Clozapine In Treatment-resistant Schizophrenia Research Articles

Multimodal prediction of the need of clozapine in treatment resistant schizophrenia; a pilot study in first-episode psychosis

As many as one third of the patients diagnosed with schizophrenia do not respond to first-line antipsychotic medication. This group may benefit from the atypical antipsychotic medication clozapine, but initiation of treatment is often delayed, which may worsen prognosis. Predicting which patients do not respond to traditional antipsychotic medication at the onset of symptoms would provide fast-tracked treatment for this group of patients. We collected data from patient records of 38 first-episode psychosis patients, of whom seven did not respond to traditional antipsychotic medications. We used clinical data including medical records, voxel-based morphometry MRI data and inter-subject correlation fMRI data, obtained during movie viewing, to predict future treatment resistance. Using a neural network model, we correctly predicted future treatment resistance in six of the seven treatment resistance patients and 25 of 31 patients who did not require clozapine treatment. Prediction improved significantly when using imaging data in tandem with clinical data. The accuracy of the neural network model was significantly higher than the accuracy of a support vector machine algorithm. These results support the notion that treatment resistant schizophrenia could represent a separate entity of psychotic disorders, characterized by morphological and functional changes in the brain which could represent biomarkers detectable at early onset of symptoms.

Clozapine in treatment-resistant schizophrenia: Reflections from the Hallmark US clinical trial and beyond

Clozapine in treatment-resistant schizophrenia: Reflections from the Hallmark US clinical trial and beyond

Real-World Effectiveness of High-Dose Olanzapine and Clozapine for Treatment-Resistant Schizophrenia in Japan: A Retrospective Bidirectional Mirror-Image Study.

Clozapine is considered the gold standard medication for treatment-resistant schizophrenia (TRS). However, given that clozapine treatment is associated with the burden of regular blood monitoring and the risk of life-threatening adverse effects, high-dose olanzapine can serve as an alternative treatment. We conducted a bidirectional mirror-image study to evaluate the effectiveness of high-dose olanzapine compared with clozapine. We included patients with TRS who switched from olanzapine to clozapine or switched from clozapine to olanzapine, and received high-dose (>20 mg/d) olanzapine treatment for ≥4 weeks at Yamanashi Prefectural Kita Hospital. We obtained data on hospitalization, seclusion, and modified electroconvulsive therapy (mECT) during the clozapine phase and the olanzapine phase. A total of 44 patients were included. When patients switched from high-dose olanzapine to clozapine (n = 32), significant reductions were found in the total days of seclusion, the total number of mECT, and the number of patients who received mECT at least once. When patients switched from clozapine to high-dose olanzapine (n = 12), a significant reduction was found in the number of patients who received mECT at least once. When data from both directions of treatment were combined, significant reductions were found in the total days of seclusion, the total number of mECT, and the number of patients who received mECT at least once in favor of clozapine. Findings suggest that high-dose olanzapine may not be as effective as clozapine for patients with TRS in real-world practice. However, it should be noted that there are unique circumstances that restrict the use of clozapine in Japan.

Cariprazine augmentation of clozapine in schizophrenia-a retrospective chart review.

The aim of our study was to evaluate the efficacy of cariprazine augmentation of clozapine in treatment-resistant schizophrenia in a retrospective chart review. Among 916 medical records of schizophrenia patients, we identified 12 individuals treated with a combination of those drugs for a duration of 3-60weeks [median 32 (10-40)]. Clinical Global Impression-Improvement (CGI-I) scores were used to measure the treatment response between the introduction of cariprazine augmentation of clozapine and the last point of observation. The majority of the patients presented treatment response (9/12 patients, 75%) after 4-16weeks of therapy [median 6 (4-12)]. Treatment was associated with the decrease in positive, negative, affective, and anxiety symptom severity, as well as improvement of patient global functioning. One patient discontinued the treatment due to side effects (akathisia), and two patients halted the therapy due to the exacerbation of psychotic symptoms. Our study presents a thorough clinical description of the largest number of treatment-resistant schizophrenia patients medicated using cariprazine augmentation of clozapine in a "real-world" setting. Our results suggest that the use of this combination may lead to the improvement in a broad range of symptoms of patients with this condition.

