Treatment-resistant Psychosis Research Articles

A retrospective study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis

Clozapine is uniquely effective in treatment-resistant psychosis but remains underutilised, partly owing to psychotic symptoms leading to non-adherence to oral medication. An intramuscular formulation is available in the UK but outcomes remain unexplored. This was a retrospective clinical effectiveness study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis over a 3-year period. Successful initiation of oral clozapine after intramuscular prescription was the primary outcome. Secondary outcomes included all-cause clozapine discontinuation 2 years following initiation, and 1 year after discharge. Discontinuation rates were compared with a cohort prescribed only oral clozapine. Propensity scores were used to address confounding by indication. Among 39 patients prescribed intramuscular clozapine, 19 received at least one injection, whereas 20 accepted oral clozapine when given an enforced choice between the two. Thirty-six (92%) patients successfully initiated oral clozapine after intramuscular prescription; three never transitioned to oral. Eight discontinued oral clozapine during the 2-year follow-up, compared with 83 out of 162 in the comparator group (discontinuation rates of 24% and 50%, respectively). Discontinuation rates at 1-year post-discharge were 21%, compared with 44% in the comparison group. Intramuscular clozapine prescription was associated with a non-significantly lower hazard of discontinuation 2 years after initiation (hazard ratio 0.39, 95% CI 0.14-1.06) and 1 year after discharge (hazard ratio 0.37, 95% CI 0.11-1.24). The only reported adverse event specific to the intramuscular formulation was injection site pain and swelling. Intramuscular clozapine prescription allowed transition to oral maintenance in an initially non-adherent cohort. Discontinuation rates were similar to patients only prescribed oral clozapine and comparable to existing literature.

The introduction of mindfulness groups to a psychiatric rehabilitation in-patient setting: a feasibility study

BackgroundPatients within psychiatric rehabilitation services have multiple, complex and enduring difficulties, and are frequently described as ‘treatment resistant’. This group have diagnoses of major mental health conditions, most commonly schizophrenia, often alongside a history of complex trauma, co-morbid alcohol/ substance misuse, and cognitive impairment. There is no known effective medical treatment other than Clozapine in this patient group, however, there is preliminary evidence that mindfulness can help individuals with psychosis by improving their ability to cope with stressful internal experiences. This study aimed to determine if mindfulness practice groups are an acceptable therapeutic intervention in an in-patient rehabilitation setting. The study also aimed to monitor the well-being of those who participated.MethodsMindfulness practice groups were offered three times weekly on a 15-bedded rehabilitation ward in a psychiatric hospital over 5 months, and weekly in a second ward over an 18 month period. The sessions were delivered by Clinical Psychologists in accordance with adaptations for a psychosis population. Attendance data were gathered on both wards and additional measures of well-being were collected on one ward. Qualitative interviews were conducted with a sample of patients, group facilitators, and staff, to provide supplementary information about the acceptability of the intervention.ResultsIn both wards around two thirds (65, 67%) of in-patients attended at least one group and smaller proportion (around a third) went on to attend regularly. There was no discernible impact on well-being using the Warwick-Edinburgh well-being scale. Qualitative interviews suggested a number of benefits to individuals attending as well as the potential for groups to enhance the therapeutic culture within wards.ConclusionsClinical guidelines suggest that all patients with a diagnosis of psychosis should have access to psychological therapies, but delivering psychological therapy within an in-patient rehabilitation setting can be challenging. This preliminary feasibility study suggests that mindfulness practice groups are an acceptable intervention, and that further research to look at the effectiveness of mindfulness for symptoms of treatment-resistant psychosis is both possible and merited.

