Synergistic psychedelic - NMDAR modulator treatment for neuropsychiatric disorders.

Modern research data suggest a therapeutic role for serotonergic psychedelics in depression and other neuropsychiatric disorders, although psychotomimetic effects may limit their widespread utilization. Serotonergic psychedelics enhance neuroplasticity via serotonin 2 A receptors (5HT2AR) activation and complex serotonergic-glutamatergic interactions involving the ionotropic glutamate receptors, tropomyosin receptor kinase B (TrkB) and the mammalian target of rapamycin (mTOR). N-methyl-d-aspartate receptors (NMDAR) channel antagonists, i.e. ketamine, and glycine modulatory site full and partial agonists, i.e., D-serine (DSR) and D-cycloserine (DCS), share some of these mechanisms of action and have neuroplastic and antidepressant effects. Moreover, procognitive effects have been reported for DSR and DCS and 5HT2AR-NMDAR interactions modulate neuronal excitability in prefrontal cortex and represent a target for new antipsychotics. We hypothesize that the synchronous administration of a psychedelic and a NMDAR modulator may increase the therapeutic impact of each of the treatment components and allow for dose adjustments and improved safety. We propose to initially focus research on the acute concurrent administration of psilocybin and DSR or DCS in depression.

Could psychedelic drugs have a role in the treatment of schizophrenia? Rationale and strategy for safe implementation.

Schizophrenia is a widespread psychiatric disorder that affects 0.5-1.0% of the world's population and induces significant, long-term disability that exacts high personal and societal cost. Negative symptoms, which respond poorly to available antipsychotic drugs, are the primary cause of this disability. Association of negative symptoms with cortical atrophy and cell loss is widely reported. Psychedelic drugs are undergoing a significant renaissance in psychiatric disorders with efficacy reported in several conditions including depression, in individuals facing terminal cancer, posttraumatic stress disorder, and addiction. There is considerable evidence from preclinical studies and some support from human studies that psychedelics enhance neuroplasticity. In this Perspective, we consider the possibility that psychedelic drugs could have a role in treating cortical atrophy and cell loss in schizophrenia, and ameliorating the negative symptoms associated with these pathological manifestations. The foremost concern in treating schizophrenia patients with psychedelic drugs is induction or exacerbation of psychosis. We consider several strategies that could be implemented to mitigate the danger of psychotogenic effects and allow treatment of schizophrenia patients with psychedelics to be implemented. These include use of non-hallucinogenic derivatives, which are currently the focus of intense study, implementation of sub-psychedelic or microdosing, harnessing of entourage effects in extracts of psychedelic mushrooms, and blocking 5-HT2A receptor-mediated hallucinogenic effects. Preclinical studies that employ appropriate animal models are a prerequisite and clinical studies will need to be carefully designed on the basis of preclinical and translational data. Careful research in this area could significantly impact the treatment of one of the most severe and socially debilitating psychiatric disorders and open an exciting new frontier in psychopharmacology.

A randomized add-on trial of high-dose D-cycloserine for treatment-resistant depression.

Antagonism of N-methyl-D-aspartate glutamatergic receptors (NMDAR) may represent an effective antidepressant mechanism. D-cycloserine (DCS) is a partial agonist at the NMDAR-associated glycine modulatory site that at high doses acts as a functional NMDAR antagonist. Twenty-six treatment-resistant major depressive disorder patients participated in a double blind, placebo-controlled, 6-wk parallel group trial with a gradually titrated high dose (1000 mg/d) of DCS added to their antidepressant medication. DCS treatment was well tolerated, had no psychotomimetic effects and led to improvement in depression symptoms as measured by Hamilton Depression Rating Scale (HAMD; p = 0.005) and Beck Depression Inventory (p = 0.046). Of the 13 subjects treated with DCS, 54% had a ≥ 50% HAMD score reduction vs. 15% of the 13 patients randomized to placebo (p = 0.039). A significant (p = 0.043) treatment× pre-treatment glycine serum levels interaction was registered. These findings indicate that NMDAR glycine site antagonism may be a cost-effective target for development of mechanistically novel antidepressants. Larger-sized DCS trials are warranted.

Glycine site agonists of the N-methyl-D-aspartate receptor and Parkinson's disease: a hypothesis.

