Clozapine In Treatment-resistant Schizophrenia Research Articles

Duration of prior psychotic illness and clozapine response: a retrospective observational study using electronic health records

Background: Clozapine is the gold-standard medication for treatment-resistant schizophrenia (TRS) yet its initiation is often delayed. Objective: To examine whether earlier initiation of clozapine in TRS is associated with lower Clinical Global Impression – Severity (CGI-S) scores at 2 years. Methods: This was a retrospective cohort study from electronic health records of patients with first adequate trial of clozapine at the South London and Maudsley mental health service between 1 January 2007 and 31 December 2016. Dates of illness onset and clozapine commencement were manually extracted from anonymised case notes. CGI-S scores were rated blind to illness duration. Ordinal logistic regression was used to describe the association between illness duration at baseline and CGI-S outcome score at 2 years, following adjustment for CGI-S start score and other key covariates. Results: Among the 401 patients included, there was an association between illness duration and CGI-S outcome score with a 4% increase in the odds of a higher (worse) outcome CGI-S score per year of illness [adjusted odds ratio (AOR) = 1.04; 95% confidence interval (CI): 1.01–1.06]. The association between illness duration and clozapine response was most marked at less than 4 years illness duration. There were too few clozapine initiations within the first 2 years of illness to draw any conclusions about early clozapine initiation. Conclusion: Initiation of clozapine within 2–4 years of psychotic illness onset offers the best outcome for TRS, but the advantage, if any, of earlier initiation is unclear from these data.

Antipsychotic treatment strategies for acute phase and treatment resistance in schizophrenia: A systematic review of the guidelines and algorithms

BackgroundTo 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. MethodsWe 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. ResultsWe 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. ConclusionThe 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.

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.

An evaluation of barriers to the initiation of clozapine in patients with treatment-resistant schizophrenia

AimsThis evaluation aimed to identify patient, practitioner and infrastructural barriers to initiation of clozapine treatment in patients with treatment-resistant schizophrenia (TRS). In response to recent research supporting use of clozapine as the most effective treatment for patients with TRS, concerted efforts have been made to establish why clozapine is underutilised in the NHS. Following a study conducted by South London and Maudsley NHS Foundation Trust, which identified barriers and made recommendations, this evaluation aimed to identify barriers to initiation of clozapine in patients under the care of Mersey Care NHS Foundation Trust.This evaluation also aimed to make further recommendations to increase use of clozapine in Mersey Care's TRS patients and assess whether there have been any differences to concerns about clozapine initiation compared to previous evaluations.MethodAn online questionnaire containing a series of Likert scales was e-mailed to all Consultant Psychiatrists in Mersey Care NHS Foundation Trust. The questionnaire asked Consultants to rate how often they felt a range of barriers interfered with successful initiation of Clozapine treatment. The barriers chosen were based on the 2019 systematic review “Barriers to using clozapine in treatment-resistant schizophrenia.”ResultNineteen consultant psychiatrists completed the online questionnaire. All 19 indicated they either “agreed” (16%) or “strongly agreed” (84%) that they were confident in diagnosing TRS. This was a significant increase compared to the South London and Maudsley evaluation, with only 81% of participants in that study being “fairly familar” or “very familiar” with clozapine guidelines.Furthermore, concerns about inadequate blood testing facilities appear to have been addressed, with no participants in this evaluation staing there were insufficient blood testing facilities. However, 53% of Consultants who completed this evaluation stated they “often” (37%) or “very often” (16%) have patients who refuse clozapine because of the requirement for regular blood testing. Refusal to agree to required blood testing was the commonest reason identified for failure to initiate clozapine in TRS patients. This was consistent with the results from the South London and Maudsley study.ConclusionThose Mersey Care consultants surveyed identified that providing patients with further information about clozapine would be the most valuable intervention to increase likelihood of uptake of clozapine in the treatment of TRS. Significant progress has been made in improving the likelihood that clozapine can be successfully initiated, especially in the removal of practitioner barriers. This evaluation suggests interventions should now be aimed at reducing patient barriers to initiation of treatment.