M170. GENETIC CHARACTERIZATION OF A COHORT OF PATIENTS AFFECTED BY SCHIZOPHRENIA. THE ROLE FOR RARE STRUCTURAL VARIANTS IN MODULATING TREATMENT RESISTANT ENDOPHENOTYPES: PRELIMINARY DATA

BackgroundSchizophrenia (SCZ) is a debilitating mental illness characterized by a highly complex, heterogeneous, non-mendelian genetic background. Recent progress in dissecting genetic architecture of SCZ has accelerated over the last decade due to new advanced technologies. Genome-Wide Association Studies (GWAS) on extremely large samples of patients identified and replicated hundreds of Single-Nucleotide Polymorphism (SNPs), each exhibiting only a modest effect. The analysis of genomic Copy Number Variations (CNVs) clarified the role of rare structural variants conferring significant risk by disrupting multiple genes involved in neurodevelopmental pathways, and linked to SCZ. In this scenario, the aim of our study is to carry out a genetic characterization of a cohort of patients affected by SCZ, in order to assess the risk of recurrence, to elucidate putative pathogenetic mechanisms and, whenever possible, to conceive tailored interventions and therapies.Methods34 patients (8 women and 26 men) affected by SCZ and admitted to Day Hospital at Psychiatric Division for Treatment Resistant Psychosis of the University of Naples Federico II were recruited, and underwent: i) psychopathological evaluation and assessment of clinical response to antipsychotics; ii) genetic counseling; iii) further diagnostic investigation by using Comparative Genomic Hybridization (CGH) + Single Nucleotide Polymorphism (SNP) microarray with 2x400k Agilent’s platform “GenetiSure” for detecting unbalanced chromosomal abnormalities and regions of homozygosity (ROHs).ResultsStructural pathogenetic rearrangements resulted in 9 (27%) patients. Those identified were the following: 15q13.3 deletion, 16p13.11 duplication, 22q11.22 deletion (TOP3B), 22q11.22 (PRODH, DGCR5, DGCR6), RBFOX1 deletion, TCF4 deletion, derivative X chromosome (X;Y translocation).Potentially pathogenic rearrangements, involving genes associated with psychiatric disorders or implicated in neurodevelopment, resulted in 15 patients (44%).No relevant CNVs were detected in 10 patients (29%), although they showed the presence of ROHs that may contain susceptibility loci, since many neurodevelopmental genes map onto or near these specific regions.Certain of these rearrangements occur in many patients, and certain patients showed likewise multiple rearrangements.DiscussionThe analysis of CNVs and SNPs allowed us to characterize the genetic disease structure in the whole cohort of patients and helped to refine the diagnosis in a few cases, thereby ascertaining an underlying specific genetic condition. A further extension of the study, in terms of sample size and more accurate investigations (i.e genetic mapping of ROHs) is underway. According to literature, rare risk-associated CNVs account for 2% of SCZ cases, but their higher prevalence (27%) in our sample may be influenced by a larger percentage of Treatment Resistant and more severely ill patients (since they were recruited in a highly specialized Unit for Treatment Resistant Psychosis). Therefore, our future purpose is to demonstrate a robust genetic modulation of Treatment Resistant endophenotypes of SCZ.Moreover, we believe that the role of genetic counseling in psychiatric services should be emphasized, and that genetic testing in this field should not be restricted to suspected childhood neuropsychiatric disorders. According to the neurodevelopmental hypothesis of SCZ, that suggests a brain development disruption in early life (due to genetic and early environmental factors), prompting to a subsequent later emergence of the disease in adulthood, even chronic complex adult mental illness, such as SCZ, deserves detailed investigations and a more exhaustive genetic evaluation.

S202. PROXIMAL AND DISTAL FACTORS ASSOCIATED WITH CLOZAPINE EXPOSURE IN A SAMPLE OF TREATMENT RESISTANT AND TREATMENT RESPONSIVE SCHIZOPHRENIA PATIENTS

