Treatment-resistant Schizophrenia Research Articles

Opening Treatment Windows for Treatment-Resistant Schizophrenia: Improving Emotion Regulation Strategies Using the Unified Protocol in a Case Study in Spain

Approximately 30%-50% of people with schizophrenia worldwide have treatment-resistant schizophrenia (TRS). Currently available standard psychopharmacological and psychological treatments have proven insufficient to achieve full recovery in these patients. Alternative psychological interventions focused on improving emotion regulation, such as the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP), could potentially improve treatment outcomes in this difficult to treat population. The aim of the present case study is to demonstrate how the UP can be adapted for the treatment of TRS. We decided to use UP to treat this particular patient due to the presence of intense unpleasant emotions, aversive reactions, and emotional avoidance strategies. After completing the full treatment protocol, the patient showed significant decreases in scores on the Difficulties in Emotion Regulation Scale (DERS), including total and emotional rejection, life interference, and emotional lack of control. A significant reduction was also observed in anxiety (OASIS) and depressive symptoms (ODSIS). The intervention had a positive impact on auditory hallucinations, with decreased severity, less intense anxiety, and less interference in life. The treatment led to greater control over voices and the patient reported feeling more confident in her relationship with those voices. These results provide preliminary support for the use of UP for the treatment of TRS.

Alteration of DNA Methylation and Epigenetic Scores Associated With Features of Schizophrenia and Common Variant Genetic Risk

BackgroundUnpacking molecular perturbations associated with features of schizophrenia is a critical step toward understanding phenotypic heterogeneity in this disorder. Recent epigenome-wide association studies have uncovered pervasive dysregulation of DNA methylation in schizophrenia; however, clinical features of the disorder that account for a large proportion of phenotypic variability are relatively underexplored. MethodsWe comprehensively analyzed patterns of DNA methylation in a cohort of 381 individuals with schizophrenia from the deeply phenotyped Australian Schizophrenia Research Bank. Epigenetic changes were investigated in association with cognitive status, age of onset, treatment resistance, Global Assessment of Functioning scores, and common variant polygenic risk scores for schizophrenia. We subsequently explored alterations within genes previously associated with psychiatric illness, phenome-wide epigenetic covariance, and epigenetic scores. ResultsEpigenome-wide association studies of the 5 primary traits identified 662 suggestively significant (p < 6.72 × 10−5) differentially methylated probes, with a further 432 revealed after controlling for schizophrenia polygenic risk on the remaining 4 traits. Interestingly, we uncovered many probes within genes associated with a variety of psychiatric conditions as well as significant epigenetic covariance with phenotypes and exposures including acute myocardial infarction, C-reactive protein, and lung cancer. Epigenetic scores for treatment-resistant schizophrenia strikingly exhibited association with clozapine administration, while epigenetic proxies of plasma protein expression, such as CCL17, MMP10, and PRG2, were associated with several features of schizophrenia. ConclusionsOur findings collectively provide novel evidence suggesting that several features of schizophrenia are associated with alteration of DNA methylation, which may contribute to interindividual phenotypic variation in affected individuals.

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)-present in some but not all cells-remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p= 2.68e-4), with recurrent somatic deletions of exons 1-5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5' deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk.

Can brexpiprazole be switched safely in patients with schizophrenia and dopamine supersensitivity psychosis? A retrospective analysis in a real-world clinical practice.

Several studies have reported that a switch to the dopamine partial agonist (DPA) aripiprazole (ARP), especially when the switch is abrupt, is likely to fail and sometimes worsen psychosis in schizophrenia patients already under high-dose antipsychotic treatment. Such a switching failure is speculated to be related to be the dopamine supersensitivity state. The risks of switching to the DPA brexpiprazole (BREX) have not been reported. We retrospectively analyzed the cases of 106 patients with schizophrenia to identify any factors related to the success or failure of switching to BREX. The comparison between the patients with dopamine supersensitivity psychosis (n = 44) and those without (n = 62) revealed no significant difference in the switching failure judged at the sixth week. A comparison of the patients with successful switching (n = 80) and those who failed (n = 26) revealed that patients with treatment-resistant schizophrenia (TRS) were significantly more likely to fail. A logistic regression analysis also revealed that patients with past failure of switching to ARP are likely to succeed in switching to BREX. The 2-year follow-up of the patients with successful switching to BREX suggested that the patients who were treated with BREX, even temporarily, experienced some improvement in their Global Assessment of Functioning and Clinical Global Impression-Severity scores. Overall, the results indicate that patients with schizophrenia can be switched more safely to BREX compared to ARP. However, the failure of switching to BREX could be higher in patients with TRS, and thus, starting BREX treatment in refractory patients warrants careful monitoring.

