Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update

Growing consistent evidence indicates that hypofunction of N-methyl-D-aspartate (NMDA) transmission plays a pivotal role in the neuropathophysiology of schizophrenia. Hence, drugs which modulate NMDA neurotransmission are promising approaches to the treatment of schizophrenia. The aim of this article is to review clinical trials with novel compounds acting on the NMDA receptor (NMDA-R). This review also includes a discussion and translation of neuroscience into schizophrenia therapeutics. Although the precise mechanism of action of minocycline in the brain remains unclear, there is evidence that it blocks the neurotoxicity of NMDA antagonists and may exert a differential effect on NMDA signaling pathways. We, therefore, hypothesize that the effects of minocycline on the brain may be partially modulated by the NMDA-R or related mechanisms. Thus, we have included a review of minocycline neuroscience. The search was performed in the PubMed, Web of Science, SciELO, and Lilacs databases. The results of glycine and D-cycloserine trials were conflicting regarding effectiveness on the negative and cognitive symptoms of schizophrenia. D-serine and D-alanine showed a potential effect on negative symptoms and on cognitive deficits. Sarcosine data indicated a considerable improvement as adjunctive therapy. Finally, minocycline add-on treatment appears to be effective on a broad range of psychopathology in patients with schizophrenia. The differential modulation of NMDA-R neurosystems, in particular synaptic versus extrasynaptic NMDA-R activation and specific subtypes of NMDA-R, may be the key mediators of neurogenesis and neuroprotection. Thus, psychotropics modulating NMDA-R neurotransmission may represent future monotherapy or add-on treatment strategies in the treatment of schizophrenia.

Animal models of prenatal immune challenge and their contribution to the study of schizophrenia: a systematic review

Prenatal immune challenge (PIC) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism. Based on this, the goal of this article was to review the main contributions of PIC models, especially the one using the viral-mimetic particle polyriboinosinic-polyribocytidylic acid (poly-I:C), to the understanding of the etiology, biological basis and treatment of schizophrenia. This systematic review consisted of a search of available web databases (PubMed, SciELO, LILACS, PsycINFO, and ISI Web of Knowledge) for original studies published in the last 10 years (May 2001 to October 2011) concerning animal models of PIC, focusing on those using poly-I:C. The results showed that the PIC model with poly-I:C is able to mimic the prodrome and both the positive and negative/cognitive dimensions of schizophrenia, depending on the specific gestation time window of the immune challenge. The model resembles the neurobiology and etiology of schizophrenia and has good predictive value. In conclusion, this model is a robust tool for the identification of novel molecular targets during prenatal life, adolescence and adulthood that might contribute to the development of preventive and/or treatment strategies (targeting specific symptoms, i.e., positive or negative/cognitive) for this devastating mental disorder, also presenting biosafety as compared to viral infection models. One limitation of this model is the incapacity to model the full spectrum of immune responses normally induced by viral exposure.

Family expectation, social adjustment and gender differences in a sample of schizophrenic patients

A case series to study factors related to family expectation regarding schizophrenic patients was conducted in an out-patient setting in the city of S. Paulo, Brazil. Patients diagnosed as presenting schizophrenia by the ICD 9th Edition and having had the disease for more than four years were included in the study. Family Expectation was measured by the difference between the Katz Adjustment Scale (R2 and R3) scores based on the relative's expectation and the socially expected activities of the patient (Discrepancy Score), and social adjustment was given by the DSM-III-R Global Assessment Scale (GAS) . Outcome assessments were made independently, and 44 patients comprised the sample (25 males and 19 females). The Discrepancy mean score was twice as high for males as for females (p < 0.02), and there was an inverse relationship between the discrepancy score and social adjustment (r =-0.46, p < 0.001). Moreover, sex and social adjustment exerted independent effects on the discrepancy score when age, age at onset and number of psychiatric admissions were controlled by means of a multiple regression technique. There was an interaction between sex and social adjustment, the inverse relationship between social adjustment and discrepancy score being more pronounced for males. These findings are discussed in the light of the potential association between the family environment, gender and social adjustment of schizophrenic patients, and the need for further research, i.e. ethnographic accounts of interactions between patient and relatives sharing households particularly in less developed countries.

