Treatment-resistant Symptoms Of Schizophrenia Research Articles

Impacts of duloxetine augmentation on clozapine in the treatment of negative symptoms in treatment resistant schizophrenia

Impacts of duloxetine augmentation on clozapine in the treatment of negative symptoms in treatment resistant schizophrenia

The longitudinal structure of negative symptoms in treatment resistant schizophrenia

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

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

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

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

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

Resting-state functional MRI in treatment-resistant schizophrenia.

Abnormalities in brain regions involved in the pathophysiology of schizophrenia (SCZ) may present insight into individual clinical symptoms. Specifically, functional connectivity irregularities may provide potential biomarkers for treatment response or treatment resistance, as such changes can occur before any structural changes are visible. We reviewed resting-state functional magnetic resonance imaging (rs-fMRI) findings from the last decade to provide an overview of the current knowledge on brain functional connectivity abnormalities and their associations to symptoms in treatment-resistant schizophrenia (TRS) and ultra-treatment-resistant schizophrenia (UTRS) and to look for support for the dysconnection hypothesis. PubMed database was searched for articles published in the last 10 years applying rs-fMRI in TRS patients, i.e., who had not responded to at least two adequate treatment trials with different antipsychotic drugs. Eighteen articles were selected for this review involving 648 participants (TRS and control cohorts). The studies showed frontal hypoconnectivity before the initiation of treatment with CLZ or riluzole, an increase in frontal connectivity after riluzole treatment, fronto-temporal hypoconnectivity that may be specific for non-responders, widespread abnormal connectivity during mixed treatments, and ECT-induced effects on the limbic system. Probably due to the heterogeneity in the patient cohorts concerning antipsychotic treatment and other clinical variables (e.g., treatment response, lifetime antipsychotic drug exposure, duration of illness, treatment adherence), widespread abnormalities in connectivity were noted. However, irregularities in frontal brain regions, especially in the prefrontal cortex, were noted which are consistent with previous SCZ literature and the dysconnectivity hypothesis. There were major limitations, as most studies did not differentiate between TRS and UTRS (i.e., CLZ-resistant schizophrenia) and investigated heterogeneous cohorts treated with mixed treatments (with or without CLZ). This is critical as in different subtypes of the disorder an interplay between dopaminergic and glutamatergic pathways involving frontal, striatal, and hippocampal brain regions in separate ways is likely. Better definitions of TRS and UTRS are necessary in future longitudinal studies to correctly differentiate brain regions underlying the pathophysiology of SCZ, which could serve as potential functional biomarkers for treatment resistance.

The effects of duloxetine augmentation on clozapine in the treatment of negative symptoms in treatment resistant schizophrenia

The negative symptoms of schizophrenia have always been a challenge in treatment. The intensity and chronicity of these symptoms has direct impact on the life quality and treatment response. Current psychopharmacological agents have not offered a satisfactory result in addressing the negative symptoms of schizophrenia. The clinicians struggle with the approaches that can be utilized to target the negative symptoms of schizophrenia as no well-defined evidence exist. We present a case of treatment resistant schizophrenia with negative symptoms that responded well with augmentation of Duloxetine to Clozapine treatment.

Serum kynurenine metabolites might not be associated with risk factors of treatment-resistant schizophrenia

BackgroundAbout a third of patients with schizophrenia do not respond adequately to currently available antipsychotics and thus experiences symptoms of greater severity, known as treatment-resistant schizophrenia (TRS). Some evidence suggests that the tryptophan (TRP) pathway (comprising 5-HT and kynurenine sub-pathways) has an important influence on response to antipsychotics. We therefore hypothesized that TRS is linked to metabolites of TRP pathway. MethodsWe measured TRP metabolites in 54 patients with TRS and compared them to 49 age- and sex-matched patients who responded to antipsychotics (NTRS), and 62 healthy controls using liquid chromatography-tandem mass spectrometry. Psychopathology and clinical symptoms were assessed by means of schizophrenia positive and negative scales. Working memory abilities, cortical thickness and white matter diffusion tensor imaging fractional anisotropy were appraised in enrolled subjects by neurophysiological tests, as spatial span and digital sequencing tests, and 3T magnetic resonance imaging. ResultsPatients with TRS had a significantly higher 5-HT/TRP ratio (p = 0.009) than patients with NTRS. However, the two groups did not differ in kynurenine-pathway metabolites or ratios. Additionally, 5-HT/TRP was positively correlated with disorganized symptoms in TRS (r = 0.59, p < 0.001), and negatively correlated with digit-sequencing test scores (r = −0.34, p = 0.02). These correlations were insignificant among patients with NTRS and healthy controls. In patients with TRS, 5-HT/TRP was strongly linked to the right supramarginal cortex (t = −3.2, p = 0.003), and in healthy controls, to the right transverse temporal (t = 3.40, p = 0.001), but significance disappeared after FDR correction. ConclusionsPresent results indicate that an upregulated 5-HT biosynthetic pathway can be associated to TRS, suggesting that targeting mechanisms of 5-HT conversion from tryptophan could shed light on the development of new pharmacological approaches of TRS.