M-RESIST, a Mobile Therapeutic Intervention for Treatment-Resistant Schizophrenia: Feasibility, Acceptability, and Usability Study

Background In the European Union, around 5 million people are affected by psychotic disorders, and approximately 30%-50% of people with schizophrenia have treatment-resistant schizophrenia (TRS). Mobile health (mHealth) interventions may be effective in preventing relapses, increasing treatment adherence, and managing some of the symptoms of schizophrenia. People with schizophrenia seem willing and able to use smartphones to monitor their symptoms and engage in therapeutic interventions. mHealth studies have been performed with other clinical populations but not in populations with TRS. Objective The purpose of this study was to present the 3-month prospective results of the m-RESIST intervention. This study aims to assess the feasibility, acceptability, and usability of the m-RESIST intervention and the satisfaction among patients with TRS after using this intervention. Methods A prospective multicenter feasibility study without a control group was undertaken with patients with TRS. This study was performed at 3 sites: Sant Pau Hospital (Barcelona, Spain), Semmelweis University (Budapest, Hungary), and Sheba Medical Center and Gertner Institute of Epidemiology and Health Policy Research (Ramat-Gan, Israel). The m-RESIST intervention consisted of a smartwatch, a mobile app, a web-based platform, and a tailored therapeutic program. The m-RESIST intervention was delivered to patients with TRS and assisted by mental health care providers (psychiatrists and psychologists). Feasibility, usability, acceptability, and user satisfaction were measured. Results This study was performed with 39 patients with TRS. The dropout rate was 18% (7/39), the main reasons being as follows: loss to follow-up, clinical worsening, physical discomfort of the smartwatch, and social stigma. Patients’ acceptance of m-RESIST ranged from moderate to high. The m-RESIST intervention could provide better control of the illness and appropriate care, together with offering user-friendly and easy-to-use technology. In terms of user experience, patients indicated that m-RESIST enabled easier and quicker communication with clinicians and made them feel more protected and safer. Patients’ satisfaction was generally good: 78% (25/32) considered the quality of service as good or excellent, 84% (27/32) reported that they would use it again, and 94% (30/32) reported that they were mostly satisfied. Conclusions The m-RESIST project has provided the basis for a new modular program based on novel technology: the m-RESIST intervention. This program was well-accepted by patients in terms of acceptability, usability, and satisfaction. Our results offer an encouraging starting point regarding mHealth technologies for patients with TRS. Trial Registration ClinicalTrials.gov NCT03064776; https://clinicaltrials.gov/ct2/show/record/NCT03064776 International Registered Report Identifier (IRRID) RR2-10.1136/bmjopen-2017-021346

Safety aspects during treatment with clozapine. : Monitoring and rechallenge - a narrative review

Due to its unique efficacy in treatment-resistant schizophrenia, discontinuation of treatment with clozapine is frequently associated with asignificant worsening of symptoms, but also with an increased risk of suicide. Based on the literature, this review aims at summarizing different monitoring recommendations in order to be able to continue this therapy despite the occurrence of side effects. In addition, we provide recommendations when rechallenge of apreviously stopped treatment with clozapine can be considered and when adefinite discontinuation must take place. Medline, the Guideline for the use of clozapine 2013 of the Netherlands Clozapine Collaboration Group, and the S3Guideline for Schizophrenia of the German Association of Psychiatry, Psychotherapy and Psychosomatics were searched for relevant literature, the last query dating from April28th, 2023. If agranulocytosis or cardiomyopathy develops, treatment with clozapine must be discontinued and should not be resumed thereafter. In contrast, treatment with clozapine which had to be discontinued due to myocarditis or prolongation of the QTc interval may be continued if left ventricular function is normal or after normalization of the QTc interval. Other side effects are usually not absolute contraindications for rechallenge but often require the adjunctive use of additional pharmacologic and non-pharmacologic measures. Taking into consideration various monitoring recommendations, cessation of treatment with clozapine can often be prevented or treatment with clozapine that has been discontinued due to side effects can be resumed.

