Strategies For Treatment Of Schizophrenia Research Articles

THE FIRST GENERATION AND SECOND-GENERATION ANTIPSYCHOTIC DRUGS AND THEIR PHARMACOLOGY IN TREATMENT OF SCHIZOPHRENIA

Schizophrenia is a complex and severe psychiatric disorder that affects millions of people worldwide. Antipsychotic drugs have been widely used for the treatment of schizophrenia for over 60 years. The first-generation antipsychotic drugs (FGAs) were introduced in the 1950s and revolutionized the treatment of schizophrenia. However, their use is associated with a number of adverse effects, including Extrapyramidal Symptoms (EPS) and Tardive Dyskinesia (TD). Second-generation antipsychotic drugs (SGAs), also known as atypical antipsychotics, were developed in the 1990s and have become the preferred treatment for schizophrenia due to their lower incidence of EPS and TD. They also have a broader range of therapeutic effects, such as improving negative symptoms and cognitive impairment associated with schizophrenia. This review article summarizes the pharmacology of both FGAs and SGAs, including their mechanism of action, pharmacokinetics, and adverse effects. The efficacy and safety of these drugs in the treatment of schizophrenia are also discussed. In addition, this review examines the controversy surrounding the use of SGAs and their potential metabolic side effects, such as weight gain, hyperlipidemia, and diabetes. Despite the availability of SGAs, FGAs still have a role in the treatment of schizophrenia, particularly for patients who are unresponsive to SGAs or experience intolerable side effects. Furthermore, research continues to identify new pharmacological targets and treatment strategies for schizophrenia. Understanding the pharmacology and clinical use of antipsychotic drugs is essential for optimizing the treatment of schizophrenia and improving patient outcomes.

Pharmacokinetic/pharmacodynamic modeling of cortical dopamine concentrations after quetiapine lipid core nanocapsules administration to schizophrenia phenotyped rats.

Schizophrenia (SCZ) response to pharmacological treatment is highly variable. Quetiapine (QTP) administered as QTP lipid core nanocapsules (QLNC) has been shown to modulate drug delivery to the brain of SCZ phenotyped rats (SPR). In the present study, we describe the brain concentration-effect relationship after administrations of QTP as a solution or QLNC to SPR and naïve animals. A semimechanistic pharmacokinetic (PK) model describing free QTP concentrations in the brain was linked to a pharmacodynamic (PD) model to correlate the drug kinetics to changes in dopamine (DA) medial prefrontal cortex extracellular concentrations determined by intracerebral microdialysis. Different structural models were investigated to fit DA concentrations after QTP dosing, and the final model describes the synthesis, release, and elimination of DA using a pool compartment. The results show that nanoparticles increase QTP brain concentrations and DA peak after drug dosing to SPR. To the best of our knowledge, this is the first study that combines microdialysis and PK/PD modeling in a neurodevelopmental model of SCZ to investigate how a nanocarrier can modulate drug PK and PD, contributing to the development of new treatment strategies for SCZ.

EE367 Cost-Effectiveness Analysis of Different Treatment Strategies for Schizophrenia in China

To estimate the cost-effectiveness of different treatment strategies for schizophrenia and to provide evidence for clinical decision-making in China.

Identification of a Hypoxia-Related Signature as Candidate Detector for Schizophrenia Based on Genome-Wide Gene Expression

