Meta-analysis reveals no association of the Val66Met polymorphism of brain-derived neurotrophic factor with either schizophrenia or bipolar disorder

BACKGROUND: A long-term controversy exists on whether or not major psychotic disorders can be discretely divided into two groups, for example, schizophrenia and bipolar disorder. Many genes and polymorphisms have been studied for a role in both disorders, including the Val66Met (also known as rs 6265 or G196A) variant of brain-derived neurotrophic factor (BDNF). Many case-control association studies have been performed to see if BDNF could serve as a useful clinical diagnostic biomarker for schizophrenia or bipolar disorder, but results have been equivocal. OBJECTIVE: To determine, by meta-analysis, if the Val66Met polymorphism of BDNF influences risk for either schizophrenia, bipolar disorder, or both. METHODS: We searched Pubmed, Medline, and PsycInfo using keywords including Val66Met, Rs6265, G196A, BDNF, schizophrenia, and bipolar disorder. A total of 13 studies for schizophrenia and 11 studies for bipolar disorder were combined by random-effects meta-analysis. MAIN RESULTS: The pooled results from the schizophrenia sample (2955 patients; 4035 controls) and the bipolar disorder sample (3143 patients; 6347 controls) indicated lack of significance with either of the two psychoses, with pooled odds ratios of 1.00 (P=0.944) and 0.95 (P=0.161), respectively. CONCLUSION: Although there are some limitations on the study, our results indicate there is a lack of association between the Val66Met polymorphism and either of the two psychoses. A larger sample size, and evaluation of more single-nucleotide polymorphisms are needed to obtain more robust and conclusive findings regarding the relationship between the BDNF gene and psychosis.     

Reliability of an fMRI paradigm for emotional processing in a multisite longitudinal study

Multisite neuroimaging studies can facilitate the investigation of brain‐related changes in many contexts, including patient groups that are relatively rare in the general population. Though multisite studies have characterized the reliability of brain activation during working memory and motor functional magnetic resonance imaging tasks, emotion processing tasks, pertinent to many clinical populations, remain less explored. A traveling participants study was conducted with eight healthy volunteers scanned twice on consecutive days at each of the eight North American Longitudinal Prodrome Study sites. Tests derived from generalizability theory showed excellent reliability in the amygdala ( = 0.82), inferior frontal gyrus (IFG; = 0.83), anterior cingulate cortex (ACC; = 0.76), insula ( = 0.85), and fusiform gyrus ( = 0.91) for maximum activation and fair to excellent reliability in the amygdala ( = 0.44), IFG ( = 0.48), ACC ( = 0.55), insula ( = 0.42), and fusiform gyrus ( = 0.83) for mean activation across sites and test days. For the amygdala, habituation ( = 0.71) was more stable than mean activation. In a second investigation, data from 111 healthy individuals across sites were aggregated in a voxelwise, quantitative meta‐analysis. When compared with a mixed effects model controlling for site, both approaches identified robust activation in regions consistent with expected results based on prior single‐site research. Overall, regions central to emotion processing showed strong reliability in the traveling participants study and robust activation in the aggregation study. These results support the reliability of blood oxygen level‐dependent signal in emotion processing areas across different sites and scanners and may inform future efforts to increase efficiency and enhance knowledge of rare conditions in the population through multisite neuroimaging paradigms. Hum Brain Mapp 36:2558–2579, 2015. © 2015 Wiley Periodicals, Inc .     

Dynamic Hyperinflation Correlates with Exertional Oxygen Desaturation in Patients with Chronic Obstructive Pulmonary Disease

Background

Dynamic hyperinflation (DH) causes exercise limitation and exertional dyspnea in patients with chronic obstructive pulmonary disease (COPD). Exertional desaturation (ED) also occurs commonly in COPD but neither routine physiologic parameters nor imaging predict ED accurately. In this study we evaluated the relationship between DH and ED during 6-min walk testing (6MWT).

Methods

We measured ED and DH in patients with stable COPD. SpO₂ was measured by continuous pulse oximetry during 6MWT. ED was defined as a decline in SpO₂ (ΔSpO₂) ≥4 %. DH was determined by measuring inspiratory capacity (IC) before and after the 6MWT using a handheld spirometer. DH was defined as ΔIC >0.0 L. We correlated DH and ED with clinical and pulmonary physiologic variables by regression analysis, χ ², and receiver operator curve (ROC) analysis.

Results

Thirty males [age = 65 ± 9.4 years, FEV₁ % predicted = 48 ± 14 %, and DLCO % predicted = 50 ± 21 % (mean ± SD)] were studied. ΔSpO₂ correlated with ΔIC (r = 0.49, p = 0.005) and age (r = 0.39, p = 0.03) by univariate analysis; however, only ΔIC correlated on multivariate regression analysis (p = 0.01). ΔSpO₂ did not correlate with FEV₁, FVC, FEF_25–75, RV, DLCO % predicted, BMI, smoking, BORG score, or distance covered in 6MWT. DH strongly correlated with ED (p = 0.001). On ROC analysis, DH had an area under the curve of 0.92 for the presence of ED (sensitivity = 90 %; specificity = 77 %, p < 0.001).