Non-Psychosis Symptoms of Clozapine Withdrawal: a Systematic Review.

Clozapine is a potent antipsychotic medication with a complex receptor profile. It is reserved for treatment-resistant schizophrenia. We systematically reviewed studies of non-psychosis symptoms of clozapine withdrawal. CINAHL, Medline, PsycINFO, PubMed, and the Cochrane Database of Systematic Reviews were searched using the keywords 'clozapine,' and 'withdrawal,' or 'supersensitivity,' 'cessation,' 'rebound,' or 'discontinuation'. Studies related to non-psychosis symptoms after clozapine withdrawal were included. Five original studies and 63 case reports / series were included in analysis. In 195 patients included in the five original studies, approximately 20% experienced non-psychosis symptoms following discontinuation of clozapine. In 89 patients in four of the studies, 27 experienced cholinergic rebound, 13 exhibited extrapyramidal symptoms (including tardive dyskinesia), and three had catatonia. In 63 case reports / series included, 72 patients with non-psychosis symptoms were reported, which were catatonia (n=30), dystonia or dyskinesia (n=17), cholinergic rebound (n=11), serotonin syndrome (n=4), mania (n=3), insomnia (n=3), neuroleptic malignant syndrome (NMS) [n=3, one of them had both catatonia and NMS], and de novo obsessive compulsive symptoms (n=2). Restarting clozapine appeared to be the most effective treatment. Non-psychosis symptoms following clozapine withdrawal have important clinical implications. Clinicians should be aware of the possible presentations of symptoms to ensure early recognition and management. Further research is warranted to better characterise the prevalence, risk factors, prognosis, and optimal drug dosing for each withdrawal symptom.

Relationships Between Adherence to Guideline Recommendations for Pharmacological Therapy Among Clinicians and Psychotic Symptoms in Patients With Schizophrenia.

Clinician adherence to guideline recommendations in the pharmacological therapy of schizophrenia is important for favorable patient outcomes. To evaluate whether prescriptions followed the guidelines for pharmacological therapy of schizophrenia, we recently developed a summary indicator of multiple quality indicators: the individual fitness score (IFS). It is unclear whether adherence to the guidelines is related to patient outcomes. Here, we investigated correlations between the IFS values and psychotic symptoms in patients with schizophrenia. We assessed whether patients' current prescriptions adhered to the guideline recommendations using the IFS in 47 patients with treatment-resistant schizophrenia (TRS) and 353 patients with non-TRS (total n = 400), respectively. We investigated correlations between the IFS and total scores and scores on the 5 subscales of the Positive and Negative Syndrome Scale (PANSS). Furthermore, we explored correlations between over 2-year longitudinal changes in IFS values and changes in psychotic symptoms in some patients (n = 77). We found significant negative correlation between the IFS and PANSS total score in all patients with schizophrenia (β = -0.18, P = 9.80 × 10-5). The IFS was significantly and nominally negatively correlated with the PANSS total score in patients with non-TRS (Spearman's rho = -0.15, P = 4.40 × 10-3) and patients with TRS (rho = -0.37, P = .011), respectively. The IFS was also significantly and nominally negatively correlated with several factors, such as the negative and depressed factors, in patients with non-TRS and patients with TRS, respectively (P < .05). Furthermore, the change in IFS values was marginally negatively correlated with the changes in PANSS total scores and scores on the positive and depressed factors (P < .05). These findings suggest that efforts to improve clinician adherence to guideline recommendations for pharmacological therapy of schizophrenia, as assessed by the IFS, may lead to better outcomes in patients with schizophrenia.

Significant improvement of psychotic symptoms in treatment-resistant schizophrenia with clozapine in an adolescent with SHINE syndrome: a case report

This report highlights a rare single-gene cause of early-onset, treatment-resistant schizophrenia, and its unique responsiveness to clozapine therapy. This case describes a pediatric female who was diagnosed with early-onset schizophrenia and catatonia in her early adolescence, and was later found to have DLG4-related synaptopathy, also known as SHINE syndrome. SHINE syndrome is a rare neurodevelopmental disorder caused by dysfunction of the postsynaptic density protein-95 (PSD-95), encoded by the DLG4 gene. After failing three antipsychotic drug treatments, the patient was started on clozapine, which resulted in significant improvements in positive and negative symptoms. This case illustrates the impact of clozapine in treatment-resistant early-onset psychosis and exemplifies practical implications for genetic testing in early-onset schizophrenia.