The longitudinal structure of negative symptoms in treatment resistant schizophrenia

Background and hypothesisThe negative symptoms of schizophrenia are strong prognostic factors but remain poorly understood and treated. Five negative symptom domains are frequently clustered into the motivation and pleasure (MAP) and emotional expression (EE) ‘dimensions’, but whether this structure remains stable and behaves as a single entity or not remains unclear. Study designWe examined a cohort of 153 patients taking clozapine for treatment-resistant schizophrenia in a regional mental health clinic. Patients were assessed longitudinally over a mean period of 45 months using validated scales for positive, negative and mood symptoms. Network analyses were performed to identify symptom ‘communities’ and their stability over time. The influence of common causes of secondary negative symptoms as well as centrality measures were also examined. Study resultsAcross patients at baseline, two distinct communities matching the clinical domains of MAP and EE were found. These communities remained highly stable and independent over time. The communities remained stabled when considering psychosis, depression, and sedation severity, and these causes of secondary negative symptoms were clustered into the MAP community. Centrality measures also remained stable over time, with similar centrality measures across symptoms. ConclusionsOur results suggest that MAP and EE are independent dimensions that remain highly stable over time in chronic schizophrenia patients treated with clozapine. Common causes of secondary negative symptoms mapped onto the MAP dimension. Our results emphasise the need for clinical trials to address either MAP or EE, and that treating causes of secondary negative symptoms may improve MAP.

Reply to Dr Yucel's Comments on the Article “Long-term Outcome of Clozapine in Treatment-Resistant Schizophrenia”

Reply to Dr Yucel's Comments on the Article “Long-term Outcome of Clozapine in Treatment-Resistant Schizophrenia”

Critical Feedback on Article by Lee and Colleagues: "Long-Term Outcome of Clozapine in Treatment-Resistant Schizophrenia".

Critical Feedback on Article by Lee and Colleagues: "Long-Term Outcome of Clozapine in Treatment-Resistant Schizophrenia".

Changes in immunoglobulin levels during clozapine treatment in schizophrenia

Background and hypothesisUse of clozapine in treatment-resistant schizophrenia is often limited due to risk of adverse effects. Cross-sectional associations between clozapine treatment and low immunoglobulin levels have been reported, however prospective studies are required to establish temporal relationships. We tested the hypothesis that reductions in immunoglobulin levels would occur over the first 6 months following initiation of clozapine treatment. Relationships between immunoglobulin levels and symptom severity over the course of clozapine treatment were also explored. DesignThis prospective observational study measured immunoglobulin (Ig) levels (A, M and G) in 56 patients with treatment-resistant schizophrenia at 6-, 12- and 24-weeks following initiation with clozapine. Clinical symptoms were also measured at 12 weeks using the positive and negative syndrome scale (PANSS). ResultsIgA, IgG and IgM all decreased during clozapine treatment. For IgA and IgG the reduction was significant at 24 weeks (IgA: β = –32.66, 95% CI = -62.38, −2.93, p = 0.03; IgG: β = -63.96, 95% CI = -118.00, −9.31, p = 0.02). For IgM the reduction was significant at 12 and 24 weeks (12 weeks: β = –23.48, 95% CI = -39.56, −7.42, p = 0.004; 24 weeks: β = –33.12, 95 %CI = -50.30, −15.94, p = <0.001). Reductions in IgA and IgG during clozapine treatment were correlated with reductions in PANSS-total over 12 weeks (n = 32, IgA r = 0.59, p = 0.005; IgG r = 0.48, p = 0.03). ConclusionsThe observed reductions in immunoglobulin levels over six months of clozapine treatment add further evidence linking clozapine to secondary antibody deficiency. Associations between Ig reduction and symptom improvement may however indicate that immune mechanisms contribute to both desirable and undesirable effects of clozapine.