Clozapine Induced Insulin Dependence

Background: Antipsychotic medications come with an array of potential side effects in a difficult-to-treat population, particularly if management of other comorbidities is required. A review of the literature shows some studies have discussed the possibility of antipsychotic medication inducing hyperglycemia by blocking pancreatic M3 receptors. Other studies have shown dramatic worsening of metabolic parameters in patients who already have Type 2 Diabetes Mellitus after starting Clozapine. Clinical Case: A 23 year old African American Male with a past history of treatment resistant Schizophrenia presented to the ED with hyperglycemia and altered mental status. Blood sugar 489 mg/dL, anion gap 28 mmol/L, bicarb 13 mmol/L, white Blood Cell count 9.0 x10^3/cmm. Urine positive for Ketones. Chest Xray and EKG were normal, there were no obvious signs of infection. This was the sixth admission for Diabetic Ketoacidosis (DKA) in the past 10 months. Antibodies obtained showed negative Glutamic Acid Decarboxylase Autoantibodies (<5 IU/mL), Islet Cell Antibody IgG, Zinc Transporter 8 Antibody (<10 U/mL), IA-2 (<5.4 U/mL). C-peptide levels were in the low normal range (1.12 ng/mL) with a blood sugar 204 mg/dL. Prior to 10 months ago, the patient did not have a diagnosis of diabetes, with labs showing expected normal fasting blood sugar levels (90s mg/dL) and triglyceride levels of 150 - 200 mg/dL. One month after starting Clozapine for treatment resistant Schizophrenia, A1c doubled to 12.3%, Triglycerides increased to 1,378 mg/dL. The patient had been insulin dependent since the time of starting Clozapine. On this admission, Clozapine was held, DKA resolved with intravenous fluid, potassium replacement, and insulin drip. Repeat testing of c-peptide with blood glucose levels analyzed with the Homeostasis Model Assessment (HOMA) showed increasing HOMA%S (from 93% to 174%) and decreasing HOMA-IR with stopping Clozapine. Psychiatry recommended Clozapine as required treatment of his Schizophrenia, therefore the patient required chronic insulin. Conclusion: This case study shows Clozapine as the only major change in medications or lifestyle in this patient’s case. He demonstrated severe hyperglycemia and development of Diabetes Mellitus within a 4-week period of medication initiation as evidenced by multiple admissions for DKA, with low/normal C-peptide levels and insulin resistance. He has since been managed as a patient with Type 1 Diabetes. Clinicians should take a multidisciplinary approach to clinical surveillance during changes in schizophrenia treatment, particularly with second generation antipsychotics such as Clozapine, with attention to metabolic derangements including DKA.

Clozapine-induced stuttering in the absence of known risk factors: a case report

BackgroundStuttering is a rare side effect of clozapine. It has been shown to occur in the presence of one or more factors such as abnormal electrophysiological findings and seizures, extrapyramidal symptoms, brain pathology, and a family history of stuttering. Few case reports have documented the occurrence of clozapine-induced stuttering in the absence of these risk factors.Case presentationA 29-year-old African male on clozapine for treatment-resistant schizophrenia presented with stuttering at a dosage of 400 mg/day that resolved with dose reduction. Electroencephalogram findings were normal, and there was no clinical evidence of seizures. The patient had no prior history or family history of stuttering, had a normal neurological examination, and showed no signs of extrapyramidal symptoms.ConclusionClinicians ought to be aware of stuttering as a side effect of clozapine, even in the absence of known risk factors. Further research should investigate the pathophysiology of clozapine-induced stuttering.

Fatal poisonings involving clozapine: A 16-year review of Australian coronial investigations.

Concerns about intentional and unintentional poisoning present a barrier to wider use of clozapine in treatment-resistant schizophrenia. The objective of this study was to investigate decedent demographics and trends in fatal poisonings in Australia involving clozapine. This was a retrospective case series of all fatal drug toxicity reported to an Australian coroner between 1 May 2000 and 31 December 2016 where toxicological analysis detected clozapine. Cases were identified using the National Coronial Information System. Demographics extracted included age and gender of the decedent, year and location of death, cause and manner of death and drugs detected in post-mortem samples. There were 278 poisoning deaths where clozapine was detected in toxicological analyses. Three-quarters of all cases (n = 207) involved men and the median age at death was 38.5 years (interquartile range: 16 years). Three-quarters of the deaths occurred in the home. Overall, 15.8% of deaths were deemed intentional, 57.5% unintentional and 24.5% of unknown intent. While the annual number of intentional self-poisonings remained constant with <5 per year, the overall number of fatalities increased due to an increase in unintentional poisonings. Multiple drug toxicity was reported in 55.0% of cases and clozapine alone in 45.0% of cases. The most common co-reported medications were antidepressants, benzodiazepines and opioids detected in 47.1%, 44.4% and 41.2% of multiple drug toxicities, respectively. This was the first Australia-wide review of all fatal drug poisonings reported to a coroner involving clozapine. Fatalities were most common in men and occurred at home. Multiple drug toxicity generally involved psychotropic, sedative or opioid analgesic medications. Despite increasing clozapine use, rates of intentional poisoning have remained constant and low. Developing a better knowledge of unintentional fatalities presents an opportunity to minimise harm.