Body mass index, waist circumference, insulin, and leptin plasma levels differentiate between clozapine-responsive and clozapine-resistant schizophrenia.

Between 25% and 50% of patients suffering from treatment-resistant schizophrenia fail to achieve a clinical response with clozapine. The rapid identification and treatment of this subgroup of patients represents a challenge for healthcare practice. To evaluate the relationship between metabolic alterations and the clinical response to clozapine. A multicenter, observational, case-control study was performed. Patients diagnosed with schizophrenia treated with clozapine were eligible (minimum dose 400 mg/d for at least 8 weeks and/or clozapine plasma levels ⩾ 350 µg/mL). According to the Positive and Negative Syndrome Scale (PANSS) total score, patients were classified as clozapine-responsive (CR) (<80 points) or clozapine non-responsive (CNR) (⩾80 points). Groups were compared based on demographic and treatment-related characteristics, together with body mass index (BMI), waist circumference, insulin, leptin, and C-reactive protein plasma levels. Plasma levels of clozapine and its main metabolite, nor-clozapine, were measured in all the participants. In addition, the potential relationship between PANSS scores and leptin or insulin plasma levels was assessed. A total of 46 patients were included: 25 CR and 21 CNR. BMI and waist circumference, fasting insulin and leptin plasma levels were lower in the CNR group, while C-reactive protein was not different. Moreover, significant negative correlations were observed between PANSS positive and general psychopathology subscores, on one hand, and insulin and leptin plasma levels, on the other hand, as well as between PANSS negative subscores and leptin plasma levels. Our results suggest that the lack of metabolic effect induced by clozapine is associated with the lack of clinical response.

Sex differences in the association of treatment-resistant schizophrenia and serum interleukin-6 levels

BackgroundLow-grade inflammation and altered inflammatory markers have been observed in treatment-resistant schizophrenia (TRS). Interleukin-6 (IL-6) is one of the pro-inflammatory cytokines linked with TRS and receives increasing attention. Previous studies showed that patients with TRS might have higher IL-6 levels compared with healthy individuals and treatment-responsive patients. Besides, emerging evidence has suggested that there are sex differences in the associations between IL-6 levels and various illnesses, including chronic hepatitis C, metabolic syndrome, etc.; however, there is limited study on TRS. In this present study, we aimed to compare the serum IL-6 levels of TRS and partially responsive schizophrenia (PRS) and explore potential sex differences in the association of TRS and IL-6 levels.MethodsThe study population consisted of a total of 90 patients with schizophrenia: 64 TRS patients (45.3% males and 54.7% females) and 26 PRS patients (46.2% males and 53.8% females). We measured serum IL-6 levels using enzyme-linked immunosorbent assay (ELISA) and analyzed them separately by gender, controlling for confounders (age, education, medication, body mass index, and PANSS scores) rigorously.ResultThe results showed that patients with TRS had higher serum IL-6 levels than patients with PRS (p = 0.002). In females, IL-6 levels increased significantly in the TRS group compared with the PRS group (p = 0.005). And a positive correlation tendency was observed between IL-6 levels and PANSS general sub-scores (r = 0.31, p = 0.039), although this correlation was not significant after correcting for multiple comparisons. Whereas, there were no differences in IL-6 levels between the TRS and PRS (p = 0.124) in males.ConclusionOur findings provided evidence supporting the hypothesis that the inflammatory response system (IRS) may play a role in the pathogenesis of TRS in a sex-dependent manner. In addition, sex differences in the immune dysfunction of individuals with schizophrenia cannot be neglected, and inflammation in male and female TRS should be discussed separately.

