Omega-3 fatty acids reduce cardiometabolic risk in first-episode schizophrenia patients treated with antipsychotics: Findings from the OFFER randomized controlled study.

Metabolic syndrome (MetS) increases the risk of premature mortality observed in schizophrenia (SCZ). N-3 polyunsaturated fatty acid (PUFA) deficiency has been reported in different stages of schizophrenia. N-3 PUFA supplementation was found to be beneficial in both chronic SCZ and MetS. No intervention studies based on n-3 PUFA as add-on therapy to antipsychotics have examined the changes in MetS risk in first-episode schizophrenia. AIM: This randomized placebo-controlled trial assesses the effect of a 26-week intervention composed of either 2.2 g/day of n-3 PUFA or olive oil placebo on the frequency of MetS and the changes in its constituents as a secondary outcome measure. METHODS: Seventy-one adult inpatients diagnosed with first-episode schizophrenia were randomly assigned to study groups. The active intervention used a 3:2 mixture of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. Metabolic syndrome components were monitored throughout the study. RESULTS: A significant reduction in the frequency of MetS was observed in the EPA + DHA group (p = 0.0408); as well as some specific MetS components: e.g., a decrease in fasting blood glucose (p = 0.045). The beneficial effects of EPA + DHA were even more pronounced in patients treated mainly with olanzapine, e.g. significant reductions of total cholesterol (p = 0.037) and blood glucose levels (p = 0.034). Significant positive correlations were found between the general psychopathology subscale of PANSS (primary outcome) and triglyceride level changes. CONCLUSION: N-3 PUFA supplementation in early SCZ may constitute a safe and affordable intervention that can reduce the risk of MetS and its lethal complications.

Higher order language impairments can predict the transition of ultrahigh risk state to psychosis-An empirical study.

AIM: Higher order language skills, for example, non-literal language, humour, prosody deal with 'what is meant' and they are necessary for communicative exchange and relationships; No study has investigated their link with conversion to psychosis. The purpose of this study was to determine whether such skills could act as predictors of the onset of psychosis, and compare those of individuals converting and non-converting to psychosis with control of cognitive functions. METHODS: Seventy-three patients, aged 15 to 32 years, fulfilling ultrahigh risk criteria took part: 14% of whom were receiving antipsychotic drugs. The study was observational, prospective and longitudinal in nature, and scheduled for 60 months. Pragmatic language skills were evaluated using the Polish version of the right hemisphere language battery. The ultrahigh risk (UHR) criteria were evaluated with Comprehensive Assessment of At-Risk Mental States; attention, intelligence and verbal fluency were controlled. RESULTS: The conversion rate was 25%; converters demonstrated impaired humour comprehension and metaphor explanation abilities; composite score of pragmatic language was associated with a hazard ratio of 6.0 (95% CI 1.8-20.5) and AUC of .73. Verbal fluency was an independent predictor of conversion, but attention and intelligence were not; pragmatic language skills were associated with social function but not with prodromal symptoms. CONCLUSIONS: The results suggest that deficits in humour comprehension and metaphor explanation could predict conversion to psychosis. These findings could improve diagnosis and create implications for speech and language therapy in UHR groups. Further studies on the mechanisms of pragmatic skills should analyze their relationship with abstract measures and semantic coherence.

The correlation between white matter integrity and pragmatic language processing in first episode schizophrenia.

OBJECTIVE: Higher-order language disturbances could be the result of white matter tract abnormalities. The study explores the relationship between white matter and pragmatic skills in first-episode schizophrenia. METHODS: Thirty-four first-episode patients with schizophrenia and 32 healthy subjects participated in a pragmatic language and Diffusion Tensor Imaging study, where fractional anisotropy of the arcuate fasciculus, corpus callosum and cingulum was correlated with the Polish version of the Right Hemisphere Language Battery. RESULTS: The patients showed reduced fractional anisotropy in the right arcuate fasciculus, left anterior cingulum bundle and left forceps minor. Among the first episode patients, reduced understanding of written metaphors correlated with reduced fractional anisotropy of left forceps minor, and greater explanation of written and picture metaphors correlated with reduced fractional anisotropy of the left anterior cingulum. CONCLUSIONS: The white matter dysfunctions may underlie the pragmatic language impairment in schizophrenia. Our results shed further light on the functional neuroanatomical basis of pragmatic language use by patients with schizophrenia.