Introduction: Schizophrenia (SCZ), a severe neuropsychiatric disorder with high genetic susceptibility, has high rates of misdiagnosis due to the unavoidably subjective factors and heterogeneous clinical presentations. Hypoxia has been identified as an importantly risk factor that participates in the development of SCZ. Therefore, development of a hypoxia-related biomarker for SCZ diagnosis is promising. Therefore, we dedicated to develop a biomarker that could contribute to distinguishing healthy controls and SCZ patients. Methods: GSE17612, GSE21935, and GSE53987 datasets, consisting of 97 control samples and 99 SCZ samples, were involved in our study. The hypoxia score was calculated based on the single-sample gene-set enrichment analysis using the hypoxia-related differentially expressed genes to quantify the expression levels of these genes for each SCZ patient. Patients in high-score groups were defined if their hypoxia score was in the upper half of all hypoxia scores and patients in low-score groups if their hypoxia score was in the lower half. GSEA was applied to detect the functional pathway of these differently expressed genes. CIBERSORT algorithm was utilized to evaluate the tumor-infiltrating immune cells of SCZ patients. Results: In this study, we developed and validated a biomarker consisting of 12 hypoxia-related genes that could distinguish healthy controls and SCZ patients robustly. We found that the metabolism reprogramming might be activated in the patient with high hypoxia score. Finally, CIBERSORT analysis illustrated that lower composition of naive B cells and higher composition of memory B cells might be observed in low-score groups of SCZ patients. Conclusion: These findings revealed that the hypoxia-related signature was acceptable as a detector for SCZ, providing further insight into effective diagnosis and treatment strategies for SCZ.

Paeoniflorin Rescued MK-801-Induced Schizophrenia–Like Behaviors in Mice via Oxidative Stress Pathway

Schizophrenia (SCZ) affects approximately 1% population worldwide, and the first-line antipsychotics have partial reactivity or non-reactivity with side effects. Therefore, there is an urgent need to find more effective drugs. Paeoniflorin (PF) is the main effective component of traditional Chinese medicine from white peony, red peony and peony bark, which acts as a neuroprotective agent. The purpose of this study was to investigate whether PF can rescue MK-801 induced schizophrenia-like behavior in mice. Our results demonstrated that intragastric administration of PF ameliorated MK-801 induced schizophrenia–like behaviors in mice as demonstrated by prepulse inhibition of acoustic startle response, fear conditioning test for memory and open field test for activity. In contrast, the first-line antipsychotics-olanzapine reversed the prepulse inhibition deficits and hyperactivities, but not memory deficits, in the model mice. Further analysis showed that PF reduced oxidative stress in the MK-801-treated mice, as evidenced by the increased superoxide dismutase levels and decreased malondialdehyde levels in the blood of the model mice. In addition, PF treatment inhibited the expression of the apoptotic protein Bax and restored the expression of tyrosine hydroxylase in the brains of the model mice. in vitro data indicated that PF protected against oxidative stress induced neurotoxicity in the primary cultured hippocampal neurons. In conclusion, our results were the first to provide evidence that PF rescued schizophrenia-like behaviors (both positive symptoms and cognitive impairments) in rodents through oxidative stress pathway, and therefore provide a novel strategy for treatment of SCZ. However, more pre-clinical and clinical research are needed to translate the present findings into clinics for a treatment of schizophrenia.

Connectivity Analyses of Bioenergetic Changes in Schizophrenia: Identification of Novel Treatments.

We utilized a cell-level approach to examine glycolytic pathways in the DLPFC of subjects with schizophrenia (n= 16) and control (n= 16) and found decreased mRNA expression of glycolytic enzymes in pyramidal neurons, but not astrocytes. To replicate these novel bioenergetic findings, we probed independent datasets for bioenergetic targets and found similar abnormalities. Next, we used a novel strategy to build a schizophrenia bioenergetic profile by a tailored application of the Library of Integrated Network-Based Cellular Signatures data portal (iLINCS) and investigated connected cellular pathways, kinases, and transcription factors using Enrichr. Finally, with the goal of identifying drugs capable of "reversing" the bioenergetic schizophrenia signature, we performed a connectivity analysis with iLINCS and identified peroxisome proliferator-activated receptor (PPAR) agonists as promising therapeutic targets. We administered a PPAR agonist to the GluN1 knockdown model of schizophrenia and found it improved long-term memory. Taken together, our findings suggest that tailored bioinformatics approaches, coupled with the LINCS library of transcriptional signatures of chemical and genetic perturbagens, may be employed to identify novel treatment strategies for schizophrenia and related diseases.

