Cannabis use influence on peripheral brain-derived neurotrophic factor levels in antipsychotic-naïve first-episode psychosis.

The objective of this study is to determine whether cannabis influences BDNF levels in patients with psychosis (FEP) and healthy volunteers (HV) to help understand the role of BDNF in psychosis. We assessed the association between BDNF and cannabis in a cohort of FEP antipsychotic-naïve patients and HV, whilst controlling for other potential confounding factors. 70 FEP drug-naive patients and 57 HV were recruited. A sociodemographic variable collection, structured clinical interview, weight and height measurement, substance use determination, and blood collection to determine BDNF levels by ELISA analysis were done. In FEP patients, cannabis use was associated with BDNF levels (high cannabis use was associated with lower BDNF levels). Moreover, cannabis use was statistically significantly associated with age (high use of cannabis was associated with younger age). In HV, no relationship between cannabis use and BDNF levels was observed. Otherwise, cannabis use was significantly associated with tobacco use, so that high cannabis users were also high tobacco users. This study showed a different association between cannabis use and BDNF levels in FEP patients compared with HV, particularly, with high doses of cannabis. These findings may help understand the deleterious effects of cannabis in some vulnerable individuals, as well as discrepancies in the literature.

Impact of cognitive impairment, depression, disease activity, and disease damage on quality of life in women with systemic lupus erythematosus.

OBJECTIVES: To define the relative role of cognitive impairment, depression, disease activity, and disease damage in the decreased health-related quality of life (HRQoL) frequently observed in systemic lupus erythematosus (SLE) patients. METHOD: We studied 101 Chilean female SLE patients and applied the 12-item Medical Outcomes Study (MOS) Short Form Health Survey version 2 (SF-12v2) to assess HRQoL and the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess cognitive function. Analysis of covariance (ANCOVA) models included demographic and disease-related factors and cognitive function tests of sustained attention, memory, and executive function. RESULTS: All measures of HRQoL were lower in the 101 female SLE patients compared to the women from the Chilean general population. HRQoL was associated with the following factors: (i) depression symptoms, which were detrimental to all components of the physical and mental HRQoL scores; (ii) executive dysfunction (spatial planning), which was associated with lower scores on role limitations due to physical health problems and emotional problems, and general health perceptions; (iii) higher activity and organ damage were deleterious to role physical, bodily pain, and physical summary scores; and (iv) higher damage also impacted physical function. Impairments in sustained attention and memory did not decrease the HRQoL. CONCLUSIONS: Our results highlight the relevance of executive dysfunction to poor physical and mental health components of HRQoL in SLE together with depression, while disease activity and disease damage are associated with lower HRQoL physical components. The need for cognitive function evaluation and rehabilitation in SLE is indicated.

Psychometric precision in phenotype definition is a useful step in molecular genetic investigation of psychiatric disorders.

Affective disorders are highly heritable, but few genetic risk variants have been consistently replicated in molecular genetic association studies. The common method of defining psychiatric phenotypes in molecular genetic research is either a summation of symptom scores or binary threshold score representing the risk of diagnosis. Psychometric latent variable methods can improve the precision of psychiatric phenotypes, especially when the data structure is not straightforward. Using data from the British 1946 birth cohort, we compared summary scores with psychometric modeling based on the General Health Questionnaire (GHQ-28) scale for affective symptoms in an association analysis of 27 candidate genes (249 single-nucleotide polymorphisms (SNPs)). The psychometric method utilized a bi-factor model that partitioned the phenotype variances into five orthogonal latent variable factors, in accordance with the multidimensional data structure of the GHQ-28 involving somatic, social, anxiety and depression domains. Results showed that, compared with the summation approach, the affective symptoms defined by the bi-factor psychometric model had a higher number of associated SNPs of larger effect sizes. These results suggest that psychometrically defined mental health phenotypes can reflect the dimensions of complex phenotypes better than summation scores, and therefore offer a useful approach in genetic association investigations.

Behavioural and molecular endophenotypes in psychotic disorders reveal heritable abnormalities in glutamatergic neurotransmission.

Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders.

Anti-N-methyl-D-aspartate receptor and anti-ribosomal-P autoantibodies contribute to cognitive dysfunction in systemic lupus erythematosus.