Limitations of current pharmacological approaches to Parkinson's disease (PD) highlight the need for the development of nondopaminergic therapeutic strategies. The potential role of glutamatergic neurotransmission modulators, including those active at the N-methyl-D-aspartate receptor (NMDAR), is presently under investigation. Most literature proposes the use of NMDAR antagonists based on neurodegenerative theories of NMDAR function. Nevertheless, NMDAR antagonism has proven disappointing in clinical trials and may be associated with serious adverse events. More recent theories indicate that NMDAR target selectivity may be a cardinal prerequisite for efficacy, with present efforts being devoted primarily to development of NMDAR-NR2B subunit antagonists. We propose a novel hypothesis according to which NMDAR stimulation, accomplished through allosteric modulation via the glycine modulatory site, may be beneficial in late-phase PD. This hypothesis stems from: (1) meta-analysis of randomized controlled trials performed in schizophrenia, indicating that glycine site agonists (eg, glycine, D-serine) alleviate antipsychotic-induced parkinsonian symptoms; (2) clinical observations indicating that NMDAR hypofunction is associated with motor disturbances; (3) results of a preliminary D-serine trial in PD; (4) data indicating glycine efficacy in a rat tardive dyskinesia model; and (5) no evidence of excitotoxic damage following chronic high-dose glycine nutritional supplementation. This hypothesis is discussed in the context of glycine site agonist effects on intrasynaptic NMDAR subunits and striatal synaptic plasticity.

D-serine adjuvant treatment alleviates behavioural and motor symptoms in Parkinson's disease.

Parkinson's disease (PD) manifestations include motor symptoms and behavioural deficits that resemble schizophrenia negative symptoms. The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) represents a novel pharmacological target in PD. D-serine (DSR) allosterically modulates in-vivo NMDAR-mediated neurotransmission and has been shown to improve negative and antipsychotic drug-induced parkinsonian symptoms in schizophrenia patients. This pilot study assessed DSR effects in ten PD patients who completed a 6-wk double-blind, placebo-controlled, crossover adjuvant treatment trial with 30 mg/kg.d DSR. Primary outcome analyses consisted of separate repeated-measures multivariate analyses of variance for Unified Parkinson's Disease Rating Scale (UPDRS), Simpson-Angus Scale for Extrapyramidal Symptoms (SAS), Abnormal Involuntary Movement Scale (AIMS), and Positive and Negative Syndrome Scale (PANSS) scores. DSR treatment was well tolerated and resulted in increased DSR serum levels (p=0.001) and significantly reduced UPDRS (p=0.02), SAS (p=0.009) and PANSS (0.05) total scores. These preliminary findings suggest that DSR treatment may be beneficial in PD. Larger-sized studies with optimized DSR dosages are warranted.

D-aspartate oxidase gene duplication induces social recognition memory deficit in mice and intellectual disabilities in humans.

The D-aspartate oxidase (DDO) gene encodes the enzyme responsible for the catabolism of D-aspartate, an atypical amino acid enriched in the mammalian brain and acting as an endogenous NMDA receptor agonist. Considering the key role of NMDA receptors in neurodevelopmental disorders, recent findings suggest a link between D-aspartate dysmetabolism and schizophrenia. To clarify the role of D-aspartate on brain development and functioning, we used a mouse model with constitutive Ddo overexpression and D-aspartate depletion. In these mice, we found reduced number of BrdU-positive dorsal pallium neurons during corticogenesis, and decreased cortical and striatal gray matter volume at adulthood. Brain abnormalities were associated with social recognition memory deficit at juvenile phase, suggesting that early D-aspartate occurrence influences neurodevelopmental related phenotypes. We corroborated this hypothesis by reporting the first clinical case of a young patient with severe intellectual disability, thought disorders and autism spectrum disorder symptomatology, harboring a duplication of a chromosome 6 region, including the entire DDO gene.

Pilot controlled trial of D-serine for the treatment of post-traumatic stress disorder.