Safety aspects during treatment with clozapine: : Adverse effects, titration, and therapeutic drug monitoring - a narrative review

According to current guidelines, clozapine should be used as athird step in treatment resistant schizophrenia (TRS). In everyday clinical practice, however, it is frequently used at amuch later stage, which leads to asignificant deterioration of prognosis. The first part of this narrative overview focuses on the most frequent side effects of clozapine, on the relevance of slow titration, and on specific aspects of therapeutic drug monitoring (TDM). Medline, the Guideline for the use of clozapine 2013 of the Netherlands Clozapine Collaboration Group, and the S3Guideline for Schizophrenia of the German Association for Psychiatry, Psychotherapy and Psychosomatics were searched for relevant literature, the last query dating from April28th, 2023. Despite its unique efficacy clozapine is underused in clinical practice and prescription varies between and within countries. Next to hematological, metabolic, and vegetative side effects, clozapine induced inflammation manifesting in the form of pneumonia or myocarditis, which is mainly associated with rapid titration, represents amajor clinical challenge with CRP monitoring being of particular relevance. In this context, it also has to be noted that sex, smoking behavior, and ethnic origin impact clozapine metabolism, thus requiring personalized dosing. Slow titration when possible, TDM, and CYP diagnostics when appropriate increase patient safety during treatment with clozapine and thus the likelihood of early prescription of this compound in TRS.

Evaluation of Serum Complement Levels and Factors Affecting Treatment Resistance in Patients with Schizophrenia.

There are increasing investigations about the potential role of the complement system in disorders affecting the central nervous system, including schizophrenia. Therefore, we aim to evaluate the levels of complement 3 and complement 4 and the factors affecting treatment resistance in schizophrenia patients. This cross-sectional study was conducted between January 2020 and January 2021 and included schizophrenia patients resistant to treatment or in remission and healthy controls. The Structured Clinical Interview for Diagnostic and Statistical Manual-5 was used to confirm the diagnosis according to Diagnostic and Statistical Manual -5 criteria. We evaluated the patients with some scales and forms. The complement 3 and complement 4 levels were measured from blood samples. In the treatment-resistant schizophrenia group, complement 3 (P = .001) and complement 4 (P = .001) levels were significantly higher compared to schizophrenia patients in remission and healthy controls. While the Brief Psychiatric Rating Scale (P < .001), the Positive and Negative Syndrome Scale-positive (P < .001), the Positive and Negative Syndrome Scale-negative (P < .001), the Positive and Negative Syndrome Scale-psychopathology (P < .001), the Positive and Negative Syndrome Scale-total (P < .001), and the Clinical Global Impression Scale-Severity (P < .001) scores were significantly higher in treatment-resistant schizophrenia patients, the General Assessment of Functioning (P < .001), and Beck Cognitive Insight Scale (P < .001) scores were significantly lower compared to the other groups. In schizophrenia patients, complement 3 levels were positively correlated with the Positive and Negative Syndrome Scale-negative (P = .046), the Positive and Negative Syndrome Scale-psychopathology (P = .001), the Positive and Negative Syndrome Scale -total (P = .025), and Clinical Global Impression Scale-Severity of Disease (P = .004). Also, complement 4 levels were positively correlated with Brief Psychiatric Rating Scale (P = .004), the Positive and Negative Syndrome Scale-positive (P = .003), the Positive and Negative Syndrome Scale -negative (P = .014), the Positive and Negative Syndrome Scale-psychopathology (P < .001), the Positive and Negative Syndrome Scale-total (P = .002), and Clinical Global Impression Scale-Severity of Disease (P = .001) in patients with schizophrenia. It was determined that a higher C4 level increased the risk of treatment resistance (odds ratio: 1.133, 95% CI: 1.012-1.268; P = .030), while a higher Beck Cognitive Insight Scale score decreased the risk of treatment resistance (odds ratio: 0.317, 95% CI: 0.191-0.526; P < .001). In light of the analyses, it can be said that complement concentration increases in certain stages of schizophrenia, and its imbalance may be associated with symptom severity and treatment resistance.

Cariprazine: an augmentation strategy for treatment-resistant schizophrenia with pro-cognitive and anti-hostility effects.

Schizophrenia is a chronic mental health condition treated with antipsychotics. A significant number of patients fail to respond to standard treatment and develop treatment-resistant schizophrenia (TRS). The only current treatment for TRS is clozapine, which has significant side effects and may only be effective in 40% of cases. We describe two cases of patients with TRS who have failed multiple antipsychotic trials and have had extensive hospitalization history due to aggression/hostility. Both patients responded to dual antipsychotic therapy with a long-acting injectable antipsychotic plus cariprazine. Both patients demonstrated improvement in hostility and cognition/memory. Cariprazine's novel mechanism of action may allow it to be uniquely effective in dual antipsychotic therapy for TRS. Cariprazine has a higher affinity than dopamine for D3 receptors and has a 10-fold higher affinity for D3 than D2. This may contribute to its pro-cognitive and anti-hostility effects. Further studies are warranted to determine the role of cariprazine in TRS.