BackgroundClozapine is the gold standard for Treatment Resistant Schizophrenia (TRS) and its use is strongly recommended after failure of two/three antipsychotics. Nonetheless, prescribing trends do not appear to follow the global guidelines and switching to clozapine is often delayed or improper. Reasons for clozapine underuse are quite understood, whereas little is known on clozapine misuse. In fact, more stringent operative criteria to define TRS should be used in clinical practice, taking advantage of standardized assessment tools in order to avoid false TRS positive.In these perspectives, we studied the patterns of clozapine prescription in a sample of TRS and non-TRS patients, in order to identify psychopathological variables associated with lifetime exposure to clozapine.Methods198 consecutive patients have been screened for eligibility criteria from 2016 until 2019 at Treatment Resistant Psychosis Centre of the University of Naples “Federico II”. Only stabilized schizophrenic patients aged between 18 and 65 were enrolled. All relevant clinical-demographic data were recorded. TRS diagnosis was based on TRRIP working group operational criteria and clear pseudo-resistance factors were excluded. Patients were subdivided into two groups: those having received or currently under clozapine treatment (eCLZ) and those never treated by clozapine (nCLZ). Patients were assessed for psychotic symptoms (PANSS), cognitive performances (BACS), neurological soft signs (NES), functional capacity (UPSA), social functioning (PSP and SLOF scales), and severity of illness (CGI-S).ResultsAmong the patients included (92), eCLZ were 50 (54.3%), of which 20% being non-TRS. Compared to nCLZ, eCLZ had a significantly earlier age at onset, more hospitalizations, higher daily antipsychotic doses; eCLZ patients had significantly higher scores on the CGI-S, PANSS total, PANSS Negative, General Psychopathology and PAUSS subscale and, according to the Five Factor PANSS Model, higher score on Negative and Disorganization Factors; eCLZ had also more impaired Working Memory performances, higher NES Total score, lower PSP and all SLOF areas scores, except Area4.Then we use univariate and multivariate analysis to delineate predictors of clozapine exposure and to evaluate whether these factors may organize in proximal (independent) and distal (mediated) associations. We found five independently associated variables that mediate all the other ones: high antipsychotic doses, higher disease severity, suicide attempts, impaired working memory, more severe Stereotyped Thinking.DiscussionWhile it is expected that some TRS patients might not receive clozapine, the observation that non-TRS patients had been exposed to clozapine may surprise. A possible explanation may be the lack of systematized procedure to diagnose TRS, which is often merely coincident with a nonspecific lack of response to antipsychotics.Due to mediation analysis, we further gained insights into the hierarchy of these variables’ impact on clozapine prescription and we finally compose a complex network of proximal and distal factors predicting clozapine exposure in schizophrenic patients.The above-mentioned independent variables significantly associated with clozapine exposure let intend that eCLZ patients may belong to a subset of more severely ill ones, beyond reaching the response threshold.Earlier onset patients may suffer from a more severe disease, be more prone to suicide attempts, and less responsive to antipsychotics.This result needs to be replicated in wider samples, and this relevant therapeutic issue should be further debated in order to gather robust evidence to support or discourage clozapine off-label use and misuse.

Increasing the Clinical Psychiatric Knowledge Base About Pathogenic Copy Number Variation.

Specific copy number variants (CNVs) have been robustly associated with intellectual disability, autism, and schizophrenia. Most of the literature focus has been on documenting the existence of these phenomena. There are few data to guide therapeutic choices for these “orphan” diseases. We call for systematic and longitudinal case reports which, if carefully conducted, may provide crucial initial knowledge to guide therapeutics. We provide a step-by-step overview, a tailored set of consensus criteria for high-quality case reports, and a specific set of learning resources.

Physical health trajectories of young people commenced on clozapine.

Clozapine is the most effective antipsychotic medication, but it has the highest propensity for metabolic side effects. A clozapine clinic was established within an early intervention for psychosis service to facilitate the timely commencement of clozapine and to manage the associated adverse effects. This study describes the changes in the weight, body mass index (BMI), waist circumference and blood pressure after 6 months in young people commenced on clozapine. This was a prospective cohort study of all young people, aged 15-24 years, commenced on clozapine within an early intervention service in Melbourne, Australia, between 01.04.2016 and 30.06.2018. Continuous data were analyzed with paired t-test and categorical with Wilcoxon signed-rank test. Twenty-six young people received 6 months of treatment with clozapine, of whom the mean age was 19.8 years (s.d. ±3.1) and 66.7% were male. After 6 months, the mean weight gain was 5.1 kg (s.d. ±10.1 kg) and over half (53.8%) gained clinically significant weight. The proportion of young people classified as either overweight or obese rose from 69.2% to 88.5% (p = 0.006). The proportion of young people with a waist circumference above the recommended parameters increased from 57.9% to 78.9% (p = 0.008). Hypertension was present in 30%, and after 6 months, 45% had hypertension (p = 0.64). Metformin was prescribed to 34.6%, typically to those with the greatest and most rapid weight gain. Among young people with treatment resistant psychosis, clozapine is associated with significant metabolic side effects in the early stages of commencement. More interventions aimed at attenuating this weight gain are needed.

