Treatment-refractory Schizophrenia Research Articles

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.

Constipation screening in people taking clozapine: A diagnostic accuracy study

ObjectiveClozapine is the favoured antipsychotic for treatment-refractory schizophrenia but its safe use requires careful adverse-effect management. Clozapine-induced gastrointestinal hypomotility (CIGH or ‘slow-gut’) is one of the most common and serious of clozapine's adverse effects. CIGH can lead to paralytic ileus, bowel obstruction, gastrointestinal ischaemia, toxic megacolon, and death. Enquiring about constipation is a simple and commonly used screening method for CIGH but its diagnostic accuracy has not previously been assessed. MethodsFirst, we examined the reliability of asking about constipation compared with asking about Rome constipation criteria in inpatients treated with clozapine (n = 69). Second, we examined the diagnostic accuracy of (1) self-reported constipation and (2) the Rome criteria, compared with the reference standard of gastrointestinal motility studies. ResultsAfter 30 motility tests, it was clear constipation screening had very poor diagnostic properties in this inpatient group and the study was terminated. Although 73% of participants had objective CIGH on motility testing, only 26% of participants self-reported constipation, with sensitivity of 18% (95% CI: 5–40%). Specificity and positive predictive values were higher (95% CI: 63–100% and 40–100%, respectively). Adding in Rome criteria improved sensitivity to 50% (95% CI: 28.2–71.8%), but half the cases were still missed, making this no more accurate than tossing a coin. ConclusionsCIGH is often silent, with self-reported constipation having low sensitivity in its diagnosis. Treating CIGH based on self-reported symptoms questions will miss most cases. However, universal bowel motility studies are impractical. In the interests of patient safety, prophylactic laxatives are suggested for people taking clozapine.

Activation of Astroglial Connexin is Involved in Concentration-Dependent Double-Edged Sword Clinical Action of Clozapine.

Clozapine (CLZ) is a gold-standard antipsychotic against treatment-refractory schizophrenia, but is one of the most toxic antipsychotic agents. Pharmacological mechanisms of the double-edged sword clinical action of CLZ remain to be clarified. To explore the mechanisms of CLZ, the present study determined the astroglial transmission associated with connexin43 (Cx43), which is the most principal expression in astrocytes and myocardial cells, and expression of Cx43 in primary cultured astrocytes. Both acute and subchronic administrations of CLZ concentration-dependently increased Cx43-associated astroglial release of l-glutamate and d-serine, whereas therapeutic-relevant concentration of CLZ acutely did not affect but subchronically increased astroglial release. In contrast, after the subchronic administration of therapeutic-relevant concentration of valproate (VPA), acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43-associated astroglial releases. VPA increased Cx43 expression in cytosol fraction without affecting plasma membrane fraction, whereas CLZ increased Cx43 expression in both fractions. Acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43 expression in the plasma membrane fraction of astrocytes subchronically treated with VPA. The present findings suggest that CLZ-induced the activation of Cx43-associated channel activity and transported Cx43 to plasma membrane, probably contribute to the double-edged sword clinical action of CLZ, such as improvement of cognitive dysfunction and CLZ-induced myocarditis.

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.

Systematic review and meta-analysis of rates of clozapine-associated myocarditis and cardiomyopathy.

Clozapine is the most effective medication for treatment refractory schizophrenia, but is associated with cardiac adverse drug reactions. Myocarditis and cardiomyopathy are the most serious cardiac adverse drug reactions although reported rates of these conditions vary in the literature. We systematically reviewed and meta-analysed the event rates, the absolute death rates and case fatality rates of myocarditis and cardiomyopathy associated with clozapine. PubMed, EMBASE and PsycINFO were searched for studies that reported on the incidence of cardiomyopathy or myocarditis in people exposed to clozapine. Data were meta-analysed using a random effects model, with subgroup analysis on study size, time frame, region, quality, retrospective vs prospective, and diagnostic criteria of myocarditis or cardiomyopathy. 28 studies of 258,961 people exposed to clozapine were included. The event rate of myocarditis was 0.007 (95% confidence interval [CI] = [0.003, 0.016]), absolute death rate was 0.0004 (95% CI = [0.0002, 0.0009]) and case fatality rate was 0.127 (95% CI = [0.034, 0.377]). The cardiomyopathy event rate was 0.006 (95% CI = [0.002, 0.023]), absolute death rate was 0.0003 (95% CI = [0.0001, 0.0012]) and case fatality rate was 0.078 (95% CI = [0.018, 0.285]). Few included studies provided information on criteria for diagnosis of myocarditis and cardiomyopathy. Event rates of cardiomyopathy and myocarditis were higher in Australia. Clarity of diagnostic criteria for myocarditis remains a challenge. Observation bias may, in part, influence higher reported rates in Australia. Monitoring for myocarditis is warranted in the first 4 weeks, and treatment of comorbid metabolic syndrome and diabetes may reduce the risk of cardiomyopathy. The risks of myocarditis and cardiomyopathy are low and should not present a barrier to people with treatment refractory schizophrenia being offered a monitored trial of clozapine.