Exploration of the role of emotional expression of treatment-resistant schizophrenia patients having followed virtual reality therapy: a content analysis

BackgroundEmotional responses are an important component of psychotherapeutic processes. Avatar therapy (AT) is a virtual reality-based therapy currently being developed and studied for patients suffering from treatment resistant schizophrenia. Considering the importance of identifying emotions in therapeutical processes and their impact on the therapeutic outcome, an exploration of such emotions is needed.MethodsThe aim of this study is to identify the underlying emotions at the core of the patient-Avatar interaction during AT by content analysis of immersive sessions transcripts and audio recordings. A content analysis of AT transcripts and audio recordings using iterative categorization was conducted for 16 patients suffering from TRS who underwent AT between 2017 and 2022 (128 transcripts and 128 audio recordings). An iterative categorization technique was conducted to identify the different emotions expressed by the patient and the Avatar during the immersive sessions.ResultsThe following emotions were identified in this study: Anger, Contempt/ Disgust, Fear, Sadness, Shame/ Embarrassment, Interest, Surprise, Joy and Neutral. Patients expressed mostly neutral, joy and anger emotions whereas the Avatar expressed predominantly interest, disgust/contempt, and neutral emotions.ConclusionsThis study portrays a first qualitative insight on the emotions that are expressed in AT and serves as a steppingstone for further investigation in the role of emotions in the therapeutic outcomes of AT.

Neuroimaging glutamatergic mechanisms differentiating antipsychotic treatment-response

Glutamatergic dysfunction is associated with failure to respond to antipsychotic medication in individuals with schizophrenia. Our objective was to combine neurochemical and functional brain imaging methods to investigate glutamatergic dysfunction and reward processing in such individuals compared with those with treatment responsive schizophrenia, and healthy controls. 60 participants played a trust task, while undergoing functional magnetic resonance imaging: 21 classified as having treatment-resistant schizophrenia, 21 patients with treatment-responsive schizophrenia, and 18 healthy controls. Proton magnetic resonance spectroscopy was also acquired to measure glutamate in the anterior cingulate cortex. Compared to controls, treatment responsive and treatment-resistant participants showed reduced investments during the trust task. For treatment-resistant individuals, glutamate levels in the anterior cingulate cortex were associated with signal decreases in the right dorsolateral prefrontal cortex when compared to those treatment-responsive, and with bilateral dorsolateral prefrontal cortex and left parietal association cortex when compared to controls. Treatment-responsive participants showed significant signal decreases in the anterior caudate compared to the other two groups. Our results provide evidence that glutamatergic differences differentiate treatment resistant and responsive schizophrenia. The differentiation of cortical and sub-cortical reward learning substrates has potential diagnostic value. Future novel interventions might therapeutically target neurotransmitters affecting the cortical substrates of the reward network.

Disability and quality of life in patients with treatment-resistant schizophrenia on long- term clozapine therapy.

To assess disability and quality of life (QOL) in treatment resistant schizophrenia (TRS) on long term clozapine therapy and assess their correlation with positive, negative and cognitive symptoms. Disability and QOL in forty patients with TRS (as per modified Kane's criteria) were assessed using World Health Organization Disability Assessment Schedule 2.0 and World Health Organization Quality of Life-BREF. Scale for assessment of positive symptoms, scale for assessment of negative symptoms and Addenbrooke's cognitive examination-III were used to assess positive, negative and cognitive symptoms. Medication adherence rating scale assessed medication adherence. Disability and QOL correlated significantly with medication adherence, negative and cognitive symptoms but not with positive symptoms. Subgroup analysis revealed significant difference between medication adherence (good vs poor) and cognitive (impairment vs non-impairment) groups. Negative and cognitive symptoms, and medication adherence correlated with disability and QOL.

Deep brain stimulation and digital monitoring for patients with treatment-resistant schizophrenia and bipolar disorder: A case series.