Obsessive–compulsive symptoms and disorder in clozapine-treated schizophrenia

BackgroundObsessive–compulsive symptoms (OCS) and obsessive–compulsive disorder (OCD) are commonly reported in patients with schizophrenia. Furthermore, the use of clozapine in treatment-resistant schizophrenia has been thought to induce or aggravate these disorders. To date, there is a paucity of research regarding the prevalence and associated factors. Hence, this study aims to report the prevalence of OCS and OCD, and examine potential risk factors, in clozapine-treated schizophrenia. MethodsThis is a cross-sectional study conducted in the only tertiary hospital for psychiatric patients in Singapore. In total, 162 patients on a stable dose of clozapine were recruited for this study; 159 patients with a diagnosis of schizophrenia or schizoaffective disorder were included in the current analysis. Sociodemographic, clinical and treatment factors were analysed to identify factors associated with OCS and OCD. ResultsThe prevalence of OCS and OCD is 21.4% and 12.6% respectively. Factors associated with OCS include younger age (OR:0.96, p=0.033) and younger age of onset of psychosis (OR:0.92, p=0.017). There were no significant factors associated with OCD. However, in an analysis of both OCS and/or OCD, factors associated include younger age (OR:0.96, p=0.027) and younger age of onset of psychosis (OR:0.91, p=0.016). Severity of psychotic illness and Clozapine dose were not associated with OCS or OCD in clozapine-treated schizophrenia. Discussion & conclusionsOur results suggest a high prevalence of OCS and OCD in clozapine-treated schizophrenia which clinicians should routinely screen for. Further research is warranted to establish the link between the factors identified in this study and OCS/OCD in clozapine-treated schizophrenia.

Clozapine in treatment-resistant schizophrenia: Who designed that famous US clinical trial?

Clozapine in treatment-resistant schizophrenia: Who designed that famous US clinical trial?

Clozapine in Treatment-Resistant Schizophrenia and Its Augmentation with Electroconvulsive Therapy in Ultra-Treatment-Resistant Schizophrenia.

Clozapine is considered the gold standard for patients with treatment-resistant schizophrenia (TRS) who have previously tried other antipsychotics at adequate doses (two or more, with at least one being atypical). However, despite optimal treatment, a subgroup of TRS patients with what is known as ultra-treatment-resistant schizophrenia (UTRS) fails to respond to clozapine, which occurs in 40-70% of cases. The most common approach to manage UTRS involves augmenting clozapine with pharmacological or non-pharmacological interventions, with a growing body of evidence that supports the use of electroconvulsive therapy (ECT) as an augmenter. This prospective non-randomized 8-week study, which followed the TRIPP Working Group guidelines and is one of few that separate TRS from UTRS, aimed to evaluate the effectiveness of clozapine in TRS patients and the efficacy of ECT augmentation of clozapine in UTRS patients. Patients with TRS were assigned to receive clozapine alone (clozapine group), whereas UTRS patients received bilateral ECT in addition to their current medication regimen (ECT plus clozapine group). The severity of symptoms was evaluated using the Clinical Global Impression Scale (CGI) and Positive and Negative Syndrome Scale (PANSS) at baseline and at the end of the 8-week trial. Both treatment approaches resulted in improved CGI and PANSS scores. The results suggest that both clozapine and ECT are effective treatment options for patients with TRS and UTRS, respectively, and that adherence to guidelines should provide a better frame for future clinical studies.

Long-Term Outcome of Clozapine in Treatment-Resistant Schizophrenia.

The favorable effect of clozapine on psychotic symptoms in patients with treatment-resistant (TR) schizophrenia (SCZ) in short-term studies is well established. However, prospective studies of the long-term outcome of clozapine treatment on psychopathology, cognition, quality of life, and functional outcome in TR-SCZ are limited. Here, we have examined the long-term (mean duration of follow-up 14 years) effects of clozapine on those outcomes in a prospective, open label study in 54 TR-SCZ patients. Assessments were performed at baseline, 6 weeks, 6 months, and at the last follow-up. Brief Psychiatric Rating Scale (BPRS) total, positive symptoms, and anxiety/depression at the last follow-up improved significantly from baseline, as well as from the 6-month evaluation ( P < 0.0001), with a 70.5% responder rate (≥20% improvement at the last follow-up from baseline). Quality of Life Scale (QLS) total improved by 72% at the last follow-up, with 24% of patients rated as having "good" functioning compared with 0% at baseline. Suicidal thoughts/behavior was significantly reduced at the last follow-up from the baseline. No significant change in negative symptoms was found at the last follow-up in the total sample. Short-term memory function declined at the last follow-up from baseline, but there was no significant change in processing speed. The QLS total showed a significant negative correlation with BPRS positive symptoms but not with cognitive measures, or negative symptoms, at the last follow-up. For patients with TR-SCZ, improving psychotic symptoms with clozapine seems to have a more significant impact than negative symptoms or cognition on improving psychosocial function.