Mortality among patients with non-affective functional psychoses in a metropolitan area of South-Eastern Brazil

High mortality rates among those suffering from schizophrenia and related psychoses have been consistently described in developed societies. However, to date there is a lack of data on this matter in Brazil. In order to examine this issue, a prospective 2-year follow-up study was carried out in S. Paulo. The sample consisted of 120 consecutive admissions to psychiatric hospitals in a defined catchment area, aged 18 to 44 years old, with clinical diagnoses of non-affective functional psychoses according to the ICD-9. After 2 years, 116 (96.7%) subjects were traced. During the study period there were 7 deaths (6.0% of those traced), 5 (4.3%) due to suicide. All but one of the suicides occurred in the first year after discharge from hospital. Age and sex Standardised Mortality Ratios (relative to rates for the population of the city of Sao Paulo) were 8.4 for overall mortality (95% confidence interval: 4.0-15.9) and 317.9 for deaths due to suicide (95% confidence interval: 125.2-668.3). These results are in agreement with previous studies, and show that in Brazil non-affective functional psychoses are life-threatening illnesses, which need adequate care, particularly when patients go back to live in the community after hospital discharge.

Predicting the revolving door phenomenon among patients with schizophrenic, affective disorders and non-organic psychoses

OBJECTIVE: The aim of the study was to identify the variables that predict the revolving door phenomenon in psychiatric hospital at the moment of a second admission. METHODS: The sample consisted of 3,093 patients who have been followed during 5 to 24 years after their first hospital admission due to schizophrenia, and affective or psychotic disorders. Those who had had four or more admissions during the study period were considered as revolving door patients. Logistic regression analyses were used to assess the impact of gender, age, marital status, urban conditions, diagnosis, mean period of stay on the first admission, interval between the first and second admissions on the patterns of hospitalization. RESULTS: The variables with the highest predictive power for readmission were the interval between first and second admissions, and the length of stay in the first admission. CONCLUSIONS: These data may help public health planners in providing optimal care to a small group of patients with more effective utilization of the available services.

Proton magnetic resonance spectroscopy of the frontal lobe in schizophrenics: a critical review of the methodology

Schizophrenic patients undergoing proton magnetic resonance spectroscopy show alterations in N-acetyl aspartate levels in several brain regions, indicating neuronal dysfunction. The present review focuses on the main proton magnetic resonance spectroscopy studies in the frontal lobe of schizophrenics. A MEDLINE search, from 1991 to March 2004, was carried out using the key-words spectroscopy and schizophrenia and proton and frontal. In addition, articles cited in the reference list of the studies obtained through MEDLINE were included. As a result, 27 articles were selected. The results were inconsistent, 19 papers reporting changes in the N-acetyl aspartate levels, while 8 reported no change. Methodological analysis led to the conclusion that the discrepancy may be due the following factors: (i) number of participants; (ii) variation in the clinical and demographic characteristics of the groups; (iii) little standardization of the acquisition parameters of spectroscopy. Overall, studies that fulfill strict methodological criteria show N-acetyl aspartate decrease in the frontal lobe of male schizophrenics.

Dislipidemias e antipsicóticos atípicos

OBJETIVO: Um progressivo número de evidências surge associando o uso de antipsicóticos atípicos a dislipidemias, situação pouco atentada por considerável número de psiquiatras e preditora importante de doenças cardiovasculares (DCVs) e de morbimortalidade. O propósito deste estudo é revisar a associação entre o uso de antipsicóticos atípicos e o desenvolvimento de dislipidemias em pacientes com esquizofrenia. MÉTODOS: A pesquisa bibliográfica utilizou os bancos de dados MEDLINE e Scientific Electronic Library Online (SciELO), com os descritores: schizophrenia, dyslipidemia, hyperlipidemia e lipids, para identificar artigos originais publicados no período de 1997 a setembro de 2006. RESULTADOS: Os artigos foram agrupados segundo cada agente terapêutico, de acordo com o seu impacto sobre o perfil lipídico. CONCLUSÃO: Observa-se maior risco de desenvolvimento de dislipidemias em pacientes com esquizofrenia em uso de alguns antipsicóticos atípicos. Intervenções comportamentais e farmacológicas devem ser associadas nos indivíduos com esquizofrenia em tratamento antipsicótico e que desenvolvem dislipidemias.