Case Studies Suggest DBS May Improve Symptoms in Treatment-Resistant Schizophrenia

Case Studies Suggest DBS May Improve Symptoms in Treatment-Resistant Schizophrenia

The effects of duloxetine augmentation on clozapine in the treatment of negative symptoms in treatment resistant schizophrenia

The negative symptoms of schizophrenia have always been a challenge in treatment. The intensity and chronicity of these symptoms has direct impact on the life quality and treatment response. Current psychopharmacological agents have not offered a satisfactory result in addressing the negative symptoms of schizophrenia. The clinicians struggle with the approaches that can be utilized to target the negative symptoms of schizophrenia as no well-defined evidence exist. We present a case of treatment resistant schizophrenia with negative symptoms that responded well with augmentation of Duloxetine to Clozapine treatment.

Efficacy of Intensive Cerebellar Intermittent Theta Burst Stimulation (iCiTBS) in Treatment-Resistant Schizophrenia: a Randomized Placebo-Controlled Study

Trans-cranial magnetic stimulation (TMS) can noninvasively modulate specific brain regions to dissipate symptoms in treatment-resistant schizophrenia (TRS). Citing impaired resting state connectivity between cerebellum and prefrontal cortex in schizophrenia, we aimed to study the effect of intermittent theta burst stimulation (iTBS) targeting midline cerebellum in TRS subjects on a randomized rater blinded placebo control study design. In this study, 36 patients were randomly allocated (using block randomization method) to active and sham iTBS groups. They were scheduled to receive ten iTBS sessions, two per day (total of 1200 pulses) for 5 days in a week. The Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Schizophrenia Cognition Rating Scale (SCoRS), Simpson-Angus Extrapyramidal Side Effects Scale (SAS), and Clinical Global Impression (CGI) were assessed at baseline, after last session, and at 2 weeks post-rTMS. Thirty patients (16 and 14 in active and sham groups) completed the study. Intention to treat analysis (ITT) using mixed (growth curve) model analysis was conducted. No significant group (active vs sham) × time (pretreatment–end of 10th session–end of 2 weeks post iTBS) interaction was found for any of the variable. No major side effects were reported. Our study fails to show a significant effect of intensive cerebellar iTBS (iCiTBS) on schizophrenia psychopathology, cognitive functions, and global improvement, compared with sham stimulation, in treatment resistant cases. However, we conclude that it is safe and well tolerated. Trials using better localization technique with large sample, longer duration, and better dosing protocols are needed.Electronic supplementary materialThe online version of this article (10.1007/s12311-020-01193-9) contains supplementary material, which is available to authorized users.

Clozapine and Psychosocial Function in Schizophrenia: A Systematic Review and Meta-Analysis.