Conclusion

Routine pulmonary function test results and clinical variables did not correlate with ED in patients with stable COPD. Dynamic hyperinflation strongly correlates with exertional desaturation and could be a reason for this desaturation.     

A comparative profile analysis of neuropsychological functioning in patients with schizophrenia and bipolar psychoses.

Evidence for neuropsychological deficits in schizophrenia is substantial whereas evidence for the specificity of dysfunction is relatively sparse. To assess specificity, we compared neuropsychological function in patients with chronic schizophrenia, patients with chronic psychotic bipolar disorder and normal controls. Groups were comparable on age, ethnicity and expected intellectual ability (based on single word reading). Patients with schizophrenia and bipolar psychoses were also relatively similar on age at onset and number of hospitalizations. Using multivariate analyses of variance with sex and parental SES as covariates (our primary analyses), patients with schizophrenia were significantly more impaired than controls on seven of eight neuropsychological functions (all but verbal ability), and were significantly more impaired than bipolar patients on abstraction, perceptual-motor speed and vigilance. Bipolar patients were significantly impaired compared to controls on declarative verbal memory, and showed moderate-to-large effect size decrements on abstraction, perceptual-motor speed and vigilance. Results were not attenuated when IQ was controlled, which was significantly lower in patients with schizophrenia. Analyses indicated that the two psychiatric groups had similar profile patterns, but that patients with schizophrenia had a more severe impairment than patients with bipolar psychoses. Further research is required to determine whether similar mechanisms underly the neurocognitive deficits in these disorders.     

Familial association between attention deficit disorder and anxiety disorders

BACKGROUND AND METHOD: This study tested hypotheses about patterns of familial association between attention deficit disorder (ADD) and anxiety disorders among 356 first-degree relatives of 73 clinically referred children with ADD and 26 normal comparison children. Through structured diagnostic interviews with trained raters, relatives were assessed for adult and childhood psychopathology. After stratifying the sample of ADD probands into those with anxiety disorders and those without, the authors examined patterns of aggregation of ADD and anxiety disorders in the relatives of these probands as well as in the relatives of the normal comparison subjects. RESULTS: Familial risk analyses revealed that 1) familial risk for anxiety disorders was higher among all ADD probands than among the normal subjects; 2) familial risk for ADD was similar in the relatives of the ADD probands and of the probands with ADD and anxiety disorder; 3) the relatives of the ADD probands with and without anxiety disorders were at greater risk for ADD than the relatives of the normal subjects; 4) the risk for anxiety disorders was two times higher in the relatives of the probands who had ADD with anxiety disorder than in those of the ADD probands without anxiety disorders; and 5) there was a tendency for ADD probands' relatives who themselves had ADD to have a higher risk for anxiety disorders than ADD probands' relatives who did not have ADD (cosegregation). CONCLUSIONS: The results were most consistent with the hypotheses indicating that ADD and anxiety disorders segregate independently in families.     

Understanding predisposition to schizophrenia: toward intervention and prevention.

OBJECTIVE: Early intervention to prevent schizophrenia is one of the most important goals of schizophrenia research. However, the field is not yet ready to initiate trials to prevent prodromal or psychotic symptoms in people who are at risk for developing the disorder. In this paper, we consider some of the major obstacles that must be studied before prevention strategies become feasible. METHOD AND RESULTS: One of the most important hurdles is the identification of a syndrome or set of traits that reflects a predisposition to schizophrenia and that might provide potential targets for intervention. In a recent reformulation of Paul Meehl's concept of schizotaxia, we integrate research findings obtained over the last 4 decades to propose a syndrome with meaningful clinical manifestations. We review the conceptualization of this syndrome and consider its multidimensional clinical expression. We then describe preliminary research diagnostic criteria for use in adult, nonpsychotic, first-degree relatives of patients diagnosed with schizophrenia, based on negative symptoms and neuropsychological deficits. We follow this with evidence supporting the validity of the proposed syndrome, which mainly includes social dysfunction and response to a low dosage of one of the newer antipsychotic medications. CONCLUSIONS: Continued progress toward the eventual initiation of prevention strategies for schizophrenia will include sustained efforts to validate the traits reflecting a predisposition to develop the disorder (for example, schizotaxia), follow-up studies to confirm initial findings, and the identification of potentially useful preventive interventions.     

Major depression with mood-congruent or mood-incongruent psychotic features: outcome after 40 years

Using cross-sectional evaluations 40 years after index admissions, the authors compared depressed patients with mood-congruent and those with mood-incongruent psychotic features. These patients were then compared with patients with nonpsychotic major depression, schizophreniform disorder, or schizophrenia. Outcome in the mood-congruent group resembled that in the nonpsychotic group and was significantly better than that in the mood-incongruent group. Patients in this latter group, however, had significantly better follow-up scores than did schizophrenic patients. These findings are consistent with a short-term outcome and family history study and suggest that patients with major depression and mood-incongruent psychotic features constitute a more diagnostically heterogeneous group than do those with mood-congruent psychotic features.