An increase in plasma brain derived neurotrophic factor levels is related to n-3 polyunsaturated fatty acid efficacy in first episode schizophrenia: secondary outcome analysis of the OFFER randomized clinical trial.

RATIONALE: N-3 polyunsaturated fatty acids (n-3 PUFA) influence multiple biochemical mechanisms postulated in the pathogenesis of schizophrenia that may influence BDNF synthesis. OBJECTIVES: A randomized placebo-controlled study was designed to compare the efficacy of a 26-week intervention composed of either 2.2 g/day of n-3 PUFA or olive oil placebo, with regard to symptom severity in first-episode schizophrenia patients. The secondary outcome measure of the study was to describe the association between n-3 PUFA clinical effect and changes in peripheral BDNF levels. METHODS: Seventy-one patients aged 16-35 were enrolled in the study and randomly assigned to the following study arms: 36 to the EPA + DHA group and 35 to the placebo group. Plasma BDNF levels were assessed three times, at baseline and at weeks 8 and 26 of the intervention. BDNF levels were determined in plasma samples using Quantikine Human BDNF ELISA kit. Plasma BDNF level changes were further correlated with changes in the severity of symptoms in different clinical domains. RESULTS: A significantly greater increase in plasma BDNF levels was observed in the intervention compared to the placebo group (Cohen's d = 1.54). Changes of BDNF levels inversely correlated with change in depressive symptoms assessed using the Calgary Depression Rating Scale in Schizophrenia (Pearson's r = - 0.195; p = 0.018). CONCLUSIONS: The efficacy of a six-month intervention with n-3 PUFA observed in first-episode schizophrenia may be related to an increase in BDNF levels, which may be triggered by the activation of intracellular signaling pathways including transcription factors such as cAMP-reactive element binding protein.

Short clinically-based prediction model to forecast transition to psychosis in individuals at clinical high risk state.

OBJECTIVE: The predictive accuracy of the Clinical High Risk criteria for Psychosis (CHR-P) regarding the future development of the disorder remains suboptimal. It is therefore necessary to incorporate refined risk estimation tools which can be applied at the individual subject level. The aim of the study was to develop an easy-to use, short refined risk estimation tool to predict the development of psychosis in a new CHR-P cohort recruited in European country with less established early detection services. METHODS: A cohort of 105 CHR-P individuals was assessed with the Comprehensive Assessment of At Risk Mental States12/2006, and then followed for a median period of 36 months (25th-75th percentile:10-59 months) for transition to psychosis. A multivariate Cox regression model predicting transition was generated with preselected clinical predictors and was internally validated with 1000 bootstrap resamples. RESULTS: Speech disorganization and unusual thought content were selected as potential predictors of conversion on the basis of published literature. The prediction model was significant (p < 0.0001) and confirmed that both speech disorganization (HR = 1.69; 95%CI: 1.39-2.05) and unusual thought content (HR = 1.51; 95%CI: 1.27-1.80) were significantly associated with transition. The prognostic accuracy of the model was adequate (Harrell's c- index = 0.79), even after optimism correction through internal validation procedures (Harrell's c-index = 0.78). CONCLUSIONS: The clinical prediction model developed, and internally validated, herein to predict transition from a CHR-P to psychosis may be a promising tool for use in clinical settings. It has been incorporated into an online tool available at: https://link.konsta.com.pl/psychosis. Future external replication studies are needed.

A developmentally-stable pattern of premorbid schizoid-schizotypal features predicts psychotic transition from the clinical high-risk for psychosis state.