Preliminary examination of the validity of the NIH toolbox cognition battery in treatment-resistant psychosis

Objective: Prior research has suggested that treatment-resistant psychosis (TRP) may be a categorically distinct subtype from treatment-responsive psychotic disorders. However, relatively few studies have investigated the cognitive profile of individuals with TRP. Moreover, no prior studies have investigated the effectiveness of using the NIH Toolbox Cognition Battery (NTCB) for assessing cognition among psychiatric inpatients despite its promising efficiency and practicality in such settings. The current study aimed to investigate the validity of the NTCB and the associated cognitive profile of inpatients with TRP.Methods: Participants (N = 38) were administered the NTCB and a neuropsychological test battery. The Positive and Negative Syndrome Scale and the Routine Assessment of Patient Progress measured psychosis symptomatology and daily functioning, respectively.Results: Results showed deficits relative to normative values in fluid cognitive abilities using the NTCB, as predicted. There was strong convergent validity and adequate divergent validity between the NTCB subtests and corresponding neuropsychological measures, though no NTCB subtest correlated with performance on the Wisconsin Card Sorting Task. NTCB performance correlated with positive and disorganized symptoms of psychosis as well as daily functioning.Conclusions: Taken together, the NTCB appears to be a relatively strong tool for cognitive screening among psychiatric inpatients and may be used to identify which patients might benefit from further neuropsychological evaluation.

Low-Dose Lithium for Long-Term Treatment of Clozapine- Induced Neutropenia: A Case Series

Background: Treatment-resistant psychosis makes schizophrenia a disabling and costly illness. Clozapine is an effective treatment for treatment-resistant psychosis, though it is underutilized mainly due to prescribing providers’ fear of a serious yet uncommon complication, clozapine-induced neutropenia. Clozapine-induced neutropenia predisposes patients to potentially life-threatening infections leading prescribers to stop use when blood counts start to drop even well above the recommended cut-off point. Colonystimulating factors are effective options for reducing risk and duration of neutropeniarelated events though they add a significant cost burden to the patient and healthcare system. There is a great need for feasible and cost-effective pharmacotherapies in the mental health care setting for the management of clozapine-induced neutropenia. Objective: We evaluated adjunctive use of lithium when prescribed at a low-dose to stabilize dropping blood count in patients receiving clozapine for treatment-resistant psychosis. Methods & Results: A case series analysis of three patients who were followed in a mental health outpatient clinic for the management of schizophrenia. Blood counts of all the patients were stabilized by low-dose lithium treatment and continued to receive long term treatment of clozapine. Conclusion: Results suggest low-dose lithium as a feasible and cost-effective pharmacotherapeutic option enabling the continuation of clozapine, an effective treatment for treatment-resistant psychosis.

Prevalence of treatment-resistant psychoses in the community: A naturalistic study.

Treatment-resistant schizophrenia (TRS) is a major cause of disability. Clozapine is currently the only antipsychotic medication licensed for its treatment. However, the rate of treatment resistance among outpatients with schizophrenia or other psychoses, and the rate of use of clozapine among them, is not known. The aims of this study are (a) to determine the point prevalence of treatment-resistant psychosis in a community sample, and (b) to determine the number of patients with TRS who have never had a clozapine trial. Clinico-demographic data were extracted from the case notes for 202 patients from two community mental-health teams. We found that 56% (99/176) had a diagnosis of TRS, and 52% (51/99) of these patients had never been treated with clozapine. Patients of non-white ethnicity were less likely to have had a clozapine trial (p=0.009). The point prevalence of treatment resistance within the bipolar affective disorder sample was 19% (5/26). These findings suggest that TRS is common in the community mental-health team, and a large proportion of these patients have not received clozapine. These findings indicate that identifying and treating treatment resistance should be a focus of community services for schizophrenia.

Clinical indicators of treatment-resistant psychosis.