Management of clozapine treatment during the COVID-19 pandemic.

Clozapine is the only available treatment for refractory schizophrenia but its use involves frequent physical contact with healthcare workers for the purpose of mandatory blood monitoring. During the COVID-19 pandemic, patients taking clozapine will be self-isolating to reduce the risk of infection, not least because these patients are at high risk of serious illness and fatality because of high rates of diabetes, obesity and pulmonary disease and an increased risk of pneumonia. Problems may also arise because both clozapine-induced myocarditis and neutropenic sepsis share signs and symptoms with COVID-19 (fever, chest pain, dyspnoea, etc.). We recommend decreasing the frequency of physical contacts by extending the blood monitoring interval to 12 weeks in those patients taking clozapine for more than 1 year. To distinguish COVID-19 from clozapine-related physical adverse effects, we suggest an urgent antigen test alongside a full blood count. In those taking clozapine who develop COVID-19, we suggest continuing with clozapine whenever possible (even during ventilation), reducing the dose if necessary in line with blood assay results. Blood monitoring should continue but clozapine should only cease if there is a significant fall in neutrophils (COVID-19 is linked to lymphopenia but not neutropenia). To protect against the likelihood and severity of respiratory infection, we recommend the use of vitamin D in all clozapine patients. Initiation of clozapine is likely to remain problematic while the risk of infection remains, given the degree of physical contact required to assure safety.

An Evaluation of the Variation and Underuse of Clozapine in the United Kingdom

Background: 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 in the United Kingdom compared to other European countries, and the extent of any regional variation within the UK remains unclear. Methods: We obtained data relating to all clozapine prescribing in the UK from the relevant clozapine registries. We compared the UK rate of clozapine use per 100,000 population to that described in other European countries. We also examined regional variation in clozapine use across England, corrected for the known prevalence of Severe Mental Illness (SMI). Findings: Clozapine prescribing rate in the UK was lower than in several European countries. Only a third of patients eligible for clozapine were prescribed the drug whilst there was substantial variation in prescribing across different regions of England. Interpretation: There is clear regional inequity in access to the most effective treatment in refractory schizophrenia. Strategies to increase clozapine use, by overcoming both real and perceived barriers, are urgently necessary to reduce treatment inequity for patients with refractory schizophrenia. Funding Statement: No funding was received for this project. Declaration of Interests: None. Ethics Approval Statement: The study was approved by the Drugs and Therapeutics Committee of the South London and Maudsley NHS Foundation Trust.

Prediction of individual responses to electroconvulsive therapy in patients with schizophrenia: Machine learning analysis of resting-state electroencephalography

