Refractory Schizophrenia Research Articles

The Use of Clozapine in the Serious Mental Illness Patients Enrolled in an Assertive Community Treatment Program.

IntroductionHealth care cost is projected to reach 20% of the nation’s gross national product (GNP) by 2016. 6.2% of this is from mental health. The National Institute of Mental Health (NIMH) estimates the prevalence of serious mental illness (SMI) at 13.1 million or 5.2% of American adults age 18 or over. Hence, mental health care cost for this patient population is significant.Patients with SMI involved in an Assertive Community Treatment (ACT) program are individuals who experience the most intractable symptoms and the greatest level of dysfunction from their mental illness. These individuals typically are institutionalized in a long-term facility such as the state hospital.Clozapine has shown superior efficacy over first- and most second-generation antipsychotics in both treating treatment-resistant and non-treatment-resistant schizophrenia which has been supported by several large trials. There is also evidence of its efficacy in suicidality, aggression and substance misuse. In fact, clozapine has been approved by the FDA for use in refractory schizophrenia and suicidality in schizoaffective disorder. Due to the risk of agranulocytosis, clozapine is underutilized. The purpose of this study is to conduct a retrospective cohort study through chart review to analyze whether the addition of clozapine to ACT treatment of SMI patients in a community hospital from 2008 to 2018 led to decreased frequency of hospitalizations and increased clinical stability.Materials and methodsA retrospective study using electronic medical record (EMR) of patients ages 20 and above who were enrolled in the ACT program at a community hospital from December 1, 2008 to December 31, 2018. Variables were collected from the EMR and de-identified during data collation. Analysis was performed using SPSS software package.ResultsA total of 179 patients enrolled in the ACT program and their data was extracted from the EMR. Twenty-five (62.5%) of these patient enrollments were on clozapine. They were made up of 53.6% male, 81.9% White/Asian, 18.1% Black; 44.1% ages between 36 to 50 years old, 30.2% were aged 18 to 35 years old, and 25.7% greater than 50 years old. There was no difference in age, sex, race, ethnicity, and insurance type in ACT program between those using clozapine and those not on clozapine. There was a higher proportion of psychiatric hospitalizations among clozapine users compared with the non-clozapine user group (62.5% vs 41.5%, p = 0.019). However, the two groups did not differ from one another in terms of psychiatric emergency visits (p = 0.128) or frequency of ACT visits (p = 0.002).ConclusionEffective treatment that will reduce hospitalizations and the burden of chronic disability in patients with SMI would greatly reduce mental health care cost. Clozapine remains the gold standard in the treatment of refractory schizophrenia. But due to the risk of agranulocytosis, clozapine is underutilized. It was hoped that this study will support the use of clozapine in SMI patients. Disappointingly, the use of clozapine did not prevent relapses and hospitalizations in this patient population and patients on clozapine seemed to have increased hospitalizations, compared to those who were not on clozapine. Perhaps, a different outcome would have occurred if the focus was limited to the patients themselves who were on Clozapine and ascertain what the rate of hospitalization was before the start of clozapine vs after the use of clozapine.

White Matter Microstructure and Structural Networks in Treatment-Resistant Schizophrenia Patients After Commencing Clozapine Treatment: A Longitudinal Diffusion Imaging Study

Clozapine has a superior clinical effect in refractory schizophrenia, however its potential impact on white matter microstructure and neural networks is unclear. This study investigates such changes after 6 months of switching to clozapine in schizophrenia patients compared to controls, and whether any changes are related to clinical variables.

A 25-Year-Old Man with Refractory Schizophrenia and Clozapine-Induced Myocarditis Diagnosed by Non-Invasive Cardiovascular Magnetic Resonance