Around 30% of individuals with schizophrenia remain symptomatic and significantly impaired despite antipsychotic treatment and are considered to be treatment resistant. Clinicians are currently unable to predict which patients are at higher risk of treatment resistance. To determine whether genetic liability for schizophrenia and/or clinical characteristics measurable at illness onset can prospectively indicate a higher risk of treatment-resistant psychosis (TRP). In 1070 individuals with schizophrenia or related psychotic disorders, schizophrenia polygenic risk scores (PRS) and large copy number variations (CNVs) were assessed for enrichment in TRP. Regression and machine-learning approaches were used to investigate the association of phenotypes related to demographics, family history, premorbid factors and illness onset with TRP. Younger age at onset (odds ratio 0.94, P = 7.79 × 10-13) and poor premorbid social adjustment (odds ratio 1.64, P = 2.41 × 10-4) increased risk of TRP in univariate regression analyses. These factors remained associated in multivariate regression analyses, which also found lower premorbid IQ (odds ratio 0.98, P = 7.76 × 10-3), younger father's age at birth (odds ratio 0.97, P = 0.015) and cannabis use (odds ratio 1.60, P = 0.025) increased the risk of TRP. Machine-learning approaches found age at onset to be the most important predictor and also identified premorbid IQ and poor social adjustment as predictors of TRP, mirroring findings from regression analyses. Genetic liability for schizophrenia was not associated with TRP. People with an earlier age at onset of psychosis and poor premorbid functioning are more likely to be treatment resistant. The genetic architecture of susceptibility to schizophrenia may be distinct from that of treatment outcomes.

A rare case of Huntington's disease presenting with treatment-resistant psychosis.

A rare case of Huntington's disease presenting with treatment-resistant psychosis.

Neuropsychological function at first episode in treatment-resistant psychosis: findings from the ÆSOP-10 study.

Neuropsychological investigations can help untangle the aetiological and phenomenological heterogeneity of schizophrenia but have scarcely been employed in the context of treatment-resistant (TR) schizophrenia. No population-based study has examined neuropsychological function in the first-episode of TR psychosis. We report baseline neuropsychological findings from a longitudinal, population-based study of first-episode psychosis, which followed up cases from index admission to 10 years. At the 10-year follow up patients were classified as treatment responsive or TR after reconstructing their entire case histories. Of 145 cases with neuropsychological data at baseline, 113 were classified as treatment responsive, and 32 as TR at the 10-year follow-up. Compared with 257 community controls, both case groups showed baseline deficits in three composite neuropsychological scores, derived from principal component analysis: verbal intelligence and fluency, visuospatial ability and executive function, and verbal memory and learning (p values⩽0.001). Compared with treatment responders, TR cases showed deficits in verbal intelligence and fluency, both in the extended psychosis sample (t = -2.32; p = 0.022) and in the schizophrenia diagnostic subgroup (t = -2.49; p = 0.017). Similar relative deficits in the TR cases emerged in sub-/sensitivity analyses excluding patients with delayed-onset treatment resistance (p values<0.01-0.001) and those born outside the UK (p values<0.05). Verbal intelligence and fluency are impaired in patients with TR psychosis compared with those who respond to treatment. This differential is already detectable - at a group level - at the first illness episode, supporting the conceptualisation of TR psychosis as a severe, pathogenically distinct variant, embedded in aberrant neurodevelopmental processes.

Confused Connections? Targeting White Matter to Address Treatment Resistant Schizophrenia.

Despite development of comprehensive approaches to treat schizophrenia and other psychotic disorders and improve outcomes, there remains a proportion (approximately one-third) of patients who are treatment resistant and will not have remission of psychotic symptoms despite adequate trials of pharmacotherapy. This level of treatment response is stable across all stages of the spectrum of psychotic disorders, including early phase psychosis and chronic schizophrenia. Our current pharmacotherapies are beneficial in decreasing positive symptomology in most cases, however, with little to no impact on negative or cognitive symptoms. Not all individuals with treatment resistant psychosis unfortunately, even benefit from the potential pharmacological reductions in positive symptoms. The existing pharmacotherapy for psychosis is targeted at neurotransmitter receptors. The current first and second generation antipsychotic medications all act on dopamine type 2 receptors with the second generation drugs also interacting significantly with serotonin type 1 and 2 receptors, and with varying pharmacodynamic profiles overall. This focus on developing dopaminergic/serotonergic antipsychotics, while beneficial, has not reduced the proportion of patients experiencing treatment resistance to date. Another pharmacological approach is imperative to address treatment resistance both for response overall and for negative symptoms in particular. There is research suggesting that changes in white matter integrity occur in schizophrenia and these may be more associated with cognition and even negative symptomology. Here we review the evidence that white matter abnormalities in the brain may be contributing to the symptomology of psychotic disorders. Additionally, we propose that white matter may be a viable pharmacological target for pharmacoresistant schizophrenia and discuss current treatments in development for schizophrenia that target white matter.