BackgroundElectroconvulsive therapy (ECT) has strong efficacy in patients with treatment refractory schizophrenia. However, access to ECT has been limited by high costs, professional labor, treatment duration, and significant adverse effects. To provide support for the decision to perform ECT, we aimed to predict individual responses to ECT among patients with schizophrenia using machine learning analysis of resting-state electroencephalography (EEG). MethodsForty-seven patients diagnosed with schizophrenia or schizoaffective disorder with EEG recordings before the course of ECT were treated at Seoul National University Hospital. Among these patients, 29 were responders who showed scores of 3 or less on the Clinical Global Impression Severity scale after the course of ECT. Transfer entropy (TE), which represents information flow, was extracted from baseline EEG data and used as a feature. Feature selection was performed with four methods, including Random Subset Feature Selection (RSFS). The random forest classifier was used to predict individual ECT responses. ResultsThe averaged TE, especially in frontal regions, was higher in ECT responders than in nonresponders. A predictive model using the RSFS method classified ECT responders and nonresponders with 85.3% balanced accuracy, 85.2% accuracy, 88.7% sensitivity, and 81.8% specificity. The positive predictive value was 82.6%, and the negative predictive value was 88.2%. ConclusionsThe results of the current study suggest that higher effective connectivity in frontal areas may be associated with a favorable ECT response. Furthermore, personalized decisions to perform ECT in clinical practice could be augmented by resting-state EEG biomarkers of the ECT response in schizophrenia patients.

Efficacy of Asenapine in Schizophrenia Resistant to Clozapine Combined with Electroconvulsive Therapy: A Case Report.

Schizophrenic patients resistant to antipsychotics are diagnosed as having treatment-refractory schizophrenia, and they are treated with clozapine. However, clozapine is sometimes combined with electroconvulsive therapy (ECT) if clozapine monotherapy fails. In this report, a severe treatment-refractory schizophrenic patient who did not respond to clozapine even with ECT, but who recovered with asenapine monotherapy, is presented. Asenapine, considered a serotonin spectrum dopamine modulator, is a new atypical antipsychotic with unique pharmacological features that is used not only for schizophrenia, but also for bipolar disorder. The unique features of asenapine may be effective for some treatment-refractory schizophrenic patients.

Oscillatory biomarkers of early auditory information processing predict cognitive gains following targeted cognitive training in schizophrenia patients

Auditory-based targeted cognitive training (TCT) is an effective and well-validated intervention for the treatment of cognitive impairment in schizophrenia patients. Improvements in higher-order cognition, reductions in symptom severity, and increases in psychosocial functioning secondary to TCT are thought to be driven by “bottom-up” enhancement of early auditory information processing (EAIP). Despite strong evidence of efficacy at the group level, there is significant variability in response to TCT, with few well-delineated biomarkers for predicting individual benefit. EEG biomarkers of EAIP are indicators of early-treatment sensitivity that predict full-course TCT outcome; however, further characterization is necessary for biomarker-guided clinical trials. The current study examined baseline and early-treatment sensitivity (i.e., change from baseline after 1 h) in theta band oscillatory activity to deviant stimuli as moderators of full course (30 h) TCT response in treatment-refractory schizophrenia patients randomly assigned to receive either treatment-as-usual (TAU; n = 22) or TAU augmented with TCT (n = 30). Theta evoked power and phase locking at baseline predicted patient improvements in global cognitive function after 30 h of TCT. Decrease in theta activity to deviant stimuli after 1 h of TCT predicted improvements in verbal learning after 30 h. Exploratory analyses using EEG composite scores had high levels of sensitivity and specificity for identifying patients most likely to benefit from TCT. The integrity of baseline neurophysiologic activity associated with EAIP, as well as the sensitivity of the underlying circuity to change, likely reflects an intermediate therapeutic process underlying the effectiveness of TCT that can be used to predict patient response to treatment.

Feasibility of myelosuppressive chemotherapy in psychiatric patients on clozapine: A systematic review of the literature.

Clozapine is the favoured antipsychotic for treatment-refractory schizophrenia, but has a 1%-2% incidence of agranulocytosis. Patients who require chemotherapy therefore pose a unique management dilemma for haematologists, oncologists and psychiatrists. The Ovid MEDLINE and EMBASE databases were searched to identify reports describing use of clozapine concurrent with chemotherapy until 31 March 2019. The following terms (with variations) were used: neoplasm, cancer, tumour, malignancy, chemotherapy, antineoplastic and clozapine. Twenty-seven cases were included after reviewing titles and abstracts for relevance. Fifteen patients had solid organ tumours, and 12 had haematological malignancies, including three who underwent autologous haematopoietic stem cell transplantation (AutoHSCT). Clozapine was continued in 14 cases (albeit dose reduced in 2), with a reported median neutropaenic nadir of 0.29×109 /L (range 2.2 to <0.0×109 /L). Clozapine was discontinued or substituted for another antipsychotic in the remaining 13 cases, all except one of whom experienced marked psychiatric deterioration. The only neutropenia-related complication was one case of bacteraemia with high-dose melphalan conditioning for AutoHSCT. These findings argue in favour of clozapine continuation during chemotherapy. Further research is needed to develop guidance to minimise the risk of neutropenia-related complications from concurrent treatment.