Enhancement of neurotransmission mediated at N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) may be beneficial in post-traumatic stress disorder (PTSD). d-serine (DSR) is an endogenous full agonist at the NMDAR-associated glycine modulatory site. Twenty-two chronic PTSD outpatients were randomly assigned to participate in a 6-wk double-blind, placebo-controlled, crossover trial with 30 mg/kg x d DSR used as monotherapy or add-on pharmacotherapy. Outcome was assessed using the Clinician-Administered PTSD scale (CAPS), Hamilton Anxiety (HAMA) and Depression (HAMD) scales and the civilian version of the Mississippi Scale for Combat-Related PTSD (MISS). DSR treatment was well tolerated and resulted in significantly (p=0.03) increased DSR serum levels. Compared with placebo administration, DSR treatment resulted in significantly reduced HAMA (p=0.007) and MISS (p=0.001) scores and a trend (p=0.07) towards improved CAPS total scores. These preliminary findings indicate that NMDAR glycine site-based pharmacotherapy may be effective in PTSD and warrant larger-sized clinical trials with optimized DSR dosages.

Shiatsu as an adjuvant therapy for schizophrenia: an open-label pilot study.

CONTEXT: Studies have suggested a possible role for shiatsu in treating a variety of mental and physical ailments. OBJECTIVE: To determine if shiatsu can provide clinical benefit to individuals diagnosed with schizophrenia. DESIGN: An open-label pilot study. SETTING: An inpatient psychiatric ward at Herzog Memorial Hospital, Jerusalem, Israel. PATIENTS: Twelve hospitalized patients with chronic schizophrenia. INTERVENTION: Shiatsu treatment provided in a course of eight 40-minute biweekly sessions over 4 weeks. MAIN OUTCOME MEASURES: All subjects were evaluated at baseline, 2 weeks, 4 weeks (end of treatment), and 12 weeks (followup). The tools used for assessment included the Clinical Global Impression (CGI), the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), the Hamilton Rating Scale for Depression (HAM-D), the Hamilton Anxiety Rating Scale (HAM-A), and the Nurses' Observation Scale for Inpatient Evaluation (NOSIE). Side effects were measured using the Simpson-Angus Scale for Extrapyramidal Symptoms (SAS) and the Abnormal Involuntary Movement Scale (AIMS). RESULTS: On all scales of psychopathology and side effects, the subjects showed a statistically and clinically significant improvement by the end of treatment. This improvement was maintained at the 12-week follow-up. These findings, while encouraging, must be considered preliminary and require confirmation and cross-validation in larger-scale controlled studies.

The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments.

OBJECTIVE: Patients with schizophrenia frequently present with negative symptoms and cognitive impairments for which no effective treatments are known. Agents that act at the glycine site of the N-methyl-D-aspartic acid (NMDA) glutamatergic receptor have been suggested as promising treatments for moderate to severe negative symptoms and cognitive impairments. METHOD: The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST) was a 16-week double-blind, double-dummy, parallel group, randomized clinical trial of adjunctive glycine, D-cycloserine, or placebo conducted at four sites in the United States and one site in Israel. The participants were 157 inpatients and outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder and retrospective and prospective criteria for moderate to severe negative symptoms without marked positive, depressive, or extrapyramidal symptoms. The primary outcome measures were the average "rate of change" of Scale for the Assessment of Negative Symptoms (SANS) total scores and change in the average cognitive domain z scores. RESULTS: There were no significant differences in change in the SANS total score between glycine and placebo subjects or D-cycloserine and placebo subjects. A prespecified test for the site-by-treatment-by-time interaction was significant in post hoc tests. One site had greater reduction in the SANS total score for patients receiving D-cycloserine relative to patients receiving placebo. A second site had greater reduction in the SANS total score for placebo patients compared with glycine patients. There were no significant differences between glycine and placebo or D-cycloserine and placebo subjects on the average cognition z score. CONCLUSIONS: The study results suggest that neither glycine nor D-cycloserine is a generally effective therapeutic option for treating negative symptoms or cognitive impairments.

High glycine levels are associated with prepulse inhibition deficits in chronic schizophrenia patients.

Prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating, is decreased in schizophrenia. The validity of a glutamatergic, N-methyl-d-aspartate receptor (NMDAR)-mediated model of PPI disruption is presently equivocal. The NMDAR antagonist ketamine disrupts PPI in rodents, but may increase PPI in healthy volunteers. Glycine (GLY), which acts as an obligatory co-agonist at the NMDAR-GLY site, induces PPI deficits in rats although, consistent with the hypo-NMDAR hypothesis, improves negative and cognitive symptoms in schizophrenia patients. We assessed the hypothesis that GLY serum levels may affect PPI parameters in schizophrenia. Forty-five chronically ill medicated schizophrenia patients and 37 matched healthy comparison subjects were tested for PPI of the eyeblink component of the startle reflex measured by electromyogram recording. Patients' demographic variables, symptom severity scores and GLY, serine and glutamate serum levels were obtained. Patients showed deficient PPI in blocks two and three of the PPI session and differed from controls in terms of change of degree of PPI as a function of the prepulse to eliciting stimulus interval. GLY levels correlated negatively with PPI parameters, such that patients with the highest GLY levels showed decreased PPI (rs=-0.4, p=0.03). These preliminary findings indirectly support previous observations on ketamine effects upon PPI in humans and suggest a dissociation of symptomatology and PPI changes as function of NMDAR modulation in schizophrenia.

Controlled trial of D-cycloserine adjuvant therapy for treatment-resistant major depressive disorder.

BACKGROUND: Compounds that reduce N-methyl-d-aspartate receptor (NMDAR) function, including NMDAR antagonists and partial agonists at the NMDAR-associated glycine (GLY) site, may act as antidepressants. The antibiotic drug d-cycloserine (DCS) acts as a partial agonist at the NMDAR-GLY site. Preclinical and clinical data suggest that at dosages >or=100 mg/day DCS acts as a functional NMDAR antagonist and may have antidepressant effects. METHODS: Twenty-two treatment resistant major depression patients participated in a double-blind, placebo-controlled 6-week crossover trial with 250 mg/day DCS added to their ongoing antidepressant medications. RESULTS: DCS treatment was well tolerated and resulted in symptom reductions. However, biweekly-performed clinical assessments, including the Hamilton Depression Rating Scale, Hamilton Rating Scale for Anxiety and Zung Self-Rating Depression Scale did not reveal statistically significant therapeutic advantages of DCS vs. placebo adjuvant treatment. LIMITATIONS: Small sample, uneven treatment resistance criteria across subjects. The exposure to DCS (dose/length of treatment) may not have been sufficient. CONCLUSIONS: This exploratory study represents the first attempt to assess the effects of a NMDAR-GLY site partial agonist in depression treatment. The findings and limitations of this study should be taken into account in the planning of future clinical trials with NMDAR modulators in depression.

Psychiatric manifestations in Turner Syndrome: a brief survey.

Turner Syndrome (TS) is a relatively common genetic syndrome in which a woman has a 45XO or 45XO/46XX mosaic karyotype. Although it is not associated with any psychiatric syndrome, several case reports in the literature describe a similar constellation of symptoms in TS that may represent a biologically-based entity. This article reviews existing case reports and seeks common characteristics among them, which may include mild psychosis with stress-precipitated onset, prominent mood features, and some features that may resemble organic disease.

[Expressed emotions (EE) towards schizophrenic patients among staff members of psychiatric wards and hostels: comparison and clinical implications].

Expressed emotion (EE) is an interactive criterion that describes the amount and quality of emotional communication between schizophrenic patients and their families or institutional care takers. EE is empirically related to the prognosis of the disease across cultures and therapeutic settings. This study compares results of EE assessments among psychiatric wards staff and hostels staff members. Our findings indicate that in each therapeutic milieu there is correlation between the institutional culture and the expected roles and behaviors of the patient. In the psychiatric hospital the most rejected patient is the psychotic patient presenting disturbances in thought and behavior, while the patient that is not rejected is the withdrawn non-active and not disturbing individual. In the hostel, the situation differs: the expectations from the patients are high functional levels in all fields, and therefore, the most rejected patients are those who are less functional in their initiative and occupational skills. Our findings also relate to the ability of staff members to change their attitudes towards patients in the two milieus. The findings of the comparison we performed indicate the advantages of the hostel staff's characteristics in the treatment of schizophrenia patients, and suggest specific recommendations for staff training in both milieus. The study highlights issues to be considered to ensure optimal functioning of the hostel as an appropriate setting for the treatment of schizophrenic patients.

D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia.