Changes in Brain Glutamate on Switching to Clozapine in Treatment-Resistant Schizophrenia.

It has been suggested that the antipsychotic clozapine may modulate brain glutamate, and that this effect could contribute to its efficacy in treatment-resistant schizophrenia (TRS). The aim of this study was to examine the effects of clozapine on brain glutamate in TRS longitudinally. This study examined individuals with TRS before and 12 weeks after switching from a non-clozapine antipsychotic to treatment with clozapine as part of their normal clinical care. Proton magnetic resonance spectroscopy (1H-MRS) measured concentrations, corrected for voxel tissue content, of glutamate (Glucorr), and glutamate plus glutamine (Glxcorr) in the anterior cingulate cortex (ACC) and right caudate nucleus. Symptoms were monitored using the Positive and Negative Syndrome Scale (PANSS). Of 37 recruited patients (27 men, 39.30 years old, 84% clozapine naïve), 25 completed 1H-MRS at both timepoints. 12 weeks of clozapine was associated with a longitudinal reduction in Glucorr in the caudate (n = 23, F = 7.61 P = .01) but not in the ACC (n = 24, F = 0.02, P = .59). Percentage reduction in caudate Glucorr was positively correlated with percentage improvement in symptoms (total PANSS score, n = 23, r = .42, P = .04). These findings indicate that reductions in glutamate in the caudate nucleus may contribute to symptomatic improvement during the first months of clozapine treatment.

T19. GLUTAMATE AND RESPONSE TO CLOZAPINE IN TREATMENT RESISTANT SCHIZOPHRENIA

BackgroundThe mechanisms that underlie and may mediate the therapeutic response to clozapine in treatment resistant schizophrenia (TRS) are unclear. Basic science studies have indicated that clozapine may modulate brain glutamate, but this has not yet been investigated in man. The aim of this study was to determine whether clozapine alters brain glutamate levels in patients with TRS, and the associations with clinical outcome.MethodsThe study included patients with TRS who were about to start clozapine as part of their normal clinical care. Glutamate levels were measured in the anterior cingulate cortex (ACC) and right caudate nucleus using proton magnetic resonance spectroscopy (1H-MRS) before clozapine initiation (n=37) and again after 12-weeks of clozapine treatment (n=27). Symptoms were principally assessed using the PANSS. 1H-MRS scans were also acquired in a comparator group of healthy volunteers (n = 16).ResultsOver the 12 weeks of clozapine treatment there was a significant reduction in glutamate in the caudate (n = 22, F = 7.61 P < 0.05) but not in the ACC. The percentage reduction in caudate glutamate was positively associated with the percentage reduction in total PANSS score (n = 23, r = 0.42, P = 0.04). ACC Glx (glutamate plus glutamine) prior to clozapine initiation was higher in patients with TRS than in healthy volunteers (P=0.03).DiscussionImprovements in symptoms following clozapine initiation in TRS may be related to reductions in glutamate in the caudate nucleus. In contrast, ACC glutamate levels appear to remain high during the first three months of clozapine treatment.