Clozapine has unique efficacy for symptoms in treatment-resistant schizophrenia; however, symptomatic remission is not necessary nor sufficient for functional improvement. No study has pooled the effect of clozapine on psychosocial function across clinical trials. We conducted a systematic review and meta-analysis to compare the effects of clozapine with other antipsychotics on psychosocial function, and described the predictors of functional outcome. We searched MEDLINE/PubMed, PsychINFO, EMBASE, CINAHL, Scopus, Web of Science, Cochrane Central Register of controlled trials and clinical trial registries till April 2018, with no language limits. Eligible studies were randomised controlled trials of clozapine vs. typical or atypical antipsychotics among adults with treatment-resistant schizophrenia. We included studies with flexible or fixed doses of antipsychotics within the therapeutic range to reflect naturalistic care. Effect sizes of studies were pooled using generic inverse variance and random-effects models and presented as standard mean differences. Study quality was assessed in accordance with the Cochrane Collaboration guideline, and subgroup analyses were carried out to identify potential moderators and methodological biases. Nine studies with 1279 participants (69.7% male) were included. Clozapine showed beneficial effects on psychosocial function, but both short-term trials [n = 3; comparing 99 people taking clozapine with 97 controls (standardised mean difference = 0.04; 95% confidence interval - 0.24, 0.32; p = 0.77; I2 = 0%)] and long-term trials [n = 5; comparing 415 people taking clozapine with 427 controls (standardised mean difference = 0.05; 95% confidence interval - 0.16, 0.27; p = 0.64; I2 = 50%)] showed no superiority of clozapine to other antipsychotics in this regard. Only one study explored the predictors of psychosocial function. Baseline severity of illness, illicit drug use, extrapyramidal side effects, sex and cognition explained the variability in functional outcome. A range of scales measured psychosocial function, and the quality of reporting varied across trials. Clozapine does not appear superior to other antipsychotics for improvement of psychosocial function. Standardisation of psychosocial function measurement is needed to improve the quality of evidence. Further exploration of the predictors of good psychosocial outcomes with clozapine treatment may improve personalisation of care.

Discriminative stimulus properties of 1.25 mg/kg clozapine in rats: Mediation by serotonin 5-HT2 and dopamine D4 receptors

The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug discrimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects. The present study was conducted to elucidate the receptor-mediated stimulus properties that form this clozapine discriminative cue by testing selective receptor ligands in rats trained to discriminate a 1.25mg/kg dose of clozapine from vehicle in a two choice drug discrimination task. Full substitution occurred with the 5-HT2A inverse agonist M100907 and the two preferential D4/5-HT2/α1 receptor antagonists Lu 37-114 ((S)-1-(3-(2-(4-(1H-indol-5-yl)piperazin-1-yl)ethyl)indolin-1-yl)ethan-1-one) and Lu 37-254 (1-(3-(4-(1H-indol-5-yl)piperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one). Partial substitution occurred with the D4 receptor antagonist Lu 38-012 and the α1 adrenoceptor antagonist prazosin. Drugs selective for 5-HT2C, 5-HT6 muscarinic, histamine H1, and benzodiazepine receptors did not substitute for clozapine. The present findings suggest that 5-HT2A inverse agonism and D4 receptor antagonism mediate the discriminative stimulus properties of 1.25mg/kg clozapine in rats, and further confirm that clozapine produces a complex compound discriminative stimulus.

Treatment-resistant schizophrenia during life span : Epidemiology, outcomes and innovative M-Health treatments within M-RESIST Project

Treatment-resistant symptoms of schizophrenia (TRS) complicate the clinical course of the illness, and a large proportion of patients do not reach functional recovery (Englisch and Zink, 2012). Out of the estimated 5 million people (0.2–2.6 %) suffering from psychotic disorders in the European Union, 30-50 % can be considered resistant to treatment, and 10–20 % ultra-resistant (Essock et al., 1996 ; Juarez-Reyes et al., 1995). The complexity of standard intervention within this population, along with the presence of persistent positive symptomatology, extensive periods of hospital care and greater risk of multi-morbidity, lead to a high degrees of suffering for the patients, family and social environment, and a high proportion of costs to the healthcare system (Kennedy et al., 2014).At present, a uniform definition of treatment resistance in the pharmacotherapy of schizophrenia is not available (Suzuki et al., 2011), as well as generally recommendable evidence-based treatment methods (Dold and Leucht, 2014).A recent systematic review on the topic showed that TRS is poorly a studied and understood condition, contrasted to its high prevalence, clinical importance and poor prognosis. There is lack of studies on epidemiology and risk factors of this disorder, as well as on outcomes and longitudinal course. Most of the available literature focuses on medication treatments, while very few examine efficacy of adjunctive therapeutic options (Seppala et al., in preparation).Treatments based on information and communication technology (ICT) present novel possibilities to improve the outcomes of schizophrenia. Previous studies have indicated suitability and promising results of such intervention techniques (Granholm et al., 2012 ; Ben-Zeev et al., 2013). m-RESIST is an innovative project aimed to empower patients with resistant schizophrenia, to personalize treatment by integrating pharmacological and psychosocial approaches, and to further develop knowledge related to the illness using predictive models designed to exploit historical and real-time data based on environmental factors and treatment outcomes.Disclosure of interestThe author has not supplied his declaration of competing interest.