Patient: Male, 25-year-oldFinal Diagnosis: Clozapine-induced myocarditisSymptoms: Elevated troponin • fever • leukocytosis • somnolence • tachycardiaMedication: —Clinical Procedure: Cardiovascular magnetic resonance • electrocardiogram • transthoracic echocardiogramSpecialty: Cardiology • General and Internal MedicineObjective:Rare diseaseBackground:Clozapine, a second-generation antipsychotic, is often prescribed for refractory schizophrenia; however, it can cause life-threatening adverse events including agranulocytosis and myocarditis. Making the diagnosis of clozapine-induced myocarditis can be challenging given the non-specific presentation as well as risk involved in obtaining an endomyocardial biopsy. As clozapine-induced myocarditis carries a mortality risk of up to 30%, timely recognition, diagnosis, and management are vital. This report presents a case of clozapine-induced myocarditis in a 25-year-old man with refractory schizophrenia who was diagnosed using non-invasive imaging with cardiovascular magnetic resonance (CMR).Case Report:A 25-year-old man with refractory schizophrenia was admitted with severe psychotic symptoms and started on a rapid titration of clozapine. During his hospitalization he developed somnolence, fever, and tachycardia with leukocytosis, elevated inflammatory markers, and cardiac biomarkers concerning for clozapine-induced myocarditis. Alternative etiologies were ruled out and CMR was used to confirm the diagnosis. The patient’s symptoms resolved following discontinuation of clozapine and initiation of supportive therapies.Conclusions:Clozapine-induced myocarditis is challenging to diagnose due to a lack of consensus on diagnostic criteria, reliance on voluntary reporting, and non-specific presentation. This report highlights that myocarditis can be associated with clozapine pharmacotherapy in patients with schizophrenia and demonstrates the value of diagnosis using non-invasive CMR. Additional studies are needed to understand the mechanism of clozapine-induced myocarditis and how clozapine titration may affect risk.

Combined use of clozapine and cariprazine in treatment-resistant schizophrenia, is it a good choice?

IntroductionTreatment-resistant schizophrenia (TRS) affects 30% of people with a diagnosis of schizophrenia, and is defined as nonresponse to at least two trials of antipsychotic medication of adequate dose and duration. Clozapine is the only evidence-based treatment for TRS. Cariprazine may be considered significantly more efficacious than risperidone in improving negative symptoms of schizophrenia.ObjectivesTo describe the experience of using cariprazine in combination with clozapine in patients with refractory schizophrenia and negative symptoms.MethodsQualitative design. We present a case report study of a 47-year-old male with a diagnosis of TRS, treated in our outpatient mental health clinic for twenty years. The patient experiences crystallized delusional ideas of harm, self-referential, paranoid and mystical-messianic content, phenomena of theft and thought reading, egodistonic auditory hallucinations. No substance use disorder was observed. He made several suicide attempts in the context of intense suffering and psychotic anguish. Clozapine 400mg/day was instituted after no response to treatment with amisulpride, paliperidone, olanzapine or aripiprazole. The intensity of positive symptoms was reduced (experiences of damage, commenting and insulting auditory hallucinations, self-referentiality), as well as the emotional and behavioral repercussions. Persistent negative symptoms appeared such as apathy, abulia, clinophilia, anergy, social isolation, affective flattening, impairing his functionality.ResultsNeuroimaging and periodic blood tests results were normal. Oral cariprazine was added in ascending doses up to 4.5mg with good tolerance. The patient showed remission of apathy, enhancement of behavioral activation, socialization and motivation to perform occupational activities.ConclusionsCombinations of clozapine with partial agonists may improve the quality of life in refractory schizophrenia.DisclosureNo significant relationships.

Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis

Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.

Effect and Pharmacological Study of Olanzapine in the Treatment of Refractory Schizophrenia

Effect and Pharmacological Study of Olanzapine in the Treatment of Refractory Schizophrenia

An evaluation of the variation and underuse of clozapine in the United Kingdom.

Clozapine is the only licensed treatment for treatment refractory schizophrenia. Despite this, it remains grossly underused relative to the prevalence of refractory schizophrenia. The extent of underuse and the degree of regional variation in prescribing in the United Kingdom is unknown. It is also unclear, how the UK compares with other European countries in rates of clozapine prescribing. We obtained data relating to all clozapine prescribing in the UK from the relevant clozapine registries. We examined regional variation in clozapine use across England, corrected for the known prevalence of severe mental illness (SMI). We also compared the UK rate of clozapine use per 100,000 population to that described in other European countries. There is substantial variation in clozapine prescribing across different regions of England and only about a third of potentially eligible patients were prescribed the drug in the UK. Clozapine prescribing rate in the UK was lower than in several European countries. There is clear regional inequity in access to the most effective treatment in refractory schizophrenia in England. Strategies to increase clozapine use, by overcoming both real and perceived barriers, are urgently necessary to reduce treatment inequity for patients with refractory schizophrenia.