25. OLIGODENDROCYTE-BASED IMPAIRMENT OF BRAIN CONNECTIVITY AS TARGET FOR NEW TREATMENT STRATEGIES IN SCHIZOPHRENIA

Overall : This symposium has a translational approach. First, we present human post-mortem and in-vivo imaging studies on the pivotal role of oligedondrocyte loss and dysfunction with consecutive impairments of brain connectivity in schizophrenia. Natalya Uranova will show morphometric data on ultrastructural alterations of oligodendrocytes, myelin damage and degeneration and disturbed oligodendrocyte-axon interactions in post-mortem prefrontal white matter in schizophrenia. Adrienne Lahti will report diffusion tensor imaging data suggesting impaired axonal and myelin integrity. Because, MR Spectroscopy permits the non-invasive measurement of neurometabolites, such as N-acetylaspartate, a marker of neuronal integrity, and glutamate, which can be neurotoxic when overproduced, this technique provides further understanding of the relationship between white matter microstructure and neuronal function.Second, we present data from cell culture and animal models suggesting that restoration of oligodendrocyte function (in terms of energy metabolism, maturation and myelin production) is a promising target for the development of novel treatment strategies in schizophrenia. Proteomic studies in postmortem brain by Daniel Martins-de-Souza have suggested a schizophrenia-related energy metabolism dysfunction in oligodendrocytes. These findings have been followed up using oligodendroglia cell lines and induced pluripotent stem cell-derived cerebral organoids, supporting the notion that alterations in glycolysis in oligodendrocytes are pivotal to the overall energy dysfunction in schizophrenia brains. Lan Xiao′s lab has shown that oligodendrocyte dysfunction and impaired myelination in the prefrontal cortex is correlated with schizophrenia-like behavior in mice undergoing prolonged social isolation. Enhancing oligodendrocyte generation and myelin repair by FDA-approved compounds, like quetiapine (an APD) or clemastine (a histamine antagonist) successfully reversed the above phenotype.

S.18.01 Low-dose and time-limited antipsychotic treatment strategies in schizophrenia

S.18.01 Low-dose and time-limited antipsychotic treatment strategies in schizophrenia

Novel treatment strategies for schizophrenia from improved understanding of genetic risk.

Recent years have seen significant advances in our understanding of the genetic basis of schizophrenia. In particular, genome-wide approaches have suggested the involvement of many common genetic variants of small effect, together with a few rare variants exerting relatively large effects. While unequivocal identification of the relevant genes has, for the most part, remained elusive, the genes revealed as potential candidates can in many cases be clustered into functionally related groups which are potentially open to therapeutic intervention. In this review, we summarise this information, focusing on the accumulating evidence that genetic dysfunction at glutamatergic synapses and post-synaptic signalling complexes contributes to the aetiology of the disease. In particular, there is converging support for involvement of post-synaptic JNK pathways in disease aetiology. An expansion of our neurobiological knowledge of the basis of schizophrenia is urgently needed, yet some promising novel pharmacological targets can already be discerned.

RISK FACTORS FOR VIOLENCE IN PSYCHOSIS: FINDINGS FROM A META-ANALYSIS

Despite the availability of effective long-term treatment strategies in schizophrenia, relapse is still common. Relapse prevention is one of the major treatment objectives, because relapse represents burden and costs for patients, their environment, and society and seems to increase illness progression at the biological level. Valid predictors for relapse are urgently needed to enable more individualized recommendations and treatment decisions to be made.Mainly recent evidence regarding predictors and early warning signs of relapse in schizophrenia was reviewed. In addition, data from the first-episode (long-term) study (FES; Gaebel et al., 2007, 2011) performed within the German Research Network on Schizophrenia were analyzed.On the basis of FES data, premorbid adjustment, residual symptoms and some side effects are significant predictors. Although a broad spectrum of potential parameters has been investigated in several other studies, only a few and rather general valid predictors were identified consistently. Data of the FES also indicated that predictive power could be enhanced by considering interacting conjunctions, as suggested by the Vulnerability–Stress-Coping model. Prospective studies, however, are rare. In addition, prodromal symptoms as course-related characteristics likewise investigated in the FES add substantially to early recognition of relapse and may serve as early warning signs, but prognosis nevertheless remains a challenge.Comprehensive and well-designed studies are needed to identify and confirm valid predictors for relapse in schizophrenia. In this respect, broadly accepted and specifically defined criteria for relapse would greatly facilitate comparison of results across studies.