BACKGROUND: Despite the extensive research performed on prediction of psychosis from a Clinical High Risk for Psychosis state (CHR-P), the positive predictive value of the CHR-P designation remains unsatisfactory and further models including additional clinical and biological variables are required. Existing studies indicate that schizotypy assessed at baseline in "at-risk" individuals may be considered a predictor of transition from CHR-P to psychosis. This approach, however, is burdened with bias resulting from a possible overlap between current psychopathology and schizotypal features. No studies so far have assessed schizotypy in CHR-P from a developmental perspective. AIM: The aim of the study was to identify associations between a long-standing, parent-reported premorbid level of schizoid-schizotypal traits and the probability of psychotic transition in individuals with CHR-P. METHODS: The mothers of 107 individuals diagnosed as presenting CHR-P with the use of Comprehensive Assessment of At Risk Mental States12/2006 were interviewed with the Scale for the Assessment of Premorbid Schizoid-Schizotypal Traits (PSST). RESULTS: A high level of enduring schizotypy was found to be significantly associated with psychotic transition from CHR-P (HR: 1.78, 95% CI: 1.40-2.27, p < 0.0001), as indicated by the proportional hazards model, adjusted for age, sex and clinical covariates potentially related to the outcome. PSST items comprising negative schizotypy appeared to be the strongest predictors of transition. CONCLUSIONS: The assessment of parent-reported, present early in the development premorbid schizoid-schizotypal traits, which can be easily performed in clinical settings, may be of value in estimating the probability of transition from an "at risk" state to psychotic disorder.

Higher-order language dysfunctions as a possible neurolinguistic endophenotype for schizophrenia: Evidence from patients and their unaffected first degree relatives.

The purpose of the study was to examine the presence of pragmatic dysfunctions in first episode (FE) subjects and their healthy first degree relatives as a potential endophenotype for schizophrenia. Thirty-four FE patients, 34 parents of the patients (REL) and 32 healthy controls (HC) took part in the study. Pragmatic language functions were evaluated with the Right Hemisphere Language Battery, attention and executive functions were controlled, as well as age and education level. The parents differed from HC but not from their FE offspring with regard to overall level of language and communication and the general knowledge component of language processing. The FE participants differed from HC in comprehension of inferred meaning, emotional prosody, discourse dimensions, overall level of language and communication, language processing with regard to general knowledge and communication competences. The FE participants differed from REL regarding discourse dimensions. Our findings suggest that pragmatic dysfunctions may act as vulnerability markers of schizophrenia; their assessment may help in the diagnosis of early stages of the illness and in understanding its pathophysiology. In future research the adoptive and biological parents of schizophrenia patients should be compared to elucidate which language failures reflect genetic vulnerability and which ones environmental factors.

Polish individuals with an at-risk mental state: demographic and clinical characteristics.

AIM: The aim of this study is to present sociodemographic and clinical characteristics of Polish individuals with an at-risk mental state (ARMS). METHODS: A group of 99 individuals meeting the ARMS criteria were assessed in terms of sociodemographic data, psychopathological symptoms, psychosocial functioning and comorbidity. RESULTS: The sample (mean age 19 years) was 54.55% women. At baseline, nearly 73% of the sample was educated, and 20.20% were employed. Approximately 87.88% of the participants lived with their families. Nearly 77% of the sample presented attenuated psychotic symptoms (APS), 17.17% demonstrated APS with accompanying vulnerability traits and 19.19% showed vulnerability features only. The mean Social and Occupational Functioning Assessment Scale score was 49.55 (±7.70). No effect of age, gender or level of functioning on psychopathological symptoms was observed. The most common comorbid diagnoses were depressive (44.44%) and anxiety disorders (19.19%), which coexisted in 5.05% of the individuals. Approximately 28.28% of the diagnoses met the criteria for personality disorders. The dropout rate from the study was 19.09%, with stigma as the most common reason. CONCLUSIONS: Polish ARMS individuals are help-seeking young people most commonly presenting APS or vulnerability features. Despite a high level of psychosocial dysfunction, these individuals remain educationally active. Most individuals showed comorbid diagnoses (commonly depressive or anxiety disorders). Despite some differences resulting from the socioeconomic situation of the country or the specificity of the mental health services, the characteristics of the sample remain consistent with descriptions of ARMS populations worldwide. This study reaffirms the need for organizing early intervention services in non-stigmatizing settings.