Clozapine-induced Insulin-resistant Hyperglycemia in a Diabetic Patient

Clozapine is superior to all other antipsychotics in treatment-resistant schizophrenia. However, metabolic side effects are common while treating patients with clozapine. Administering clozapine in a patient who already is diabetic involves careful weighing of risks and benefits. Here, we report our experience of starting clozapine in a known diabetic patient. Clozapine was started in a patient with treatment-resistant psychosis in view of suicidal risk. Her diabetes mellitus was under good control with oral medications. After initiation of clozapine, blood sugars increased several fold within few days. Blood glucose continued to increase even with high doses of insulin and insulin infusion. Finally, blood sugars came under control only after discontinuation of clozapine. Precautionary measures while initiating clozapine in a diabetic patient are suggested – close monitoring of blood sugar during the initial few days and intensive intervention if blood sugar levels increase. Discontinuation of clozapine should also be kept in mind as a last resort.

Hippocampal volume and vasculature before and after exercise in treatment-resistant schizophrenia

BackgroundSchizophrenia is associated with poor cognitive function and elevated cardiometabolic disease risk. These health concerns may exacerbate neurocognitive dysfunction associated with hippocampal abnormalities, particularly hippocampal volume reductions. Regular exercise is thought to improve symptom severity, reduce depression, and improve cognition in schizophrenia, and may trigger exercise-mediated hippocampal growth. The potential for the benefits of exercise for treatment-resistant schizophrenia patients has not been clearly assessed. This study aims to assess the effect of exercise on hippocampal plasticity and clinical outcomes in chronic schizophrenia. MethodsSeventeen DSM-IV criteria schizophrenia or schizoaffective disorder patients completed a customized moderate intensity 12-week aerobic or weight-bearing exercise program. Adherence rates were 83% ± 9.4%) with 70% of participants completing the entire exercise program. Concomitant neuroimaging, clinical and cognitive assessments were obtained at baseline and 12-weeks. ResultsAt follow-up, symptom severity scores (t(16) = −16.8, p. ≤ 0.0001) and social functioning (t(16) = 4.4, p. = 0.0004) improved. A trend for improved depression scores (t(16) = −2.0, p. = 0.06) with no change in anxiety, or extrapyramidal symptoms were seen. Hippocampal volume increased (t(16) = −2.54, p. = 0.02), specifically in the left CA-1 field (F(16) = −2.33, p. = 0.03). Hippocampal vascular volume was unchanged. Change in hippocampal volume and vascular volume was not significantly correlated with change in symptom severity or affect scores. ConclusionsAdjunct exercise may accelerate symptom improvement in treatment-resistant psychosis patients. While the underlying mechanism remains unclear, these results indicate that chronic schizophrenia patients experience hippocampal plasticity in response to exercise. Study registrationClinical Trials.govNCT01392885.

Developmental Delay, Treatment-Resistant Psychosis, and Early-Onset Dementia in a Man With 22q11 Deletion Syndrome and Huntington's Disease.

Developmental Delay, Treatment-Resistant Psychosis, and Early-Onset Dementia in a Man With 22q11 Deletion Syndrome and Huntington's Disease.

The long-term outcome of patients with heroin use disorder/dual disorder (chronic psychosis) after admission to enhanced methadone maintenance