Lurasidone Augmentation of Clozapine in Schizophrenia—Retrospective Chart Review

The aim of our study was to evaluate the effectiveness of lurasidone augmentation of clozapine in treatment-resistant schizophrenia (SZ) in a retrospective chart review. From the medical records of 916 SZ patients, we identified 16 individuals treated with a combination of clozapine and lurasidone. The detailed clinical data are described separately for each patient. We compared the Clinical Global Impression-Severity (CGI-S) scores between three points of observation: before the treatment and one month and two months after its initiation. CGI Improvement (CGI-I) scores were used to evaluate the treatment response between the first and last points of observation. The vast majority of patients (14/16, 87.5%) responded to lurasidone augmentation of clozapine (CGI-I scores 1 or 2). Therapeutic effects were observable after 3-12 weeks of treatment (median 6 (4-6)). A reduction in CGI-S scores was observed after the first month of observation. There was an observable reduction in positive, depressive and anxiety symptoms, as well as an improvement in psychosocial functioning. Two patients discontinued treatment due to side effects. Our study suggests that lurasidone augmentation of clozapine may lead to improvements in a broad range of SZ symptom dimensions.

A comparison between lurasidone and other antipsychotics as add-on therapy to clozapine in treatment resistant schizophrenia: an observational study

A comparison between lurasidone and other antipsychotics as add-on therapy to clozapine in treatment resistant schizophrenia: an observational study

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.

Utility and Barriers to Clozapine Use: A Joint Study of Clinicians' Attitudes From Singapore and Hong Kong.

Objective: This study aimed to survey clinicians' attitudes in Singapore and Hong Kong toward clozapine and elucidate the barriers to its prescription in patients with treatment-resistant schizophrenia.Methods: All clinicians in psychiatry in both regions were invited through email to participate in an anonymous online survey. The survey collected information on the participants' characteristics, their experience with clozapine initiation, perceived usefulness of clozapine, barriers to clozapine initiation, and factors that might improve clozapine use. Data collection took place between December 2018 and March 2019 in Singapore and September 2019 and February 2020 in Hong Kong.Results: A total of 261 clinicians (156 in Singapore, 105 in Hong Kong) responded to the survey. The majority of participants believed that clozapine was an effective and satisfactory treatment for schizophrenia. Clinicians were most concerned about the need for frequent blood monitoring (84.5% in Singapore; 87.5% in Hong Kong), clozapine's tolerability (51.9% in Singapore; 61.6% in Hong Kong), and medical complications (54.8% in Singapore; 49.1% in Hong Kong). Compared to Hong Kong, more clinicians in Singapore endorsed an underutilization of clozapine (67.9% in Singapore; 51.4% in Hong Kong) and a greater need for outpatient resources in terms of clinic and administrative support (74.4% in Singapore; 59.0% in Hong Kong) to improve clozapine prescription.Conclusions: The underutilization of clozapine in treatment-resistant schizophrenia remains a concern in both regions. An integrated clozapine service that addresses the system barriers and clinicians' confidence in prescribing clozapine and managing its adverse effects would greatly improve the utilization of clozapine.

Comparison of Acute Followed by Maintenance ECT vs Clozapine on Psychopathology and Regional Cerebral Blood Flow in Treatment-Resistant Schizophrenia: A Randomized Controlled Trial.

In treatment-resistant schizophrenia (TRS), Clozapine is only approved treatment with undesirable side-effects, warranting better alternatives. Our hypothesis is acute followed by maintenance Electroconvulsive Therapy (M-ECT) will be comparable in efficacy and safety to Clozapine in TRS. In this open-label trial, 60 TRS patients were randomized equally to M-ECT (following an acute-course) or Clozapine. Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Schizophrenia Scale (CGI-SCH), Montreal Cognitive Assessment (MoCA), and Global assessment of functioning (GAF) were measured and compared within and between the groups at baseline, 6 weeks, 12 weeks, and 24 weeks. SPECT-CT brain was done at baseline and 24 weeks to compare the changes in regional cerebral perfusion between the groups and correlate with the changes in the outcome-measures. The PANSS-T scores changes from baseline over the observation-points were significant in both M-ECT and clozapine groups (P < .001), with comparatively better reduction with M-ECT (P < .001). Similar trends were observed in PANSS subscales, CGI-SCH and GAF in both groups, with significantly better improvement with M-ECT over the study-period. After 24 weeks, there was significantly better perfusion with M-ECT in bilateral prefrontal and temporal cortices (P < .05). With M-ECT, a positive correlation was found between changes in PANSS-P scores and left-lateral Temporal cortical perfusion (r = .465, P = .017). Acute followed by M-ECT was more effective than clozapine over 6 months in reducing the positive and negative symptoms, general psychopathology, illness-severity, and improving the global functionality in TRS [clinicaltrials.gov: NCT03807882].