OBJECTIVE: Autoantibodies against N-methyl-D-aspartate receptor (anti-NMDAR) and ribosomal-P (anti-P) antigens are potential pathogenic factors in the frequently observed diffuse brain dysfunctions in patients with systemic lupus erythematosus (SLE). Although studies have been conducted in this area, the role of anti-NMDAR antibodies in SLE cognitive dysfunction remains elusive. Moreover, the specific contribution of anti-P antibodies has not been reported yet. The present study attempts to clarify the contribution of anti-NMDAR and anti-P antibodies to cognitive dysfunction in SLE. METHODS: The Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to assess a wide range of cognitive function areas in 133 Chilean women with SLE. ANCOVA models included autoantibodies, patient and disease features. RESULTS: Cognitive deficit was found in 20%. Higher SLEDAI-2K scores were associated with impairment in spatial memory and learning abilities, whereas both anti-NMDAR and anti-P antibodies contributed to deficits in attention and spatial planning abilities, which reflect fronto-parietal cortex dysfunctions. CONCLUSIONS: These results reveal an association of active disease together with specific circulating autoantibodies, such as anti-NMDAR and anti-P, with cognitive dysfunction in SLE patients.

Systemic lupus erythematosus impairs memory cognitive tests not affected by depression.

OBJECTIVE: Our aim was to assess the contribution of depression to cognitive impairment in patients with systemic lupus erythematosus (SLE). METHODS: Clinical features, education, age, and Hospital Anxiety and Depression Scale (HADS) were evaluated in 82 patients with SLE and 22 healthy controls, all Chilean women. The Cambridge Neuropsychological Test Automated Battery (CANTAB eclipseTM) assessing attention, spatial memory, and learning and executive function domains was applied. Cognitive deficit definition: a cut-off for definite impairment was defined as a score below -2 standard deviations in at least one outcome measure in two or more domains. ANCOVA with stepwise selection evaluated influences of health status (SLE or control), age, education, and HADS depression and anxiety scores on cognitive outcomes. To avoid overfitting, a shrinkage method was performed. Also, adjusted p-values for multiple comparisons were obtained. RESULTS: Cognitive deficit affected 16 (20%) patients, and no controls (p=0.039). Median HADS depression score in SLE patients was 6 (range 0-19) and in controls was 0 (0-19), p<0.001). ANCOVA and shrinkage models showed that worse cognitive performance in sustained attention and spatial working memory tests was explained by the presence of SLE but not depression, whereas depression only affected a measure of executive function (I/ED Stages completed). CONCLUSION: Depression has a limited role in cognitive impairment in SLE. Impairments in sustained attention and spatial working memory are distinctly influenced by yet-unknown disease-intrinsic factors.

Speed of facial affect intensity recognition as an endophenotype of first-episode psychosis and associated limbic-cortical grey matter systems.

BACKGROUND: Psychotic disorders are highly heritable such that the unaffected relatives of patients may manifest characteristics, or endophenotypes, that are more closely related to risk genes than the overt clinical condition. Facial affect processing is dependent on a distributed cortico-limbic network that is disrupted in psychosis. This study assessed facial affect processing and related brain structure as a candidate endophenotype of first-episode psychosis (FEP). METHOD: Three samples comprising 30 FEP patients, 30 of their first-degree relatives and 31 unrelated healthy controls underwent assessment of facial affect processing and structural magnetic resonance imaging (sMRI) data. Multivariate analysis (partial least squares, PLS) was used to identify a grey matter (GM) system in which anatomical variation was associated with variation in facial affect processing speed. RESULTS: The groups did not differ in their accuracy of facial affect intensity rating but differed significantly in speed of response, with controls responding faster than relatives, who responded faster than patients. Within the control group, variation in speed of affect processing was significantly associated with variation of GM density in amygdala, lateral temporal cortex, frontal cortex and cerebellum. However, this association between cortico-limbic GM density and speed of facial affect processing was absent in patients and their relatives. CONCLUSIONS: Speed of facial affect processing presents as a candidate endophenotype of FEP. The normal association between speed of facial affect processing and cortico-limbic GM variation was disrupted in FEP patients and their relatives.