The nicotinergic receptor as a target for cognitive enhancement in schizophrenia: Barking up the wrong tree?

Cognitive symptoms have increasingly been recognized as an important target in the development of future treatment strategies in schizophrenia. The nicotinergic neurotransmission system has been suggested as a potentially interesting treatment target for these cognitive deficits. However, previous research yielded conflicting results, which may be explained by several methodological limitations, such as the failure to include both a group of smoking and non-smoking schizophrenic patients, the use of only a single nicotine dose, and the inclusion of a very limited cognitive battery. The present study aims at investigating the cognitive effects of nicotine in schizophrenia while addressing these methodological issues. In a double-blind placebo-controlled randomized crossover design, cognitive effects are assessed in smoking (n =16) and non-smoking (n =16) schizophrenic patients after receiving active (1 or 2 mg) or placebo oromucosal nicotine spray. A modest improving effect of nicotine on attention in the smoking but not the non-smoking group was found. No enhancing effects were found on measures of visual memory, working memory, processing speed, psychomotor speed, or social cognitive functioning in either patient group. These findings suggest that the nicotinic receptor only has limited value as a cognitive treatment target in schizophrenia.

Interview with P Jeffrey Conn

Dr Conn is the Lee E Limbird Professor of Pharmacology at Vanderbilt University and Director of the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD). Dr Conn received a PhD in Pharmacology from Vanderbilt in 1986 and pursued postdoctoral studies at Yale University. He served as a professor of Pharmacology at Emory University from 1988 to 2000, before moving to Merck and Co. (PA, USA) as head of the Department of Neuroscience. Dr Conn moved to Vanderbilt University in 2003 where he is the founding director of the VCNDD, with a primary mission of facilitating translation of recent advances in basic science to novel therapeutics. The VCNDD consists of approximately 100 full-time scientists and has advanced novel molecules from four major programs as development candidates for clinical testing with industry partners. Dr Conn has served in editorial positions with multiple international journals and has served the scientific advisory boards of multiple foundations and companies. He has received numerous awards based on the impact of his basic and translational research. Dr Conn’s current research is focused on development of novel treatment strategies for schizophrenia, Parkinson’s disease and other serious brain disorders. Interview conducted by Hannah Coaker, Assistant Commissioning Editor.

Are there clinically useful predictors and early warning signs for pending relapse?

ObjectiveDespite the availability of effective long-term treatment strategies in schizophrenia, relapse is still common. Relapse prevention is one of the major treatment objectives, because relapse represents burden and costs for patients, their environment, and society and seems to increase illness progression at the biological level. Valid predictors for relapse are urgently needed to enable more individualized recommendations and treatment decisions to be made. MethodsMainly recent evidence regarding predictors and early warning signs of relapse in schizophrenia was reviewed. In addition, data from the first-episode (long-term) study (FES; Gaebel et al., 2007, 2011) performed within the German Research Network on Schizophrenia were analyzed. ResultsOn the basis of FES data, premorbid adjustment, residual symptoms and some side effects are significant predictors. Although a broad spectrum of potential parameters has been investigated in several other studies, only a few and rather general valid predictors were identified consistently. Data of the FES also indicated that predictive power could be enhanced by considering interacting conjunctions, as suggested by the Vulnerability–Stress-Coping model. Prospective studies, however, are rare. In addition, prodromal symptoms as course-related characteristics likewise investigated in the FES add substantially to early recognition of relapse and may serve as early warning signs, but prognosis nevertheless remains a challenge. ConclusionsComprehensive and well-designed studies are needed to identify and confirm valid predictors for relapse in schizophrenia. In this respect, broadly accepted and specifically defined criteria for relapse would greatly facilitate comparison of results across studies.