Clozapine Is Better Tolerated in Younger Patients: Risk Factors for Discontinuation from a Nationwide Database in Japan.

Objective The effectiveness of clozapine is clearly superior to other antipsychotics in the treatment of refractory schizophrenia. Clozapine leads to various side effects, and therefore many patients are forced to discontinue. In this study, we analyzed the registry database of all cases in Japan to identify risk factors for discontinuation of clozapine. Methods The Clozaril patient monitoring service® (CPMS) database from July 31, 2009 to January 26, 2020 was acquired. We defined the following exclusion criteria: patients who had ever taken clozapine by a non-CPMS method, such as an individual import or clinical trial, patients who did not receive clozapine after being enrolled in CPMS, and patients with initial doses other than 12.5 mg (outside the current protocol). Therefore, all patients in this study are new users. Multivariate Cox regression analysis was used to investigate independent risk factors associated with time to discontinuation of clozapine. Results We identified 8,263 patients as the study population. Clozapine discontinuation was significantly associated with age 40 and older [hazard ratio (HR)=1.66, p<0.001], intolerance to olanzapine (HR=1.31, p=0.018), previous treatment with clozapine (HR=1.30, p=0.001), and leukocyte counts <6,000/mm3 (HR=1.24, p<0.001). The Kaplan-Meier curves for clozapine discontinuation by age group revealed that older age at the time of clozapine introduction tended to have lower continuation rates. Conclusion Careful administration is important because patients with these factors have a high risk of discontinuation. In addition, the initiation of clozapine during the younger period was more effective and more tolerated.

Psychotropic drug prescription patterns and their predictors among older adult patients with schizophrenia in a tertiary-referral psychiatric hospital

Objective: Medical treatments for patients with refractory schizophrenia can be roughly divided into three strategies – clozapine administration, adjuvant use of mood stabilizers, and antipsychotic polypharmacy. Few studies exist on older adult patients with schizophrenia. In this study, we intended to assess the prevalence of clozapine administration, adjuvant use of mood stabilizers, and antipsychotic polypharmacy, and to find their predictors in those patients with schizophrenia. Methods: In this cross-sectional study, we collected information of patients' sociodemographic and clinical details. Their psychotic symptoms were evaluated using a clinical interview with a positive and negative syndrome scale (PANSS). Results: We enrolled 240 study participants, with 74 patients (30.8%) receiving clozapine, 40 patients (16.7%) receiving adjuvant use of mood stabilizers, and 42 patients (17.5%) receiving antipsychotic polypharmacy. Younger age (p < 0.05), higher PANSS general symptoms subscales (p < 0.001), and higher dosage of antipsychotics (p < 0.01) were significantly related to patients with clozapine administration. As to patients with adjuvant therapy with mood stabilizers, only younger age (p < 0.01) and male gender (p < 0.05) showed significant association. Finally, patients receiving antipsychotic polypharmacy were significantly related to lower body mass index (BMI) (p < 0.05), higher PANSS positive symptoms subscale (p < 0.05), and higher dosage of antipsychotics (p < 0.001). Conclusions: Our findings showed that patients with clozapine prescription were 30.8% in prevalence which is higher than other studies in Asia. The prevalence of adjuvant mood stabilizers and antipsychotic polypharmacy were 16.7% and 17.5%, respectively. Those two findings are lower than those in other studies in Asia.