Clozapine Normalizes a Glutamatergic Transmission Abnormality Induced by an Impaired NMDA Receptor in the Thalamocortical Pathway via the Activation of a Group III Metabotropic Glutamate Receptor.

Pharmacological mechanisms of gold-standard antipsychotics against treatment-refractory schizophrenia, such as clozapine (CLZ), remain unclear. We aimed to explore the mechanisms of CLZ by investigating the effects of MK801 and CLZ on tripartite synaptic transmission in the thalamocortical glutamatergic pathway using multi-probe microdialysis and primary cultured astrocytes. l-glutamate release in the medial prefrontal cortex (mPFC) was unaffected by local MK801 administration into mPFC but was enhanced in the mediodorsal thalamic nucleus (MDTN) and reticular thalamic nucleus (RTN) via GABAergic disinhibition in the RTN–MDTN pathway. The local administration of therapeutically relevant concentrations of CLZ into mPFC and MDTN increased and did not affect mPFC l-glutamate release. The local administration of the therapeutically relevant concentration of CLZ into mPFC reduced MK801-induced mPFC l-glutamate release via presynaptic group III metabotropic glutamate receptor (III-mGluR) activation. However, toxic concentrations of CLZ activated l-glutamate release associated with hemichannels. This study demonstrated that RTN is a candidate generator region in which impaired N-methyl-d-aspartate (NMDA)/glutamate receptors likely produce thalamocortical hyperglutamatergic transmission. Additionally, we identified several mechanisms of CLZ relating to its superiority in treatment-resistant schizophrenia and its severe adverse effects: (1) the prevention of thalamocortical hyperglutamatergic transmission via activation of mPFC presynaptic III-mGluR and (2) activation of astroglial l-glutamate release associated with hemichannels. These actions may contribute to the unique clinical profile of CLZ.

Psychiatrists' attitude towards the use of clozapine in the treatment of refractory schizophrenia: A nationwide survey

ObjectivesClozapine is the most effective treatment for refractory schizophrenia, yet it remains underused in clinical practice. The current study examined the awareness, familiarity and attitude of a nationwide sample of Israeli psychiatrists regarding the use of clozapine. MethodsData were collected using questionnaires, completed by 295 psychiatrists. Participants were asked to score questions regarding clozapine procedures; familiarity with guidelines, drug properties, prescription and attitude towards specialized clozapine resources. ResultsAbout half (53.3%) of the psychiatrists reported initiating treatment with clozapine according to the guidelines, whereas 33% reported that they administered clozapine only after three or more unsuccessful antipsychotic treatments. Surprisingly, availability of specialized resources for clozapine treatment (such as clozapine clinics) was associated with delayed initiation of clozapine treatment, and a lower rate of clozapine administration. Barriers to clozapine use included concerns about patient adherence, side effects and partial compliance with the required blood monitoring. ConclusionsDelaying or avoiding clozapine treatment to potentially eligible patients, despite familiarity with the drug efficacy and treatment guidelines, is a major mental health concern. However, executive allocation of resources to support the use of clozapine may be ineffective in promoting clozapine use.

Treatment Strategies for Clozapine-Induced Sialorrhea: A Systematic Review and Meta-analysis.