Migration and mental health: Japanese Brazilians in Japan and in Brazil

OBJECTIVE: Brazil is the country with the largest community of Japanese descendants in the world, from a migration movement that started in 1908. However, more recently (1988), a movement in the opposite direction began. Many of these descendants went to Japan for work purposes and suffered mental distress. Some of them sought treatment in Japan, while others returned to Brazil to seek treatment. The aim of the present study was to compare the sociodemographic profile and diagnoses of Japanese Brazilian psychiatric outpatients in Japan (remaining group) and in Brazil (returning group). METHOD: All consecutive Japanese Brazilian outpatients who received care from the psychiatric units in Japan and Brazil from April 1997 to April 2000 were compared. The diagnoses were based on ICD-10 and were made by psychiatrists. Sociodemographic data and diagnoses in Brazil and Japan were compared by means of the Chi-Squared Test. RESULTS: The individuals who returned to Brazil were mostly male and unmarried, had lived alone in Japan, had stayed there for short periods and were classified in the schizophrenia group. The individuals who remained in Japan were mostly female and married, were living with family or friends, had stayed there for long periods and were classified in the anxiety group. Logistic regression showed that the most significant factors associated with the returning group were that they had lived alone and stayed for short periods (OR = 0.93 and 40.21, respectively). CONCLUSION: We conclude that living with a family and having a network of friends is very important for mental health in the context evaluated.

Quality of life assessment of patients with schizophrenic spectrum disorders from Psychosocial Care Centers

OBJECTIVE: Assessing the quality of life and the clinical and social-demographic factors associated in schizophrenic spectrum patients (ICD-10 F20-F29) attending CAPS at the programmatic area 3.0. METHODS: A cross-sectional study was carried out in a sample of schizophrenic spectrum patients who have been enrolled in 2008 in CAPS in programmatic area (AP) 3 at Rio de Janeiro city, using MINIPLUS to assess schizophrenia spectrum disorder and use of psychoactive substances, Positive and Negative Symptoms Scale (PANSS) to assess psychiatric symptoms and Quality of Life Scale (QLS-BR) to assess the quality of life. RESULTS: Seventy nine patients were included, of whom 74 (93.7%) presented some impairment in quality of life. The most frequently affected area was occupational performance. Variables that showed a significant association with severe impairment of quality of life were: marital status, race, occupation, who patients lived with, homelessness, having children, previous psychiatric hospitalization, negative symptoms and symptoms designated as not applicable (being characterized by a lack of typical positive and negative symptoms). CONCLUSION: The knowledge of these factors should be crucial to implement health policies and psychosocial rehabilitation programs focused on improving the quality of life of these patients.

Adesão ao tratamento medicamentoso em pacientes do espectro esquizofrênico: uma revisão sistemática da literatura

OBJETIVO: Realizar revisão sistemática para avaliar a adesão medicamentosa ao tratamento em pacientes do espectro esquizofrênico. MÉTODO: As buscas dos artigos foram conduzidas nas seguintes bases de dados: PubMed/Medline, Lilacs, SciELO e PePSIC, considerando artigos publicados entre 2001 e 2010. Na estratégia de busca, foram utilizados descritores de acordo com sua definição no DeCS e no MeSH: "schizophrenia" and "patient adherence" or "patient compliance" or "medication adherence". As correspondências em português e espanhol foram respectivamente "esquizofrenia/esquizofrenia" e "cooperação do paciente/cooperácion del paciente" ou "adesão à medicação/cumplimiento de lá medicación". Também foram realizadas buscas manuais nas referências dos artigos selecionados. RESULTADOS: A busca bibliográfica resultou em 1.692 artigos. Contudo, apenas 54 preencheram os critérios para compor esta revisão. CONCLUSÕES: A maioria dos estudos sobre o tema foi realizada em países desenvolvidos, prejudicando a aplicação dos achados à nossa realidade. As taxas da adesão e os métodos utilizados para avaliação variaram bastante, porém os fatores associados à não adesão se repetiram, como falta de insight, comorbidade com uso de substâncias psicoativas, falta de apoio social, efeitos colaterais da medicação, comportamento violento, situação de rua, tentativa de suicídio, entre outros. Assim sendo, há necessidade da realização de mais estudos nacionais para investigar potenciais variáveis associadas a não adesão e suas consequências para a população estudada.