T204. CLOZAPINE COMBINATION AND AUGMENTATION STRATEGIES IN PATIENTS WITH SCHIZOPHRENIA –RECOMMENDATIONS FROM AN INTERNATIONAL EXPERT SURVEY AMONG THE TREATMENT RESPONSE AND RESISTANCE IN PSYCHOSIS (TRRIP) WORKING GROUP

BackgroundEvidence for the management of inadequate clinical response to clozapine in treatment-resistant schizophrenia is sparse. Accordingly, an international initiative aimed to develop consensus recommendations for treatment strategies for clozapine-refractory patients with schizophrenia.MethodsWe conducted an online survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group. An agreement threshold of ≥75% (responses “agree”+“strongly agree”) was set to define a first-round consensus. Questions achieving agreement or disagreement proportions of >50% in the first round, were re-presented to develop second-round final consensus recommendations.ResultsFrom a total of 61 TRRIP members 44 (first round) and 49 (second round) participated in the consensus-process. Expert recommendations included raising clozapine plasma levels to ≥350 ng/mL for refractory positive, negative and mixed symptoms. In case of ineffective plasma level-guided dose escalation waiting for a delayed response was recommended for persistent positive symptoms. For ongoing clozapine-refractory positive symptoms, combination with a second antipsychotic, (amisulpride and oral aripiprazole) and augmentation with ECT achieved consensus. For clozapine-refractory negative symptoms, waiting for a delayed response was recommended, and as an intervention, clozapine augmentation with an antidepressant reached consensus. For clozapine-refractory suicidality, augmentation with antidepressants or mood-stabilisers, and ECT met consensus criteria. For aggression, augmentation with a mood-stabiliser or combination with antipsychotic medication achieved consensus. Generally, cognitive-behavioural therapy (CBT) and psychosocial interventions reached consensus.DiscussionThis consensus-based series of recommendations provides a framework for decision-making to manage the challenging clinical situation of CRS, where the evidence from randomised-controlled trials remains sparse.

Clozapine Combination and Augmentation Strategies in Patients With Schizophrenia -Recommendations From an International Expert Survey Among the Treatment Response and Resistance in Psychosis (TRRIP) Working Group.

Evidence for the management of inadequate clinical response to clozapine in treatment-resistant schizophrenia is sparse. Accordingly, an international initiative was undertaken with the aim of developing consensus recommendations for treatment strategies for clozapine-refractory patients with schizophrenia. We conducted an online survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group. An agreement threshold of ≥75% (responses "agree" + "strongly agree") was set to define a first-round consensus. Questions achieving agreement or disagreement proportions of >50% in the first round, were re-presented to develop second-round final consensus recommendations. Forty-four (first round) and 49 (second round) of 63 TRRIP members participated. Expert recommendations at ≥75% agreement included raising clozapine plasma levels to ≥350 ng/ml for refractory positive, negative, and mixed symptoms. Where plasma level-guided dose escalation was ineffective for persistent positive symptoms, waiting for a delayed response was recommended. For clozapine-refractory positive symptoms, combination with a second antipsychotic (amisulpride and oral aripiprazole) and augmentation with ECT achieved consensus. For negative symptoms, waiting for a delayed response was recommended, and as an intervention for clozapine-refractory negative symptoms, clozapine augmentation with an antidepressant reached consensus. For clozapine-refractory suicidality, augmentation with antidepressants or mood-stabilizers, and ECT met consensus criteria. For clozapine-refractory aggression, augmentation with a mood-stabilizer or antipsychotic medication achieved consensus. Generally, cognitive-behavioral therapy and psychosocial interventions reached consensus. Given the limited evidence from randomized trials of treatment strategies for clozapine-resistant schizophrenia (CRS), this consensus-based series of recommendations provides a framework for decision making to manage this challenging clinical situation.

Commentary on Braga et al: The Potential of Large Simple Trials to Determine the Real-World Effectiveness of Combined Electroconvulsive Therapy and Antipsychotics in Treating Patients With Treatment-Resistant Schizophrenia.

This commentary reflects upon the study of Braga et al of open-label continuation electroconvulsive therapy (ECT) plus clozapine in treatment-resistant schizophrenia (TRS), as reported in this issue of The Journal of ECT. The evidence base for ECT in TRS is scant, and the study of Braga et al is a step forward. However, their report raises other important questions including (1) what is the proper frequency of continuation ECT in TRS, and (2) should TRS patients, even TRS patients who have failed clozapine, receive acute ECT + clozapine, or is ECT + conventional antipsychotics sufficient? In this commentary, we examine these questions and outline a future research strategy for TRS that includes large simple trials.

Clozapine and all-cause mortality in treatment-resistant schizophrenia: a historical cohort study.