Clozapine is the most effective medication for treatment-refractory schizophrenia. However, it has a high burden of adverse events, including common adverse events such as sialorrhea. Sialorrhea can lead to severe physical complications such as aspiration pneumonia, as well as psychological complications including embarrassment and low self-esteem. Compromised adherence and treatment discontinuation can occur due to intolerability. There have been no meta-analyses examining strategies to mitigate clozapine-induced sialorrhea. We systematically searched Chinese and Western research databases for randomised controlled trials examining agents for clozapine-induced sialorrhea. No limit to language or date were applied to the search. Where sufficient data for individual agents was available, pairwise meta-analyses were conducted. Results were provided as risk ratios and number needed to treat. Sensitivity analysis was conducted by study quality. Adverse events were provided as number needed to harm. 19 studies provided data for use in the meta-analysis. Improvement in clozapine-induced sialorrhea was seen in meta-analyses of propantheline (studies=6, risk ratio [RR] 2.38, 95% confidence interval [CI] 1.52-3.73; number needed to treat [NNT] 3, 95% CI 1.9-2.7), diphenhydramine (studies=5, RR 3.09, 95% CI 2.36-4.03; NNT 2, 95% CI 1.5-2.0), chlorpheniramine (studies=2, RR 2.37, 95% CI 1.59-3.55; NNT 3, 95% CI 1.6-3.5), and benzamide derivatives (odds ratio [OR] 6.93, 95% CI 3.03-15.86). When meta-analyses were limited to high-quality studies, all these results remained significant. Single studies of benzhexol, cyproheptadine, doxepin and Kongyan Tang showed promise. Propantheline increased rates of constipation with a number needed to harm (NNH) of 9 (95% CI 4.2-204.1). Clozapine-induced sialorrhea is a potentially serious adverse event. Included studies in this meta-analysis were limited by poor study quality. Diphenhydramine, chlorpheniramine and benzamide derivatives appear to have the best supporting evidence and lowest reported adverse events. Caution should be exercised when using propantheline given its increased risk of constipation.

Verbal learning deficits associated with increased anticholinergic burden are attenuated with targeted cognitive training in treatment refractory schizophrenia patients

Targeted cognitive training (TCT) has been reported to improve verbal learning deficits in patients with schizophrenia (SZ). Despite positive findings, it is not clear whether demographic factors and clinical characteristics contribute to the success of TCT on an individual basis. Medication-associated anticholinergic burden has been shown to impact TCT-associated verbal learning gains in SZ outpatients, but the role of anticholinergic medication burden on TCT gains in treatment refractory SZ patients has not been described. In this study, SZ patients mandated to a locked residential rehabilitation center were randomized to treatment as usual (TAU; n=22) or a course of TAU augmented with TCT (n=24). Anticholinergic medication burden was calculated from medication data at baseline and follow-up using the Anticholinergic Cognitive Burden (ACB) Scale. MATRICS Consensus Cognitive Battery Verbal Learning domain scores were used as the primary outcome variable. The TAU and TCT groups were matched in ACB at baseline and follow-up. While baseline ACB was not associated with verbal learning in either group, increases in ACB over the course of the study were significantly associated with deterioration of verbal learning in the TAU group (r=−0.51, p=0.02). This was not seen in subjects randomized to TCT (r=−0.13, p=0.62). Our results suggest that TCT may blunt anticholinergic medication burden associated reduction in verbal learning in severely disabled SZ inpatients.

The impact of clozapine initiation and cessation on psychiatric hospital admissions and bed days: a mirror image cohort study.

Clozapine is the most effective medication for the positive symptoms of treatment-refractory schizophrenia. Although clozapine use is associated with fewer admissions, less is known about the impact of clozapine cessation on hospitalisation. The aims of this study were to investigate whether clozapine-reduced psychiatric inpatient admissions and bed days, and investigate patient factors associated with these changes from a sample of 1906 people commenced on clozapine. All people commencing clozapine during an acute hospitalisation over a 10-year period in Queensland, Australia, were included in this retrospective cohort study. A mirror image design was used to compare psychiatric bed days and hospitalisations 2years before and after clozapine treatment, and the impact of clozapine continuation or early cessation. Changes in psychiatric bed days and hospitalisations were analysed using linear regression, adjusting for the duration on clozapine, sex, age, indigenous status, country of origin and time to clozapine commencement. There was a significant reduction in bed days (29.55days vs 24.46days, p< 0.001) and admissions (2.27 vs 1.87< 0.001) associated with clozapine commencement. This remained significant among clozapine continuers, but not among those with early cessation. Longer duration on clozapine was associated with greater reductions in psychiatric bed days and admissions. Age, sex and time to clozapine commencement, indigeneity and country of origin did not impact outcomes. Longer clozapine therapy led to a greater reduction in psychiatric bed days and hospitalisations. Early cessation was associated with a return to pre-clozapine levels of bed days and admissions.