Programas metacognitivos com enfoque em cognição social na reabilitação da esquizofrenia: uma revisão sistemática

OBJETIVO: Revisar sistematicamente a literatura sobre programas psicoterapêuticos para a esquizofrenia com enfoque em CS, cujos métodos envolvam estratégias metacognitivas. MÉTODOS: Foi realizada uma busca na base MedLine, por trabalhos publicados em inglês ou português utilizando a frase "Social cognition" AND "Schizophrenia" [Mesh] AND "Psychotherapy" [Mesh] e os limitadores "Humans", "Clinical Trial", "Meta-Analysis" e "Randomized Controlled Trial". Adicionalmente, foram elaborados critérios de inclusão para selecionar os trabalhos com abordagem metacognitiva. RESULTADOS: Dezessete estudos foram selecionados, abrangendo essencialmente programas de reconhecimento do afeto facial e de emoções, Teoria da Mente (ToM), imitação e tomada de perspectiva em situações sociais. CONCLUSÃO: A maior parte dos estudos mostrou que seus programas são eficazes para melhorar medidas de psicopatologia, CS e funcionamento social. Futuras pesquisas deverão esclarecer sobre segurança, especificidade e durabilidade dessas intervenções.

Clozapine-induced severe eosinophilia: report of a case with good outcome

INTRODUCTION: Clozapine is the antipsychotic of choice in the treatment of refractory schizophrenia. However, its side effects, such as eosinophilia, may preclude its use. METHODS: Case report and literature review. RESULTS: Young woman, 19 years old, diagnosed with hebefrenic schizophrenia, admitted at Unicamp's psychiatry ward after psychotic symptoms relapse. Clozapine was started after unsuccessful attempts with risperidon and olanzapine. By the fourth week of clozapine use, eosinophils began to increase. Drug titration was stopped, but eosinophils counts continued to rise up, reaching the mark of 5200/mm³. Due to severity of psychotic symptoms and to the good response obtained with clozapine, we decided to investigate organs involvement before withdrawing the medication. As the patient had no organs involvement, clozapine was maintained and one month after eosinophils peak, it was already normalized. CONCLUSION: Eosinophilia should not necessarily lead to clozapine's withdrawal. Patients who present eosinophilia must be at rigorous observation for organs involvement, and if there is no such involvement, clozapine might be maintained, considering the possible benign and transitory nature of the eosinophils count elevation.

Psychiatric comorbidities among adolescents with and without anxiety disorders: a community study

ABSTRACT Objective To evaluate, in a community sample of adolescents, the presence of comorbidities in different anxiety disorders. Methods This is a cross-sectional study, initially composed of 2,457 adolescents, aged between 10-17 years old, from public schools of the area covered by the Basic Health Unit of a university hospital. We applied the Screen for Child Anxiety Related Emotional Disorders (SCARED) to assess for anxiety disorders. Then, 138 positive cases in the screening were assessed for mental disorders through the Schedule for Affective Disorder and Schizophrenia for School-Age Children – Present and Lifetime Version (K-SADS-PL). Results Patients with anxiety disorders had more association with other anxiety disorders, as well as depression, and enuresis. The most common comorbidity described in our study was between generalized anxiety disorder and separation anxiety disorder (OR = 4.21, 95% CI 1.88, 9.58). Significant association was observed between other disorders such as enuresis and separation anxiety disorder (OR = 3.81, 95% CI 1.16, 12.49), as well as depression and generalized anxiety disorder (OR = 3.40; 95% CI 1.52, 7.61). Conclusion Our study showed a relevant presence of comorbidities adolescents with anxiety disorders, selected from a community sample, especially regarding other anxiety disorders. Nevertheless, further studies are needed to confirm our findings.

Faux Pas Test in schizophrenic patients

ABSTRACT Objective The aim of this study is to validate the adult version of “Faux Pas Recognition Test” created by Stone and colleagues (1998) as a reliable instrument assess and discriminate social cognition among schizophrenia patients and healthy controls. Methods This is a cross-sectional study with a total of 196 participants (mean age = 26.45; CI (95%) [25.10; 27.83]) 51% male. From those, 44 (22.4%) patients with schizophrenia and 152 (77.6%) healthy controls. The participants answered a short version of the Faux Pas Recognition Test, composed by 10 stories. Results Significant differences were found between both groups regarding their scores on Faux Pas Recognition Test (p = 0.003). Patients with schizophrenia had lower score, compared to healthy controls. Story 14 was the best to distinguish both groups, and Story 16, the worst. Among the questions of Faux Pas stories, the one related to intuition presented the most significant difference between the groups (p = 0.001), followed by the one related to understanding (p = 0.003). Conclusion The Brazilian version of the Faux Pas Recognition Test is a valid test to assess social cognition in schizophrenia and can be an important instrument to be used on the clinical practice.