A history of obstetric complications is associated with the risk of progression from an at risk mental state to psychosis.

OBJECTIVE: Clinical criteria for diagnosing Clinical High Risk for psychosis are now available. However, an understanding of the factors modulating the risk of subsequent development of frank psychosis in "at risk" individuals remains elusive. The aim of the study was to identify associations between obstetric history and the development of psychotic disorders in individuals with an At Risk Mental State (ARMS). METHODS: Obstetric data was obtained from the medical records of 82 individuals meeting ARMS criteria. The participants were followed up for a mean period of 42.3 (±28.3) months for transition to psychosis. RESULTS: A history of at least one obstetric complication (OC) endorsed as definite on the Lewis and Murray Obstetric Complications Scale was found to be associated with increased risk of transition to schizophrenia (OR: 6.57, 95% CI:1.89-22.85). The number of definite OCs was found to be positively correlated with the proportion of converters (p<0.0001). The probability of conversion to schizophrenia was found to increase with a decrease of Apgar-1 and Apgar-5 scores (ORs: 0.40, 95% CI:0.22-0.74 and 0.25, 95% CI:0.10-0.63, respectively). CONCLUSIONS: The findings emphasise the potential value of including obstetric data in algorithms estimating the likelihood of transition of an ARMS to full-blown psychosis.

Telomerase level increase is related to n-3 polyunsaturated fatty acid efficacy in first episode schizophrenia: Secondary outcome analysis of the OFFER randomized clinical trial.

Schizophrenia is associated with shortening of the lifespan mainly due to cardiovascular events, cancer and chronic obstructive pulmonary disease. Both telomere attrition and decrease of telomerase levels were observed in schizophrenia. Polyunsaturated fatty acids (PUFA) influence multiple biochemical mechanisms which are postulated to accelerate telomere shortening and limit the longevity of patients with schizophrenia. Intervention studies based on add-on therapy with n-3 polyunsaturated fatty acids (n-3 PUFA) in patients with schizophrenia did not assess the changes in telomerase levels. A randomized placebo-controlled trial named OFFER was designed to compare the efficacy of a 26-week intervention composed of either 2.2g/day of n-3 PUFA or olive oil placebo with regard to symptom severity in first-episode schizophrenia patients. The secondary outcome measure of the study was to describe the association between the clinical effect of n-3 PUFA and changes in telomerase levels. Seventy-one patients aged 16-35 were enrolled in the study and randomly assigned to the study arms. The Positive and Negative Syndrome Scale (PANSS) was used to assess the change in symptom severity. Telomerase levels of peripheral blood mononuclear cells (PBMC) were assessed at three points: at baseline and at weeks 8 and 26 of the intervention. A significantly greater increase in PBMC telomerase levels in the intervention group compared to placebo was observed (p<0.001). Changes in telomerase levels significantly and inversely correlated with improvement in depressive symptoms and severity of the illness. The efficacy of a six-month intervention with n-3 PUFA observed in first-episode schizophrenia may be related to an increase in telomerase levels.

Omega-3 fatty acid supplementation may prevent loss of gray matter thickness in the left parieto-occipital cortex in first episode schizophrenia: A secondary outcome analysis of the OFFER randomized controlled study.

The aim of the study was to assess changes in cortical thickness related to the use of n-3 polyunsaturated fatty acids (PUFA) as add-on therapy in patients with first episode schizophrenia. A double-blind randomized controlled study was conducted using a 26-week intervention composed of concentrated fish oil containing 2.2g/d of eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) or placebo (olive oil). Participants underwent MRI scanning twice to assess changes in cortical thickness: at the beginning and at the end of intervention. Data of suitable quality was obtained from 29 participants. The T1-weighted images for each participant were analyzed using FreeSurfer methodology for longitudinal pipeline. Significant differences in cortical thickness loss were observed between the groups in the parieto-occipital regions of Brodmann areas 7 and 19 of the left hemisphere, dysfunctions in which may be involved in schizophrenia symptomatology. The results of the study support the previous observations carried out in older individuals and patients with mild cognitive impairment, indicating that n-3 PUFA may have neuroprotective properties, especially at early stages of neurodegenerative diseases, such as schizophrenia. If replicated, the results of the present study may encourage clinicians to consider n-3 PUFA as a promising addition to antipsychotics for long-term treatment of schizophrenia.