Resistance is not futile: treatment-refractory schizophrenia – overview, evaluation and treatment

ABSTRACTIntroduction: Schizophrenia is a debilitating condition with three main symptom domains: positive, negative, and cognitive. Approximately one-third of persons with schizophrenia will fail to respond to treatment. Growing evidence suggests that treatment-resistant (refractory) schizophrenia (TRS) may be a distinct condition from treatment-respondent schizophrenia. There is limited evidence on effective treatments for TRS, and a lack of standardized diagnostic criteria for TRS has hampered research.Areas covered: A literature search was conducted using Pubmed.gov and the EMBASE literature database. The authors discuss the pragmatic definitions of TRS and review treatments consisting of antipsychotic monotherapy and augmentation strategies.Expert opinion: Currently available first-line antipsychotic medications are generally effective at treating the positive symptoms of schizophrenia, leaving residual negative and cognitive symptoms. Before diagnosing TRS, rule out any pharmacodynamic or pharmacokinetic failures. Most evidence supports clozapine as having the most efficacy for TRS. If clozapine is used, it should be optimized, and serum levels should be at least 350–420 ng/ml. If clozapine is unable to be tolerated, some evidence suggests olanzapine at dosages up to 40mg/day can be useful. Augmentation strategies have weak evidence. Tailoring treatment to the specific domain is the preferred approach, and the use of a structured assessment/outcome measure is encouraged.

Neurophysiologic measures of target engagement predict response to auditory-based cognitive training in treatment refractory schizophrenia.

Cognitive impairment is a core feature of schizophrenia and a strong predictor of psychosocial disability. Auditory-based targeted cognitive training (TCT) aims to enhance verbal learning and other domains of cognitive functioning through "bottom-up" tuning of the neural systems underlying early auditory information processing (EAIP). Although TCT has demonstrated efficacy at the group level, individual response to TCT varies considerably, with nearly half of patients showing little-to-no benefit. EEG measures of EAIP, mismatch negativity (MMN) and P3a, are sensitive to the neural systems engaged by TCT exercises and might therefore predict clinical outcomes after a full course of treatment. This study aimed to determine whether initial malleability of MMN and P3a to 1-h of auditory-based TCT predicts improvements in verbal learning and clinical symptom reduction following a full (30-h) course of TCT. Treatment refractory patients diagnosed with schizophrenia were randomly assigned to receive treatment-as-usual (TAU; n = 22) or TAU augmented with TCT (n = 23). Results indicated that malleability (i.e., change from baseline after the initial 1-h dose of TCT) of MMN and P3a predicted improvements in verbal learning as well as decreases in the severity of positive symptoms. Examination of MMN and P3a malleability in patients after their first dose of TCT can be used to predict clinical response to a full course of treatment and shows promise for future biomarker-informed treatment assignment.

Weight gain correlated with decrease in clozapine/N-desmethyl-clozapine ratio in a man with treatment-refractory schizophrenia

Weight gain correlated with decrease in clozapine/N-desmethyl-clozapine ratio in a man with treatment-refractory schizophrenia

Clozapine Pharmacogenetic Studies in Schizophrenia: Efficacy and Agranulocytosis.

Clozapine is an efficacious atypical antipsychotic for treatment-refractory schizophrenia. Clinical response and appearance of adverse events vary among individual patients receiving clozapine, with genetic and non-genetic factors potentially contributing to individual variabilities. Pharmacogenetic studies investigate associations between genetic variants and drug efficacy and toxicity. To date, most pharmacogenetic studies of clozapine have been conducted through candidate gene approaches. A recent advance in technology made it possible to perform comprehensive genetic mapping underlying clinical phenotypes and outcomes, which allow novel findings beyond biological hypotheses based on current knowledge. In this paper, we will summarize the studies on clozapine pharmacogenetics that have extensively examined clinical response and agranulocytosis. While there is still limited evidence on clozapine efficacy, recent genome-wide studies provide further evidence of the involvement of the human leukocyte antigen (HLA) region in clozapine-induced agranulocytosis.