The use of deep brain stimulation (DBS) has been recently extended for treating resistant psychiatric disorders, but the experience in patients with schizophrenia-related disorders and bipolar disorder (BD) is scarce. We conducted an observational, one-year longitudinal study to evaluate the effects of DBS in four treatment-resistant patients with schizophrenia, schizoaffective, and BD, included in a pilot, last-resource protocol. Patients were digitally monitored for objective assessment of behavioral changes. After one year of its initiation, DBS of the nucleus accumbens (in subjects N2, N3, and N4) and subgenual anterior cingulate cortex (in N1) produced a significant clinical improvement, associated with decreases in the Clinical Global Impression (from 5.25±0.5 to 3.5±1, p=0.035) and in the Hamilton Depression Rating Scale (HADRS scores, from 14.5±6.56 to 1.5±1.29, p=0.020). We observed a notable, durable therapeutic response in two patients from this cohort (N1 and N3), a clinically relevant relief in a third (N2), and a lack of a significant response in the last one (N4). Maintenance electroconvulsive therapy sessions could be discontinued in the three patients that responded to DBS (N1-3). There were no side effects or relevant changes in cognitive functioning. There were relevant differences between physical activity and sleep time among the four participants. These results suggest initial evidence that DBS may be an effective and safe alternative for treating complex and resistant forms of schizophrenia-related disorders and BD. Digital monitoring may help to capture objective measures of behavioral changes after the intervention.

EPH69 Economic Impact of Clozapine Treatment Persistence: A Canadian Perspective

Clozapine is widely used for treatment-resistant schizophrenia (TRS). Clozapine manufacturers are required to implement a patient support program, but not all are equal. The objective of this study was to estimate the economic impact of clozapine persistence on brand vs. generic clozapine, in Quebec, Canada.

Exploring the "Insight Paradox" in Treatment-Resistant Schizophrenia: Correlations Between Dimensions of Insight and Depressive Symptoms in Patients Receiving Clozapine.

There remains a lack of clarity as to the possible cross talk of insight into illness and depressive symptoms in treatment-resistant schizophrenia. We therefore set our primary aim to evaluate relationship between insight dimensions and depressive symptoms in patients with treatment-resistant schizophrenia receiving clozapine. This was a cross-sectional, non-interventional study, conducted in daily clinical practice conditions. Patients in outpatient clinics between March 2020 and May 2020 with treatment-resistant schizophrenia (based on Treatment Response and Resistance in Psychosis), with no comorbid psychiatric disorder, and with no body mass index greater than 40.0 kg/m2 were included. We collected sociodemographic variables, scores of insight dimensions (treatment compliance, illness recognition, and symptom relabeling with the Schedule for Assessment of Insight), and depressive symptoms with Calgary Depression Score for Schizophrenia. Linear regression models were used to investigate variables associated with depressive symptoms as the outcome of interest. The final analysis sample comprised 55 patients with treatment-resistant schizophrenia, with a mean age of 42.48 (SD = 9.18) years and a predominance of the male sex (n = 42, 76.9%). Model 1 [Calgary Depression Score for Schizophrenia ~ (Schedule for Assessment of Insight + Positive and Negative Syndrome Scale)] displayed that 48% of the variation in the Calgary Depression Score for Schizophrenia can be explained by Schedule for Assessment of Insight-composite and Positive and Negative Syndrome Scale-composite (P < .001). More effectively, model 2 [Calgary Depression Score for Schizophrenia ~ (Schedule for Assessment of Insight-illness recognition + Positive and Negative Syndrome Scale-general psychopathology)] revealed that 51% of the variation in the Calgary Depression Score for Schizophrenia can be explained by the sub-scales (P < .001). We further designed a new model in which Global Assessment of Functioning scores were the response variable to explore the link between awareness into illness and functionality (Global Assessment of Functioning ~ Schedule for Assessment of Insight-illness recognition). In this model, awareness of illness did not explain a significant proportion of variance in functionality scores (R 2 = 0.045, F(1,52) = 2.48, P = 0.121). The treatment compliance part of insight was not one of the significant explanatory variables of depressive symptoms, but it explained the variance in functioning, in contrast to the illness recognition dimension of insight. If our findings were replicated in treatment-resistant schizophrenia, they would suggest that promoting treatment compliance dimension of insight instead of recognition of illness could not increase depressive symptoms.