ObjectiveLarge‐scale epidemiological studies have demonstrated a protective effect of clozapine on mortality in people with schizophrenia. Clozapine is reserved for use in patients with treatment‐resistant schizophrenia (TRS), but evidence of clozapine's effect on mortality exclusively within TRS samples is inconclusive. Hence, we aimed to investigate the effect of clozapine use on all‐cause mortality in TRS patients.MethodsA historical patient cohort sample of 2837 patients, who met criteria for TRS between 1 Jan 2008 and 1 Jan 2016, were selected from the South London and Maudsley NHS Foundation Trust (SLAM) electronic health records (EHR). The national Zaponex Treatment Access System (ZTAS) mandatory monitoring system linked to the SLAM EHR was used to distinguish which patients were initiated on clozapine (n = 1025). Cox proportional hazard models were used, adjusting for sociodemographics, clinical monitoring, mental and physical illness severity and functional status.ResultsAfter controlling for potential confounders, the protective effect of clozapine on all‐cause mortality was significant (adjusted hazard ratio 0.61; 95% confidence interval 0.38–0.97; P = 0.04).ConclusionsClozapine reduces the risk of mortality in patients who meet criteria for TRS. We provide further evidence that improving access to clozapine in TRS is likely to reduce the mortality gap in schizophrenia.

Barriers to using clozapine in treatment-resistant schizophrenia: systematic review.

Aims and methodTo systematically review the literature on barriers to the use of clozapine and identify any interventions for optimizing clozapine use in treatment-resistant schizophrenia. Journal databases were searched from 1972 to March 2018. The following search terms were used: treatment-resistant schizophrenia, clozapine, barriers, use, prescription rates, implementation, clozaril and prescribing practices. Following a review of the literature, 15 papers were included in the review. RESULTS: The major barriers that were identified included mandatory blood testing, fear of serious side-effects and lack of adherence by the patients, difficulty in identifying suitable patients, service fragmentation, and inadequate training in or exposure to using clozapine.Clinical implicationsIn view of consistent evidence across the studies on inadequate knowledge and skills as a significant barrier, we suggest that a certification requiring competence in initiating and managing side-effects of clozapine becomes a mandatory requirement in training programmes.Declarations of interestNone.

Combination of Electroconvulsive Therapy and Clozapine in Treatment-Resistant Schizophrenia

ObjectiveThis study aimed to investigate the effectiveness and tolerability of the combination of electroconvulsive therapy (ECT) in patients with clozapine-treated schizophrenia. MethodsPatients with clozapine-treated schizophrenia during five years of pre-determined period were recruited from Electronic Medical Record. Clinical effects of acute ECT on psychotic symptoms were investigated. We also tried to identify predictive variables requiring maintenance treatment of ECT. ResultsFourteen patients received ECT and clozapine and sixteen were treated with clozapine alone. In the ECT group, which could be refined as clozapine-resistance, PANSS total score was significantly reduced by 19.0±9.9 points, corresponding to a reduction rate of 18.5±8.3%. The clinical remission defined as 20% PANSS reduction criteria was achieved at 42.9%. The subscale factors were significantly reduced, among which the negative symptom was the least. There was no difference in demographic and clinical information between patients receiving and not receiving maintenance ECT, and not all patients seemed to need maintenance ECT if clozapine is continued. ConclusionCombination of ECT and clozapine in patients with clozapine-resistant schizophrenia resulted in a rapid and substantial reduction of psychotic symptoms. Further studies are needed to improve the effectiveness and tolerability of ECT.

Clozapine use in early psychosis

BackgroundThe superior efficacy of clozapine in treatment resistant schizophrenia has been clearly demonstrated, yet there are often delays in the commencement of clozapine. In this study, we aimed to determine; the proportion of young people with a first episode of psychosis (FEP) who would be considered eligible for clozapine treatment, the theoretical delay in commencing clozapine and to compare the outcomes of those treated with clozapine to those who were eligible but not treated with clozapine. MethodsThis study was conducted at Orygen Youth Health (OYH), a youth mental health service for young people aged 15–24. All clients who were treated at the Early Psychosis Prevention and Intervention Centre (EPPIC) clinic between 01.01.2011 and 31.12.2013 were included. Results544 young people presented with a FEP in the study period and 9.4% (N = 51) subsequently fulfilled criteria for treatment-resistant schizophrenia. Of these individuals, thirty (58.8%) were commenced on clozapine, in addition to a further eleven. The median delay to the commencement of clozapine was 42 weeks (I.Q.R. = 7.5–64). Of those commenced on clozapine, 76.6% achieved remission of positive psychotic symptoms and 50% were in employment or education by the time of discharge or transfer to the adult mental health services. The rate of discontinuation of clozapine was 24.4% and 60.0% of discontinuations were due to cardiac complications and the remainder were due to non-compliance. ConclusionsThese findings suggest that early intervention for psychosis services have a crucial role in ensuring timely initiation of clozapine in individuals with a diagnosis of treatment-resistant schizophrenia.