Deficits in the identification of pleasant odors predict the transition of an at-risk mental state to psychosis.

OBJECTIVE: Existing knowledge of the relationship between olfactory identification (OI) ability and clinical risk of psychosis is inconsistent. To address this inconsistency, the aim of the present study was to identify the relationship between OI ability, with regard to the hedonic attributes of odors, and the risk of transition to psychosis in individuals with an ARMS. METHODS: A group of 81 individuals meeting the ARMS criteria according to the Comprehensive Assessment of At Risk Mental State were at baseline administered with the University of Pennsylvania Smell Identification Test. The hedonic attributes of odorants were normatively established. Participants were followed up for transition to psychosis for a mean period of 36.1months (SD:27.5months). RESULTS: The presence of deficits in the identification of pleasant odors was found to be a risk factor for conversion from an ARMS to schizophrenia. The hazard ratio for each point in deficit scores in the Cox regression model was 1.455 (95% CI: 1.211-1.747), p<0.0001. Significant deficits in the identification of pleasant odors were associated with a risk for conversion at both early and late time points from baseline. CONCLUSIONS: The findings imply that the impaired identification of pleasant odorants may be a risk factor for the transition of an ARMS into a psychotic disorder, and highlights the need for further research of OI in "at-risk" cohorts, taking into account the hedonic attributes of odors.

Omega-3 fatty acids in first-episode schizophrenia - a randomized controlled study of efficacy and relapse prevention (OFFER): rationale, design, and methods.

BACKGROUND: Polyunsaturated fatty acid (PUFA) metabolism abnormalities have been long implicated in the etiology of schizophrenia. Although several randomized clinical trials have been carried out to assess the efficacy of omega-3 PUFA as add-on therapy in reducing psychopathology in populations of chronic patients with schizophrenia, only a few concern first-episode schizophrenia. The majority of these studies used a 12-week intervention based on ethyl-eicosapentaenoic acid (ethyl-EPA), however, with conflicting results. An intervention based on docosahexaenoic acid plus EPA has not been used in first-episode schizophrenia studies so far. No add-on supplementation studies have been carried out in medicated first-episode schizophrenia patients to assess the efficacy of omega-3 PUFA in preventing relapses. METHODS: A randomized placebo-controlled one-center trial will be used to compare the efficacy of 26-week intervention, composed of either 1320 mg/day of EPA and 880 mg/day of DHA, or olive oil placebo with regard to symptom severity and relapse rate in first-episode schizophrenia patients. Eighty-two patients (aged 16-35) will be recruited for the study. Eligible patients will be randomly allocated to one of two intervention arms: an active arm or a placebo arm (olive oil). The primary outcome measure of the clinical evaluation is schizophrenia symptom severity measured by the Positive and Negative Syndrome Scale (PANSS). Other outcomes include depressive symptoms, patient functioning and the level of insight. Correlates of change measured during the study will include structural brain changes, oxidative stress and defense, as well as neuroplasticity indicators. Metabolic syndrome components will also be assessed throughout the study. DISCUSSION: By comparing 26-week administration of EPA + DHA or (placebo) olive oil as add-on therapy in reducing symptom severity and one-year relapse rate in patients with first episode schizophrenia, it is intended to provide new insights into the efficacy of omega-3 PUFA and correlates of change, and contribute to the improvement of mental health care for individuals suffering from schizophrenia. TRIAL REGISTRATION: This study has been registered at Clinical Trials.gov with the following number: NCT02210962 .