BackgroundOver-standard methadone doses are generally needed in the treatment of heroin use disorder (HUD) patients that display concomitant high-severity psychopathological symptomatology. A flexible dosing regimen may lead to higher retention rates in dual disorder (DD), as we demonstrated in bipolar 1 HUD patients, leading to outcomes that are as satisfactory as those of HUD patients without high-severity psychopathological symptomatology.ObjectiveThis study aimed to compare the long-term outcomes of treatment-resistant chronic psychosis HUD patients (PSY-HUD) with those of peers without dual disorder (HUD).Methods85 HUD patients who also met the criteria for treatment resistance—25 of them affected by chronic psychosis and 60 without DD—were monitored prospectively for up to 8 years while continuing to receive enhanced methadone maintenance treatment.ResultsThe rates of endurance in the treatment of PSY-HUD patients were 36%, compared with 34% for HUD patients (p = 0.872). After 3 years of treatment, these rates tended to become progressively more stable. PSY-HUD patients showed better outcome results than HUD patients regarding CGI severity (p < 0.001) and DSM-IV-GAF (p < 0.001). No differences were found regarding good toxicological outcomes or the methadone dosages used to achieve stabilization. The time required to stabilize PSY-HUD patients was shorter (p = 0.034).ConclusionsAn enhanced methadone maintenance treatment seems to be equally effective in patients with PSY-HUD and those with HUD.

Plasma ratio of clozapine to N-desmethylclozapine can predict cognitive performance in treatment-resistant psychotic patients

Cognitive symptoms play a central role in schizophrenia and are strongly associated with social functioning. Treatment with clozapine presents controversial results regarding its effects on cognition. The opposite effects of clozapine and n-desmethylclozapine (NDMC) on cholinergic system have been suggested to underlie these inconclusive findings. The aim of this study is to determine whether clozapine/NDMC ratio can predict cognitive performance in patients with treatment-resistant psychosis. Nineteen clinically stable patients with schizophrenia or schizoaffective disorder treated with clozapine monotherapy completed demographic and clinical interviews. For the purpose of the study, patients were assessed with a neuropsychological battery and on the same day a blood sampling was obtained from each patient to measure plasma levels of clozapine and NDMC. Our results showed that clozapine/NDMC ratio, but not clozapine or NDMC plasma levels separately, was a predictive factor of cognitive performance, specifically of executive functioning. Our results showed that lower clozapine/NDMC ratios are associated with better executive functioning in clinically stable patients. These findings could be interpreted by the different pharmacodynamic properties on cholinergic, dopaminergic and serotonergic systems of NDMC compared to clozapine.

The Use of Clozapine in Children and Adolescents With Treatment-Resistant Psychosis

The Use of Clozapine in Children and Adolescents With Treatment-Resistant Psychosis

Autoantibodies against voltage-gated potassium channel and glutamic acid decarboxylase in psychosis: A systematic review, meta-analysis, and case series.

Antibodies to the voltage-gated potassium channel (VGKC) complex and glutamic acid decarboxylase (GAD) have been reported in some cases of psychosis. We conducted the first systematic review and meta-analysis to investigate their prevalence in people with psychosis and report a case series of VGKC-complex antibodies in refractory psychosis. Only five studies presenting prevalence rates of VGKC seropositivity in psychosis were identified, in addition to our case series, with an overall prevalence of 1.5% (25/1720) compared to 0.7% in healthy controls (12/1753). Meta-analysis established that the pooled prevalence of GAD65 autoantibodies was 5.8% (95% confidence interval [CI]: 2.0-15.6%; I2 = 91%; nine studies) in psychotic disorders, with a prevalence of 4.6% (95%CI: 1.2-15.9%; nine studies; I2 = 89%) and 6.2% (95%CI: 1.2-27.0%; two studies; I2 = 69%) in schizophrenia and bipolar disorder, respectively. People with psychosis were more likely to have GAD65 antibodies than controls (odds ratio [OR], 2.24; 95%CI: 1.28-3.92%; P = 0.005; eight studies; I2 = 0%). Among 21 participants with treatment-resistant psychosis, none had VGKC antibodies. The prevalence of VGKC antibodies is low in psychosis. Our preliminary meta-analysis suggests that GAD autoantibodies are more common in people with psychosis than in controls, although few studies accounted for the possibility of co-existing type 1 diabetes mellitus and the clinical significance of reported GAD titers remains unclear. The paucity of studies reporting thresholds for defining GAD abnormality and rates of comorbid type 1 diabetes mellitus precludes interpretations regarding the influence of GAD antibodies on the development of psychotic disorders and may have led to an overestimate of the prevalence of GAD. Our case series fails to support the hypothesis that VGKC antibodies are linked to treatment resistance in psychosis, but the literature to date is remarkably sparse.