Pharmacotherapeutic follow-up form for caregivers of patients with refractory schizophrenia

Introduction: Schizophrenia is one of the most relevant mental disorders in public health, causing great distress for the patient and his/her family members. The persistence of symptoms characterizes refractoriness of the disease that is treated with clozapine considered the gold standard in treatment, but its adverse reactions can be as intense as the symptoms of the disorder. Objective: To develop a pharmacotherapeutic follow-up form for caregivers of adult patients with schizophrenia would refract from the use of clozapine. Methods: The search for the articles was carried out in the government databases and websites from November 15, 2018 to January 15, 2019, published from 2012. Result: Thirty-seven articles were found, excluding 20 articles, including in this review 17 articles, 2 books, 4 clinical protocols and 1 drug monograph. Conclusion: The proposal to develop the pharmacotherapeutic follow-up form is to identify adverse reactions that may influence the treatment of pharmacological treatment and reduce the unwanted effects of treatment as a consequence to improve the patient's quality of life.

Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals.

BackgroundClozapine remains the only medication licensed for treating refractory schizophrenia. However, it remains underutilized in part due to concerns regarding adverse events.Sources of dataPublished literature.Areas of agreementCommon adverse events during clozapine treatment include sedation, hypersalivation, postural hypotension, dysphagia, gastrointestinal hypomotility, weight gain, diabetes mellitus and dyslipidaemia. Rare but serious events include agranulocytosis, cardiomyopathy, myocarditis, pneumonia, paralytic ileus and seizure.Areas of controversyIt remains unclear how best to minimize clozapine-induced morbidity/mortality (i) during dose titration, (ii) from hypersalivation and (iii) from gastrointestinal hypomotility. It is also unclear how clozapine pharmacokinetics are affected by (i) gastrointestinal hypomotility, (ii) systemic infection and (iii) passive exposure to cigarette smoke. Whether monthly haematological monitoring needs to continue after 12 months of uninterrupted therapy is also a subject of debate.Growing pointsThere is a need for better management of serious clozapine-related adverse events in addition to agranulocytosis. There is also a need for better education of patients and carers, general practitioners, A&E and ITU staff and others of the problems posed in using clozapine safely.Areas timely for developing researchThere is a need for more research on assessing clozapine dosage (i) as patients get older, (ii) with respect to exposure to cigarette smoke and (iii) optimizing response if adverse events or other factors limit dosage.

Korean Medication Algorithm for Schizophrenia 2019, Second Revision: Treatment of Psychotic Symptoms.

ObjectiveIn 2001, the Korean College of Neuropsychopharmacology and the Korean Society for Schizophrenia Research developed the Korean Medication Algorithm Project for Schizophrenia (KMAP-SPR 2001, revised 2006) through a consensus of expert opinion. The present study was carried out to support the second revision of the KMAP-SPR.MethodsBased on clinical guidelines and studies on the treatment of psychotic symptoms in schizophrenia, the Executive committee completed a draft of KMAP-SPR 2019. To obtain an expert consensus, a Review committee of 100 Korean psychiatrists was formed and 69 responded to a 30-item questionnaire. Based on their responses, the KMAP-SPR 2019 was finalized.ResultsThe revised schizophrenia algorithm now consists of 5 stages. At Stage 1, monotherapy with atypical antipsychotics was recommended by expert reviewers as the first-line strategy. At Stage 2, most reviewers recommended the use of typical or atypical antipsychotic drugs not used at Stage 1. At Stage 3, many reviewers agreed with the administration of clozapine. At Stage 4, a combination of clozapine and other agents such as antipsychotics, mood stabilizers, antidepressants, or electroconvulsive therapy was recommended. At Stage 5, most reviewers recommended combined treatment with an antipsychotic other than clozapine; and a mood stabilizer, antidepressant, or electroconvulsive therapy. At any stage, prescribing long-acting injectable antipsychotics at the discretion of the clinician was recommended.ConclusionCompared with previous versions, the KMAP-SPR 2019 now recommends using clozapine earlier in treatment-refractory schizophrenia. In addition, the use of long-acting injectable antipsychotics is now considered to be available at any stage.

Neutrophil fluorescence in clozapine users is attributable to a 14kDa secretable protein.