Functional Magnetic Resonance Imaging and Treatment Strategies in Schizophrenia

Neurobiological correlates of various treatment approaches (e.g. psychopharmacology, cognitive behavioural therapy) have become an important issue in recent neuroimaging studies. In schizophrenia, dysfunctions especially in frontal and parietal brain regions as well as the ventral striatum have been demonstrated in numerous studies. The review includes functional MRI studies about neurobiological correlates of treatment effects in schizophrenic patients. Treatment-associated changes in brain activity were shown especially in the anterior cingulate cortex, the dorsolateral prefrontal cortex, the ventral striatum and the amygdala. In addition, the differential effects of various treatment approaches including different neuroleptics (atypical neuroleptics, typical neuroleptics) as well as cognitive behavioural therapy will be considered in this review. The influence of functional differences on the differential effect of typical and atypical antipsychotics on cognitive functions will be discussed.

Subjective Well-being of Patients with Schizophrenia as a Target of Drug Treatment

An important development within the last decades is the consideration of the patient's perspective and the acknowledgement that the majority of patients are able to judge their state of well-being. Several self-report scales such as the "The Subjective Well-being under Neuroleptics Scale" (SWN) have been established. Additionally to their beneficial impact, current antipsychotics have considerable limitations. Antipsychotic-related side effects, such as extrapyramidalmotor symptoms, weight gain and obesity, apathy and anhedonia have an important influence on the patient's wellbeing. Evidence suggests that the so-called neuroleptic-induced deficit syndrome under antipsychotics might be caused by the inhibition of the dopaminergic reward system. A reduced activation of the ventral striatum, including the nucleus accumbens is associated with negative symptom severity. Second-generation antipsychotics (henceforth SGA) block striatal D2 receptors less and show a weaker binding to D2 receptors, have interactions with several other neurotransmitters and inhibit to a lesser degree the reward functions compared to first-generation antipsychotics (henceforth FGA). This may support the reduction of negative symptoms, contributes to a higher subjective well-being, a better medication adherence and thereby an improved therapeutic outcome. The involvement of the patient and the consideration of his/her subjective wellbeing will be a major aspect in the development of new treatment strategies in schizophrenia and has a significant impact on the adherence and the long-term prognosis.

A placebo-controlled study of the modafinil added to risperidone in chronic schizophrenia

In recent years, evidence suggests that modafinil may be useful for certain symptom domains of schizophrenia, especially for the negative and cognitive symptoms. However, the results are not consistent. This study was designed to investigate the effect of modafinil added to risperidone in patients with chronic schizophrenia in a double blind and randomized clinical trial. Participants were inpatients males (35) and females (11), ages 20-49 years at two teaching psychiatric hospital in Iran. All patients were in the active phase of the illness and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion 23 patients to risperidone 6 mg/day plus modafinil 200 mg/day and 23 patients to risperidone 6 mg/day plus placebo. The principal measure of outcome was the positive and negative syndrome scale (PANSS). Patients were assessed by a psychiatrist at baseline and after 2, 4, 6 and 8 weeks after the start of medication. The modafinil group had significantly greater improvement in the negative symptoms as well as PANSS total scores over the 8-week trial. Therapy with 200 mg/day of modafinil was well tolerated and no clinically important side effects were observed. The present study indicates modafinil as a potential adjunctive treatment strategy for treatment of schizophrenia particularly the negative symptoms. Nevertheless, results of larger-controlled trials are needed before recommendation for broad clinical application can be made.

Dopamine D2 and 5-hydroxytryptamine 5-HT 2A receptors assemble into functionally interacting heteromers