Transcranial Direct Current Stimulation for the Treatment of Refractory Symptoms of Schizophrenia. Current Evidence and Future Directions.

Schizophrenia is a severe and frequent neuropsychiatric disorder. Despite antipsychotic medications, up to 30% of patients with schizophrenia still report disabling treatment-resistant symptoms. Transcranial direct current stimulation (tDCS) has been proposed as a novel method to alleviate such symptoms. Here, we review studies investigating the effects of tDCS on symptoms, cognition, brain activity and cortical plasticity in patients with schizophrenia. We provide an up-to-date and comprehensive overview of the use of tDCS in patients with schizophrenia. More specifically, we first present the effects of tDCS on treatment-resistant symptoms of schizophrenia. We report that tDCS applied over the frontotemporal regions reduced auditory hallucinations, with a mean 34% reduction of symptoms. Moreover, tDCS applied over both prefrontal cortices reduced negative symptoms and catatonia. We discuss the need for further sham-controlled studies to confirm these effects. Second, we present the impact of tDCS on cognitive functions in patients with schizophrenia. Positive effects of tDCS have been reported on learning, working memory, attention and source-monitoring. Third, we review the effects of tDCS on brain activity in patients with schizophrenia. Although only few studies investigated the effects of tDCS using neuroimaging technics, these studies are helpful at identifying the mechanisms of action of tDCS in schizophrenia. Fourth, we present tDCS studies on cortical plasticity showing reduced cortical plasticity in patients with schizophrenia that tDCS may beneficially modulate. Lastly, we discuss the safety aspects of tDCS in patients with schizophrenia and potential directions to improve efficacy for this clinical populations.

Association between subjective well-being and depressive symptoms in treatment-resistant schizophrenia before and after treatment with clozapine

BackgroundWe examined the relationship between subjective well-being and depressive symptoms in patients with treatment-resistant schizophrenia before and after treatment with clozapine to contribute to the growing body of research regarding the determinants of patients' perspective of their own well-being in schizophrenia. MethodsForty patients with treatment-resistant schizophrenia were comprehensively evaluated for subjective well-being, schizophrenic symptoms, and depressive symptoms before and 8weeks after the initiation of treatment with clozapine. Correlation analysis and Fisher's z-transformation statistics were performed. ResultsThere were significant improvements in all Positive and Negative Syndrome Scale (PANSS) factor scores and Beck Depression Inventory (BDI) score over the treatment period (P<.05). Before clozapine administration, the subjective well-being score had significant negative correlations with the PANSS depression factor score (P<.05) and the BDI score (P<.05). After clozapine treatment, the subjective well-being score still had significant negative correlations with the PANSS depression factor score (P<.05) and the BDI score (P<.05) and no new associations emerged with treatment. Fisher's z-transformation statistics revealed that the correlations between the subjective well-being score and the depression score were not significantly different before and after clozapine treatment. ConclusionsThese results indicate that depressive symptoms are significantly associated with low subjective well-being in patients with treatment-resistant schizophrenia. The association was equally significant before and after treatment with clozapine, suggesting that the relationship does not change with clozapine treatment, even when depressive symptoms improve significantly, and that there may be a common pathophysiological basis for depressive symptoms and the subjective appraisal of well-being in schizophrenia.

Low-dose lamotrigine augmentation therapy improves residual symptoms in treatment-resistant schizophrenia: A report of five cases