BACKGROUND: D-serine, a selective full agonist at the glycine site of N-methyl-D-aspartate glutamate receptor, might presently be the compound of choice for counteracting the hypothesized dysfunction of this receptor class in schizophrenia. Studies performed with Taiwanese patients indicate that D-serine significantly improves schizophrenia symptoms when used as adjuvant to conventional neuroleptics but not to clozapine. We assessed the efficacy and safety of D-serine adjuvant treatment for Occidental schizophrenia patients treated with newer atypical antipsychotics. METHODS: Thirty-nine risperidone- or olanzapine-treated schizophrenia patients participated in a double-blind, placebo-controlled, 6-week crossover trial with 30 mg/kg/day D-serine added to their antipsychotic medication. Measures of clinical efficacy and side effects were determined biweekly throughout the study. Clinical laboratory parameters and amino acid serum levels were monitored. RESULTS: D-serine administration induced increased serine serum levels (p < .001) and resulted in significant (p < .001) improvements in negative, positive, cognitive, and depression symptoms, as measured by the Positive and Negative Syndrome Scale. For approximately one third of the sample, D-serine treatment resulted in significant (>20%) reductions in Brief Psychiatric Rating Scale total scores. D-serine was well tolerated, and no detrimental changes in clinical laboratory parameters were noted. CONCLUSIONS: These findings 1) indicate that risperidone and olanzapine efficacy might be augmented with D-serine adjuvant treatment; 2) confirm D-serine efficacy against main schizophrenia symptom domains; and 3) warrant the assessment of D-serine antipsychotic monotherapy for this illness.

Association between the insulin-like growth factor 2 gene (IGF2) and scores on the Eating Attitudes Test in nonclinical subjects: a family-based study.

OBJECTIVE: An interesting candidate gene for eating disorders is the gene for insulin-like growth factor 2 (IGF2). Located on chromosome 11p15.5, IGF2 is a member of the insulin family of polypeptide growth factors that is involved in development and growth. Consistent with its profile of metabolic actions, an association has been reported between a single nucleotide polymorphism (SNP) in the 3' untranslated region of the IGF2 gene (ApaI) and body mass index. This investigation extended these studies and investigated the psychological and behavioral implications of this hormone's impact on metabolism and body composition. METHOD: The authors tested nonclinical subjects from 376 families for three IGF2 SNPs and for eating disorders, as reflected in scores on the 26-item Eating Attitudes Test, a self-report questionnaire widely used as a screening instrument. RESULTS: A highly significant association was observed between the IGF2 ApaI G allele and scores on the Eating Attitudes Test overall and each of its subscales (bulimia, dieting, and oral control). Additionally, a significant association was observed between this polymorphism and body mass index. CONCLUSIONS: The current finding that the IGF2 ApaI G polymorphism, which predisposes to weight gain, may also contribute to the pathology of eating disorders is intriguing. Neurotransmitter modulation of appetitive behavior is the focus of most hypotheses regarding the etiology of severe eating disorders. The current results to some measure challenge this view, and inborn metabolic tendencies to weight gain in some women may trigger constant dieting, which in predisposed individuals eventually leads to severe eating disorders.

Relation of plasma glycine, serine, and homocysteine levels to schizophrenia symptoms and medication type.

OBJECTIVE: Altered glycine and homocysteine levels may contribute to N-methyl-D-aspartate receptor dysfunction in schizophrenia. The authors measured plasma levels of these amino acids in a group of patients with chronic schizophrenia and related them to the patients' symptom profiles and types of antipsychotic medication. METHOD: Plasma levels of amino acids in 94 patients with schizophrenia were compared with those in 34 age- and sex-matched normal subjects. The Positive and Negative Syndrome Scale was used to evaluate the patients' psychopathology. RESULTS: Plasma glycine levels and glycine-serine ratios were lower and homocysteine levels were higher in patients than in comparison subjects. Low glycine levels correlated with a greater number of negative symptoms. The glycine-serine ratios of normal subjects and patients being treated with clozapine did not differ significantly. CONCLUSIONS: These findings support the hypothesis that altered levels of glycine and homocysteine may coexist in patients with schizophrenia and contribute to pathophysiological aspects of this illness.

Association of the serotonin transporter gene with smoking behavior.