Gene-gene interaction between DRD4 and COMT modulates clinical response to clozapine in treatment-resistant schizophrenia.

Clozapine is the drug of choice for treatment-resistant schizophrenia. However, its use is associated with variable clinical responses and serious adverse effects. Polymorphisms in genes encoding proteins involved in synaptic neurotransmission may account for such variability. Here, we studied independent and epistatic genetic associations of polymorphisms in DRD4 (120-bp duplication) and COMT (Val158Met) with clinical response to clozapine in people with treatment-resistant schizophrenia. We studied 93 participants who were on stable doses of clozapine for at least 12 weeks. A total score of less than or equal to 35 on the Brief Psychiatric Rating Scale was defined as a clinical response. The genetic associations were tested using logistic regression analyses. Neither polymorphism studied was found to be independently associated with response to clozapine. However, a statistically significant gene-gene interaction was observed between the polymorphisms. Participants with the COMT Val/Met or Met/Met genotype, who also had one or two DRD4 120-bp alleles (120/240 and 120/120), showed significantly better clinical response to clozapine. Our results highlight the importance of investigating gene-gene interactions, while studying the pharmacogenetics of clozapine.

Mortality and Self-Harm in Association With Clozapine in Treatment-Resistant Schizophrenia.

This study evaluated rates of all-cause mortality and self-harm in association with clozapine treatment in individuals with treatment-resistant schizophrenia. A population-based cohort of 2,370 individuals with treatment-resistant schizophrenia after Jan. 1, 1996, was followed until death, first episode of self-harm, emigration, or June 1, 2013. Time to all-cause death and time to first episode of self-harm were analyzed in Cox regression models with time-varying treatment, adjusted for clinical and sociodemographic covariates. The rate of all-cause mortality was higher for patients not receiving clozapine than for those given clozapine (hazard ratio: 1.88, 95% confidence interval [CI]: 1.16-3.05). This was driven mainly by periods of no antipsychotic treatment (hazard ratio: 2.50, 95% CI: 1.50-4.17), with nonsignificantly higher mortality during treatment with other antipsychotics (hazard ratio: 1.45, 95% CI: 0.86-2.45). Excess mortality was observed in the year after clozapine discontinuation (hazard ratio: 2.65, 95% CI: 1.47-4.78). The rate of self-harm was higher for nonclozapine antipsychotics than for clozapine (hazard ratio: 1.36, 95% CI: 1.04-1.78). The results demonstrate a nearly twofold higher mortality rate among individuals with treatment-resistant schizophrenia not treated with clozapine compared with clozapine-treated individuals. Furthermore, the results suggest a harmful effect of other antipsychotics regarding self-harm compared with clozapine. It remains to be investigated to what extent the observed excess mortality after clozapine discontinuation is confounded by nonadherence and other unobserved factors and to what extent it is mediated by adverse effects from recent clozapine exposure or deterioration in physical or mental health precipitated by clozapine discontinuation.

Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia.

Clozapine is an atypical antipsychotic, that is established as the treatment of choice for treatment-resistant schizophrenia (SCZ). To date, no study investigating comprehensive DNA methylation changes in SCZ patients treated with chronic clozapine has been reported. The purpose of the present study is to reveal the effects of clozapine on DNA methylation in treatment-resistant SCZ. We conducted a genome-wide DNA methylation profiling in peripheral leukocytes (485,764 CpG dinucleotides) from treatment-resistant SCZ patients treated with clozapine (n = 21) in a longitudinal study. Significant changes in DNA methylation were observed at 29,134 sites after one year of treatment with clozapine, and these genes were enriched for “cell substrate adhesion” and “cell matrix adhesion” gene ontology (GO) terms. Furthermore, DNA methylation changes in the CREBBP (CREB binding protein) gene were significantly correlated with the clinical improvements. Our findings provide insights into the action of clozapine in treatment-resistant SCZ.

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

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