Treatment-resistant schizophrenia (TRS) refers to the approximately 20-30% of schizophrenia patients whose symptoms are resistant to any antipsychotic treatment. For the improvement of residual symptoms in TRS, augmentation therapy using anticonvulsants such as lamotrigine (LTG) has recently attracted attention. Randomized clinical trials (RCTs) have demonstrated robust evidence; however, the results have shown both positive and negative outcomes for the use of LTG. Although RCTs have merit, they also obscure informative clinical features present in each patient, such as the types of TRS that show the most significant effects from LTG. Thus, detailed case reports examining the efficacy of LTG may help to shed light on various treatments for complex, heterogeneous diseases such as schizophrenia. We present detailed reports on the clinical course and features of TRS in five patients suffering from severe positive symptoms who were treated with LTG augmentation therapy. After the administration of LTG augmentation therapy, two patients did not show any improvement in their residual symptoms, while the remaining three patients did experience improvement. Remarkably, patients with more severe residual positive symptoms, especially those with auditory hallucinations, seemed to respond better to low-dose LTG (50 mg daily). Additional clinical variables, such as type and dose of ongoing antipsychotics, age of onset, duration of illness, duration of untreated psychosis, number of administration cycles, and genetic heritability, were not found to be related to the effectiveness of LTG augmentation. Low-dose LTG augmentation therapy seems to improve residual symptoms in some cases of TRS. The glutamatergic properties of LTG may be the decisive factor in these symptoms, as other glutamatergic agents have also been shown to be effective based on previous glutamate hypotheses in schizophrenia.

Adding or Switching Antipsychotic Medications in Treatment-Refractory Schizophrenia

This study compared patients with schizophrenia whose antipsychotic medications were switched to manage treatment-resistant positive psychotic symptoms with those for whom another antipsychotic was added. Psychiatrists' characteristics and perceptions of effectiveness of the medication change on clinical outcomes were also reported. Psychiatrists participating in a nationally representative mailed survey (N=209) reported on the clinical features, management, and response to the change in antipsychotic medication (added versus switched) of one adult patient with treatment-refractory schizophrenia under their care for at least one year. Thirty-three percent of patients were treated with an added antipsychotic medication. Compared with patients whose antipsychotic medications were switched, those with an added antipsychotic medication were more likely to be female, to have received care from the same psychiatrist for more than two years, and to have been recently prescribed an antidepressant. Compared with psychiatrists who switched antipsychotic prescriptions, those who added an antipsychotic reported that the change was less likely to reduce positive symptoms, improve functioning, and prevent hospitalization. Psychiatrists who added rather than switched antipsychotics reported more frequent attendance at educational programs sponsored by a pharmaceutical company. Consistent with other lines of research and practice guideline recommendations, psychiatrists perceive antipsychotic polypharmacy to be a generally ineffective strategy for treatment-resistant positive psychotic symptoms. In light of these findings, efforts to identify and implement more effective evidence-based pharmacologic approaches should be undertaken.

Adding or Switching Antipsychotic Medications in Treatment-Refractory Schizophrenia

Adding or Switching Antipsychotic Medications in Treatment-Refractory Schizophrenia

Myocarditis During Clozapine Treatment

The prototypical second-generation antipsychotic clozapine has been associated with various hematologic and metabolic adverse effects. Less attention has been given to clozapine’s adverse cardiac effects, including myocarditis and cardiomyopathy, despite a high associated mortality rate. Here we present the case of a young man with psychosis who developed near-fatal myocarditis after the initiation of clozapine. We review the diagnosis, management, and hypothesized pathophysiology of clozapine-induced myocarditis. We urge clinicians to be vigilant for the condition and to balance the risk of myocarditis and other side effects against the many benefits of clozapine for patients with treatment-resistant symptoms of schizophrenia.

High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia

Background Clinical trials indicate that glycine site agonists of the N-methyl-D-aspartate (NMDA) receptors may reduce negative and cognitive symptoms in treatment-resistant schizophrenia when used as adjuvants to conventional antipsychotics but possibly not to clozapine. In this study, we assessed whether high-dose glycine may also be therapeutically beneficial when added to olanzapine and risperidone treatment. Methods Seventeen olanzapine- or risperidone-treated schizophrenia patients participated in a double-blind, placebo-controlled, 6-week crossover treatment trial with .8 g/kg/day glycine added to their ongoing antipsychotic medication. Clinical assessments were performed biweekly throughout the study. Clinical laboratory parameters and amino acid serum levels were monitored. Results Glycine treatment was well tolerated and resulted in a significant ( p < .0001) 23% ± 8% reduction in negative symptoms. Significant improvements were also registered in cognitive and positive symptoms. The negative symptoms improvement remained significant even following covariation for changes in other symptom clusters and extrapyramidal side effects. High posttreatment glycine serum levels significantly predicted ( r = .60) clinical response. Conclusions These findings indicate that the efficacy of olanzapine and risperidone may be augmented using high-dose adjuvant glycine treatment and suggest that these atypical antipsychotics may affect NMDA receptor-mediated neurotransmission differently than clozapine.