OBJECTIVE: In an ongoing molecular genetic study of temperament, participants were genotyped to examine the association of smoking with two polymorphisms of the serotonin transporter gene (SERT): the promoter region, 5-HTTLPR, and an intronic variable-number-of-tandem-repeats region (VNTR). METHOD: Full information was available for 330 families, and 244 "ever smokers" were identified (54 past smokers, 190 current smokers). The average number of cigarettes smoked per day was 13.12, and the mean Fagerstrom Tolerance Questionnaire score was 4.79. Associations of genotype, Tridimensional Personality Questionnaire scores, and smoking phenotype were tested by using a robust family design with a variance-components framework and by case-control analysis. RESULTS: There was a significant excess of the 5-HTTLPR long allele with the 12-repeat VNTR in current smokers, past smokers, and ever smokers, compared to participants who had never smoked. The results from the population design were confirmed in the family-based analysis. No association was observed between two quantitative measures of smoking and the polymorphisms. A weak association was observed between novelty seeking and the VNTR polymorphism and between reward and 5-HTTLPR. Smokers, regardless of gender, scored significantly higher on novelty seeking and did not differ on harm avoidance or reward. CONCLUSIONS: There was a highly significant association between SERT and the categorical definition of smoking, irrespective of dependence level, suggesting that this gene influences the initiation of smoking. Mediation analysis failed to substantiate the hypothesis that novelty seeking partially mediates the effect of SERT on smoking. SERT appears to independently contribute to novelty seeking and smoking.

Glutamatergic neurotransmission modulators as emerging new drugs for schizophrenia.

Schizophrenia is a neurodevelopmental mental disorder whose aetiology includes genetic and environmental factors. Because of its early onset, chronicity and characteristic interference with education, employment and socialisation, this illness represents a tremendous human and economic burden to those who suffer from it, their families and society as a whole. Conventional and atypical antipsychotics, which mainly affect dopaminergic and serotonergic neurotransmission, are currently the cornerstone of schizophrenia treatment. Although the introduction of atypical antipsychotics represents a major development and, overall, antipsychotics are efficacious against psychotic symptoms, there remains a critical unmet need for innovative medications with improved efficacy and tolerability for the negative symptoms and cognitive deficits associated with schizophrenia. These dysfunction domains are reliable predictors of long-term disability and treatment outcome and are presently viewed as crucial targets for new pharmacological treatments of schizophrenia. Within this medication development framework, the modulation of glutamatergic neurotransmission has become the focus of intense research. Glutamate (GLU)-mediated neuronal processes are critical throughout the brain and glutamatergic neurotransmission dysfunctions have been hypothesised to play a crucial role in schizophrenia pathophysiology. Glutamatergic neurotransmission may be modulated at multiple levels, with GLU receptor families and their subtypes representing a modulatory site-rich environment for drug research. Numerous types of neurotransmission modulators, acting at the NMDA, AMPA and metabotropic GLU receptors, and/or affecting GLU synaptic release, are hypothesised to be beneficial for schizophrenia treatment, and are presently in various stages of development. For some of these compounds, preliminary studies have furnished encouraging clinical data. Ongoing and planned research is expected to provide, in the near future, critical information regarding the practical utility and tolerability of glutamatergic approaches for schizophrenia pharmacotherapy.

Characteristics of schizophrenia residents and staff rejection in community mental health hostels.

BACKGROUND: In the era of deinstitutionalization, increasing numbers of schizophrenia patients reside and receive rehabilitational treatment within the framework of community hostels. The quality of staff-patient relationships is a crucial determinant of the rehabilitational process outcome. METHOD: This study examined the characteristics of 56 schizophrenia hostel residents, measured the degree of staff criticism and rejection expressed towards these patients and assessed the contribution of residents and staff characteristics to the induction of staff rejection. Measures included assessments of patients' symptoms using the Positive and Negative Syndrome Scale (PANSS), staff attitudes using the Patient Rejection Scale (PRS), and patients' living skills using the Independent Living Skills Survey (ILSS). RESULTS: Young, relatively inexperienced instructors represented 60% of the hostels staff. Residents' symptoms and staff rejection levels were overall low. However, significantly increased rejection was expressed towards patients who were more symptomatic, as measured by PANSS total and positive symptoms scores and had diminished job-related and health care living skills. Staff older age and longer professional experience were correlated with higher rejection scores. LIMITATIONS: Relatively small sample size and catchment area. CONCLUSIONS: These findings highlight the need for a better definition and understanding of schizophrenia residents selection criteria and treatment goals in community hostels. Moreover, they suggest that improvements in this area should be coupled with the provision of specialized staff training aiming at the achievement of more flexible staff attitudes. Within this framework, the PRS may serve as a practical, cost-effective tool for monitoring crucial aspects of staff-patients relationships.