Clozapine is the only antipsychotic agent with demonstrated efficacy in refractory schizophrenia. However, use of clozapine is hampered by its adverse effects, including potentially fatal agranulocytosis. Recently, we showed an association between neutrophil autofluorescence and clozapine use. In this study, we evaluated the subcellular localization of clozapine‐associated fluorescence and tried to elucidate its source. Neutrophils of clozapine users were analyzed with fluorescence microscopy to determine the emission spectrum and localization of the fluorescence signal. Next, these neutrophils were stimulated with different degranulation agents to determine the localization of fluorescence. Lastly, isolated neutrophil lysates of clozapine users were separated by SDS‐PAGE and evaluated. Clozapine‐associated fluorescence ranged from 420 nm to 720 nm, peaking at 500‐550 nm. Fluorescence was localized in a large number of small loci, suggesting granular localization of the signal. Neutrophil degranulation induced by Cytochalasin B/fMLF reduced fluorescence, whereas platelet‐activating factor (PAF)/fMLF induced degranulation did not, indicating that the fluorescence originates from a secretable substance in azurophilic granules. SDS‐PAGE of isolated neutrophil lysates revealed a fluorescent 14kDa band, suggesting that neutrophil fluorescence is likely to be originated from a 14kDa protein/peptide fragment. We conclude that clozapine‐associated fluorescence in neutrophils is originating from a 14kDa soluble protein (fragment) present in azurophilic granules of neutrophils. This protein could be an autofluorescent protein already present in the cell and upregulated by clozapine, or a protein altered by clozapine to express fluorescence. Future studies should further explore the identity of this protein and its potential role in the pathophysiology of clozapine‐induced agranulocytosis.

M161. NEURAL CHANGES INDUCED BY ELECTROCONVULSIVE THERAPY (ECT) IN SCHIZOPHRENIA PATIENTS: A SYSTEMATIC REVIEW

BackgroundDespite the remarkable progress of antipsychotic drugs, electroconvulsive therapy (ECT) remains a potent treatment option for schizophrenia. However, the underlying neural mechanism of ECT effect on schizophrenia remains unclear. For this reason, we reviewed literature which investigated structural and functional brain changes after ECT in schizophrenia patients.MethodsWe searched the PubMed, EMBASE, Cochrane Reviews database to search for eligible articles. Following medical subject headings (MeSH) terms were used: ECT AND schizophrenia AND (MRI OR MRS OR PET OR SPECT OR NIRS OR DTI).ResultsThirteen studies were eligible for the reviewing process. Of them, three studies investigated the effect of ECT upon volumetric changes of cerebral regions; 4 studies on the effect of ECT upon functional brain activities; three studies using magnetic resonance spectroscopy (MRS); and another three studies investigating blood flow changes. Medial temporal lobe (MTL) structures seemed to be increased after ECT sessions in schizophrenia patients, as in major depressive disorder (MDD) patients. Insula and left dorsolateral prefrontal cortex (DLFPC) is other potential neural substrates that might be disease specific for ECT induced changes in schizophrenia. Outcomes of functional imaging seemed to vary among studies, with divergent region of interests (ROI). MRS study results suggests the ratio of left prefrontal NAA/Cr might be increase after adequate ECT sessions. Studies investigating effect of ECT upon cerebral blood flow largely varied among studies with mixed results.DiscussionDespite the treatment effect of ECT in schizophrenia patients, there have been only a handful of studies investigating the biological mechanisms underlying ECT. Of them, the effect of ECT in schizophrenia seemed also to be mediated by structural volume increases in the MTL region (as in MDD), and the insula and left DLPFC might be other potential neural substrates of ECT effect in schizophrenia patients. Future studies are needed to validate the neural mechanisms that underlie the effect of ECT in schizophrenia, which might help to aid in tailoring treatment plans for refractory schizophrenia patients.

