inhibitors such as fluvoxamine. This drug is a potent enzymatic inhibitor of CYP1A2 and, to a lesser extent, of CYP3A4 and CYP2D6. Hence, in case of CYP's polymorphisms in youth, the use of fluvoxamine as add-on to clozapine could help in reaching clinical and biological efficacy and allowing lower clozapine dosage and a better tolerance profile as it has already been described in adults. We report four pediatric cases with severe psychiatric disorders underlying our experience with CYP polymorphism explorations and the use of fluvoxamine as add-on to clozapine. Our four patients clinically improved after the introduction of fluvoxamine, enhancing clozapine metabolism and therefore the clozapine plasma level within therapeutic range. Despite the interesting results of fluvoxamine, we report a severe issue of tolerance for one patient, emphasizing the need for caution regarding possible drug interactions when fluvoxamine is considered. Hence, we propose a detailed step-by-step multidisciplinary protocol.