In view of the co-distribution of dopamine D 2LR and 5-hydroxytryptamine 5-HT 2A receptors (D 2LR and 5-HT 2AR, respectively) within inter alia regions of the dorsal and ventral striatum and their role as a target of antipsychotic drugs; in this study we assessed the potential existence of D 2LR-5-HT 2AR heteromers in living cells and the functional consequences of this interaction. Thus, by means of a proximity-based bioluminescence resonance energy transfer (BRET) approach we demonstrated that the D 2LR and the 5-HT 2AR form stable and specific heteromers when expressed in HEK293T mammalian cells. Furthermore, when the D 2LR-5-HT 2AR heteromeric signaling was analyzed we found that the 5-HT 2AR-mediated phospholipase C (PLC) activation was synergistically enhanced by the concomitant activation of the D 2LR as shown in a NFAT-luciferase reporter gene assay and a specific and significant rise of the intracellular calcium levels were observed when both receptors were simultaneously activated. Conversely, when the D 2LR-mediated adenylyl cyclase (AC) inhibition was assayed we showed that costimulation of D 2LR and 5-HT 2AR within the heteromer led to inhibition of the D 2LR functioning, thus suggesting the existence of a 5-HT 2AR-mediated D 2LR trans-inhibition phenomenon. Finally, a bioinformatics study reveals that the triplet amino acid homologies LLT (Leu-Leu-Thr) and AIS (Ala-Ile-Ser) in TM1 and TM3, respectively of the D 2R-5-HT 2AR may be involved in the receptor interface. Overall, the presence of the D 2LR-5-HT 2AR heteromer in discrete brain regions is postulated based on the existence of D 2LR-5-HT 2A receptor–receptor interactions in living cells and their codistribution inter alia in striatal regions. Possible novel therapeutic strategies for treatment of schizophrenia should be explored by targeting this heteromer.

Identification of Metabotropic Glutamate Receptor Subtype 5 Potentiators Using Virtual High-Throughput Screening

Selective potentiators of glutamate response at metabotropic glutamate receptor subtype 5 (mGluR5) have exciting potential for the development of novel treatment strategies for schizophrenia. A total of 1,382 compounds with positive allosteric modulation (PAM) of the mGluR5 glutamate response were identified through high-throughput screening (HTS) of a diverse library of 144,475 substances utilizing a functional assay measuring receptor-induced intracellular release of calcium. Primary hits were tested for concentration-dependent activity, and potency data (EC50 values) were used for training artificial neural network (ANN) quantitative structure−activity relationship (QSAR) models that predict biological potency from the chemical structure. While all models were trained to predict EC50, the quality of the models was assessed by using both continuous measures and binary classification. Numerical descriptors of chemical structure were used as input for the machine learning procedure and optimized in an iterative protocol. The ANN models achieved theoretical enrichment ratios of up to 38 for an independent data set not used in training the model. A database of ∼450,000 commercially available drug-like compounds was targeted in a virtual screen. A set of 824 compounds was obtained for testing based on the highest predicted potency values. Biological testing found 28.2% (232/824) of these compounds with various activities at mGluR5 including 177 pure potentiators and 55 partial agonists. These results represent an enrichment factor of 23 for pure potentiation of the mGluR5 glutamate response and 30 for overall mGluR5 modulation activity when compared with those of the original mGluR5 experimental screening data (0.94% hit rate). The active compounds identified contained 72% close derivatives of previously identified PAMs as well as 28% nontrivial derivatives of known active compounds.

P03-89 - How are large scale studies of medication influencing change in our treatment strategies for schizophrenia?

BackgroundMany studies have recently been carried out to compare the effectiveness of various antipsychotic agents.Aims and ObjectivesWe wished to determine what could be learnt from these studies about the effectiveness of antipsychotics, and whether this should influence choice of treatment.MethodWe carried out a literature search using PUBMED. We directed special attention to large studies comparing medications in schizophrenia. These studies included CUTLASS, CATIE, SOHO, CAFE, and EUFEST (Kahn 2008, Haro 2006, Jones 2006, Lieberman 2005, Perkins 2008), as well as studies by Tihonen 92006, 2009) The studies were critically reviewed.ResultsThe different studies measure different aspects of care, at different phases of the illness. This illustrates the need to study schizophrenia through a stage model. Furthermore, different outcome measures are proposed. We believe that discontinuation data, on which some studiesdepend, is a weak measure of effectiveness. Important doubts arise regarding the choice of patients (those requiring switching of antipsychotic) in CUTLASS, and also regarding potential observer bias in this study.ConclusionThere is much information to be gathered from the results of such studies. However interpretation is made more difficult by problems within the study designs themselves. On balance it does appear that different antipsychotics have different effectiveness. The main difficulty in putting these results into practice is concern among clinicians and patients regarding side effects.

Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin

Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N=39) with defined cognitive deficit (>or=1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40,000 IU rhEPO (N=20) or placebo (N=19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language-semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) - perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.