S214. HEART RATE VARIABILITY PREDICTS CLOZAPINE PLASMA LEVEL IN PATIENTS WITH SCHIZOPHRENIA IN A POLYPHARMACY CONDITION

BackgroundClozapine (CLZ) is most specific suitable treatment of refractory schizophrenia; however, it might lead a variety of adverse reactions that cause drug non-compliance. Although it is necessary to conduct therapeutic drug monitoring through measuring psychoactive drug plasma concentration measurement, it has limitation in that it takes several days and it is invasive. Previous studies have suggested that the heart rate variability (HRV) might serves as non-invasive and fast marker to monitoring pharmacodynamic intra-individual effects of the drug. This study aimed to investigate whether and which HRV parameters predict CLZ plasma concentration in natural clinical and polypharmacy conditions.MethodsTotal 85 patients (Male = 49 and Female = 36; Mean age = 35.95±9.45 years old; Mean CLZ intake = 6.21±4.86 years old) with schizophrenia who had received clozapine without the change of clozapine dosage at least 7 days before blood sampling for TDM and electrocardiogram (ECG) measuring participated in this study. ECG data were collected during resting-state. Linear and nonlinear HRV analysis were ran.ResultsBased on significant results from correlational analysis with the CLZ plasma level, univerate generalized linear regression model (GLM) with gamma distribution were conducted with adjusting the effect of age and sex. As results, for linear parameters of HRV, pNN5, pNN10, and VLF were inversely associated with the CLZ plasma level (Ps<0.05). For nonlinear HRV, DFA2 and crossover were positively and CSE30 were inversely associated with the CLZ concentration (Ps<0.05). After that, step-wise multiple GLM was conducted and the result yield that pNN5 and crossover are best predictors of CLZ plasma level (β=-0.01, t=-3.85, P<0.001 and β=0.50, t=5.02, P<0.001, respectively). The final model with pNN5 and predicted 35.78% of CLZ concentration. Among dependent variables in this model, crossover were positively correlated with CLZ dose (r=0.48, P<0.001).DiscussionHRV, especially for crossover, could be a candidate of a surrogate marker of CLZ concentration for drug-monitoring in patients with treatment-resistant schizophrenia in a polypharmacy condition. Findings of this study would helpful to make a clinical decision of CLZ dosage adjustment on site without the delay.

Novel Treatment for the Most Resistant Schizophrenia: Dual Activation of NMDA Receptor and Antioxidant.

Clozapine has been regarded as the last-line antipsychotic agent for patients with refractory schizophrenia. However, many patients remain unresponsive to clozapine, referred to as "clozapineresistant", "ultra-treatment-resistant", or remain in incurable state. There has been no convincing evidence for augmentation on clozapine so far. Novel treatments including numerous N-methyl-Daspartate (NMDA) receptor (NMDAR) enhancers, such as glycine, D-serine, D-cycloserine, and Nmethylglycine (sarcosine) failed in clinical trials. Earlier, the inhibition of D-amino acid oxidase (DAAO) that may metabolize D-amino acids and activate NMDAR has been reported to be beneficial for patients with schizophrenia receiving antipsychotics except for clozapine. A recent randomized, double-blind, placebo-controlled clinical trial found that add-on sodium benzoate, a DAAO inhibitor, improved the clinical symptoms in patients with clozapine- resistant schizophrenia, possibly through DAAO inhibition (and thereby NMDAR activation) and antioxidation as well; additionally, sodium benzoate showed no obvious side effects, indicating that the treatment is safe at doses up to 2 g per day for 6 weeks. More studies are warranted to elucidate the mechanisms of sodium benzoate for the treatment of schizophrenia and the etiology of this severe brain disease. If the finding can be reconfirmed, this approach may bring new hope for the treatment of the most refractory schizophrenia. This review summarizes the current status of clinical trials and related mechanisms for treatmentresistant, especially, clozapine-resistant schizophrenia. The importance of understanding the molecular circuit switches is also highlighted which can restore brain function in patients with schizophrenia. Future directions in developing better treatments for the most difficult to cure schizophrenia are also discussed.