An evaluation of the prescribing of clozapine for treatment-resistant schizophrenia in one NHS Trust in England

Abstract Introduction As a merger of two trusts had occurred, and recent research on the impact of the delay of initiating clozapine (1), this study was initiated to investigate if NICE guidelines for the management of treatment-resistant schizophrenia (TR-SCZ) were followed. NICE recommends that clozapine is offered after a trial of two antipsychotics drugs of appropriate dose and duration. The risk of potentially fatal side effects and the need for regular blood monitoring can deter patients and prescribers in initiating clozapine at an earlier stage (1). Aim To evaluate the prescribing of clozapine in patients with TR-SCZ in a large NHS trust against NICE guidelines. Methods Due to a fixed project time scale of 3 months, the medical records of 20 patients with TR-SCZ were accessed in November 2019 in order to determine compliance with NICE guidelines. Inclusion criteria for the study included a diagnosis of TR-SCZ in patients over 18 but under 60 years-old and a first attempt of prescribing clozapine after 2017. The records were analysed to establish how many antipsychotics were prescribed before clozapine was initiated, the number of patients remaining on clozapine after nine months, and the reason for stopping (where appropriate). A collection tool was created in Excel and data was analysed using descriptive statistics. Results All 20 patients had tried at least two antipsychotics, with 75% (n=15) having tried more than two before the initiation of clozapine. The mode number of antipsychotics prescribed was three. At the point of data collection, 75% (n=15) of the patients remained on clozapine. Of the five patients no longer taking clozapine, three patients remained on it for more than nine months before it was stopped. Documented reasons for stopping included side effects (neutropenia (n=1) and tachycardia (n= 1)) and patient choice (n=3). Conclusion Clozapine is an effective treatment for TR-SCZ (1), (2). This is backed up by the majority of patients in this study remaining on the treatment after nine months. This study also agrees with previous research (1) indicating guidelines for prescribing clozapine are not followed. 75% of patients were prescribed more than the recommended two antipsychotics before clozapine was initiated. However, the patient notes did not indicate the reasons for using more than two other antipsychotics before trialling clozapine or impact of the delay of its initiation. It would therefore be prudent for future research to determine the reasons for and impact of prescribing clozapine after more than two other antipsychotics had been trialled. References (1) Shah P, Iwata Y, Plitman E, Brown EE, Caravaggio F, Kim J, Nakajima S, Hahn M, Remington G, Gerretsen P, Graff-Guerrero A. The impact of delay in clozapine initiation on treatment outcomes in patients with treatment-resistant schizophrenia: a systematic review. Psychiatry research. 2018 Oct 1;268:114-22. (2) National Institute for Health and Care Excellence. Psychosis and schizophrenia: treatment and management. (Clinical guideline 178.) c2014. [Updated 2021; cited 2021 Oct 14]. Available from: http://guidance.nice.org.uk/CG178

Subcortical volume reduction and cortical thinning 3 months after switching to clozapine in treatment resistant schizophrenia

The neurobiological effects of clozapine are under characterised. We examined the effects clozapine treatment on subcortical volume and cortical thickness and investigated whether macrostructural changes were linked to alterations in glutamate or N-acetylaspartate (NAA). Data were acquired in 24 patients with treatment-resistant schizophrenia before and 12 weeks after switching to clozapine. During clozapine treatment we observed reductions in caudate and putamen volume, lateral ventricle enlargement (P < 0.001), and reductions in thickness of the left inferior temporal cortex, left caudal middle frontal cortex, and the right temporal pole. Reductions in right caudate volume were associated with local reductions in NAA (P = 0.002). None of the morphometric changes were associated with changes in glutamate levels. These results indicate that clozapine treatment is associated with subcortical volume loss and cortical thinning and that at least some of these effects are linked to changes in neuronal or metabolic integrity.

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.