Neurosurgery for Refractory Schizophrenia: A Systematic Literature Review

AbstractSchizophrenia is a chronic and disabling psychiatric disease that can be refractory to conventional treatment. The present study aims to gather information about the circuitry related to schizophrenia to describe possible surgical targets, and to establish whether psychosurgery can be a safe and effective treatment option for refractory schizophrenia. A systematic review of the literature was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. An electronic search was performed in the Pubmed and BVSalud databases using medical subject headings (MeSH) combined with Boolean operators. Out of the 724 studies retrieved, 13 were included in the review. Regarding leucotomy without a stereotactic approach, we found side effects such as irritability, nervous excitement, cases of disinhibition, and compromised normal social control. In other stereotactic procedures, there was some improvement, mainly regarding aggressiveness and positive symptoms; an anterior capsulotomy had an efficacy rate of 74% according to the Clinical Global Impression (CGI) rating scales. The only deep brain stimulation (DBS) case report found in our study described a significant improvement in the positive and negative symptoms. The use of a stereotactic approach enables psychosurgery to be a safe and effective treatment option in cases of refractory schizophrenia, improving the quality of life and the symptoms. Cognitive and negative symptoms remain a challenge in the treatment of schizophrenia, revealing that more targets in the circuitry must be surgically explored. Furthermore, more clinical trials are needed to compare these many surgical techniques and targets, using a standard evaluation parameter. The results show that DBS has a promising future in the treatment of refractory schizophrenia.

The Synergistic Effect of Hypoglycemic Index Diet on Refractory Schizophrenia

The Synergistic Effect of Hypoglycemic Index Diet on Refractory Schizophrenia

Inhibitory Profile of Clozapine AT CiPA Cardiac Ion Channels

The atypical antipsychotic clozapine is a prominent treatment for refractory schizophrenia. This drug inhibits the human ether-à-go-go related gene (hERG) and prolongs the QT-interval on the electrocardiogram. Although these biomarkers are sensitive predictors of the risk of Torsade de Pointe (TdP) arrhythmia, the long standing clinical use of clozapine did not show consistent association with increased incidence of TdP. It has recently been suggested that inhibition of other ion channels influencing the ventricular action potential can contribute refine true torsadogenic risk assessment. Here we have profiled clozapine on seven such currents using an automated electrophysiology platform. CHO or HEK cells expressing the human ion channels retained by the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative were recorded in whole-cell mode at room temperature on a Qpatch 48X planar patch-clamp workstation (Sophion, Denmark). Cells were exposed to cumulative concentrations of clozapine in saline buffer containing 0.3% DMSO supplemented with 0.06% Pluronic F-68. Clozapine concentration-dependently inhibited currents through Kv11.1 (hERG), Cav1.2, Nav1.5 (peak), Kv7.1 and Kv4.3 channels with IC50‘s of 4.2 ± 0.6 µM, 11 ± 2.4, µM, 10 ± 1.8 µM, 12 ± 1.2 µM and 54 ± 5.5 µM, respectively. The late NaV1.5 current through persistently opened channels by the sea anemone toxin ATX-II was inhibited as strongly as hERG with an IC50 of 5.5 ± 0.3 µM. In contrast, outward currents through Kir2.1 channels were reduced by only 28 ± 2.5 % at 100 µM clozapine. These data suggest that simultaneous inhibition of multiple cardiac ion channels underlies the low pro-arrhythmia risk profile of clozapine, although the submicromolar therapeutic free plasma concentrations in patients should be taken into account. How this balanced ion-channel profile translates into QT prolongation deserves further studies in integrated systems.

The CYP2C19*2 and CYP2C19*17 Polymorphisms Influence Responses to Clozapine for the Treatment of Schizophrenia.

IntroductionClozapine (CLZ) is the gold standard drug for treatment-refractory schizophrenia (TRS). However, approximately 30% of patients partially respond to CLZ, defining this subset with super refractory schizophrenia (SRS). Alterations in enzyme activity may affect CLZ responses; the CYP3A4, CYP1A2 and CYP2C19 genes are primarily responsible for CLZ metabolism.ObjectiveThe aim of this study was to assess if CYP2C19 variants were associated with TRS or SRS.MethodsCYP2C19*2 loss-of-function and CYP2C19*17 gain-of-function polymorphism genotype testing were performed in 108 individuals undergoing pharmacological treatment for TRS or SRS. DNA was extracted and polymorphisms were analyzed by polymerase chain reaction (PCR) and sequencing.ResultsCYP2C19*17 had positive correlations with SRS and lower Brief Psychiatric Rating Scale (BPRS) scores for TRS. In addition, CYP2C19*2 was associated with lower CLZ dosages for TRS.ConclusionThese results show that CYP2C19*2 and CYP2C19*17 polymorphisms influence CLZ responses during schizophrenia treatment.