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The role of the brain-derived neurotrophic factor (BDNF) in the pathophysiology of major depressive disorder (MDD) remains to be elucidated. Recent post hoc analyses indicated a potential association of three polymorphisms in the BDNF gene with worse treatment outcome in patients with the subtype of melancholic depression. We aimed at replicating these findings in a German naturalistic multicenter follow-up. Three polymorphisms in the BDNF gene (rs7103411, rs6265 (Val66Met) and rs7124442) were genotyped in 324 patients with MDD and 470 healthy controls. We applied univariate tests and logistic regression models stratifying for depression subtype and gender. The three polymorphisms were not associated with MDD as diagnosis. Further, no associations were found in univariate tests. With logistic regression, we only found a tendency towards an association of the rs6265 (Val66Met) polymorphism with overall response to treatment (response rates: GG (val/val) < GA (val/met) < AA (met/met); p = 0.0129) and some gender differences for the rs6265 (Val66Met) and rs7103411 polymorphisms. Treatment outcome stratified for subtypes of depression did not differ significantly between the investigated polymorphisms or using haplotype analyses. However, results showed a tendency towards significance. At this stage, we cannot support an influence of these three polymorphisms. Further studies in larger patient samples to increase sample sizes of subgroups are warranted.

The synaptosomal-associated protein of 25 kDa (SNAP-25) is part of the soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment receptor (SNARE), which mediates synaptic neurotransmission. In earlier studies a possible involvement of this protein in schizophrenia has been shown. As neurocognitive impairment is a core feature in the pathology of schizophrenia and considered to be a putative endophenotype according to genetic studies we investigated the influences of different SNAP-25 polymorphisms on neuropsychological test results before and during treatment with atypical antipsychotics. A total of 104 schizophrenic patients treated with atypical antipsychotics were genotyped for three different polymorphisms of the SNAP-25 gene (MnlI, TaiI and DdeI in the 3'-UTR). Cognitive function was assessed at baseline, week 4 or 6 and week 8 or 12. Results of individual neuropsychological tests were assigned to six cognitive domains (reaction time and quality; executive function; working, verbal and visual memory) and a general cognitive index. The MnlI and TaiI polymorphisms showed no associations to deficits on neuropsychological test results. In contrast, we observed a significant relation between the DdeI polymorphism of the SNAP-25 gene and cognitive dysfunctions. Homozygote T/T allele carriers of the DdeI polymorphism showed significant better neuropsychological test results in cognitive domains verbal memory and executive functions than those with the combined T/C and C/C genotypes (P < 0.01) at all three time points, but no differences in response to treatment with atypical antipsychotics. Additionally, TT carriers exhibited significantly better results in a general cognitive index (P < 0.05). As we observed an association between the DdeI polymorphism of the SNAP-25 gene and cognitive dysfunctions of schizophrenic patients our finding suggests that the SNAP-25 gene could play a role in the pathophysiology of neurocognitive dysfunctions in schizophrenia but is not predictive for treatment response with atypical antipsychotics.

Two recently described polymorphisms in the promoter region of the apolipoprotein E (APOE), the -491A/T and Th1/E47csT/G polymorphism, have been suggested to be associated with an increased risk for Alzheimer's disease (AD) independent from the APOE epsilon 4 carrier status. We studied the association between the APOE epsilon 4 polymorphism and the -491A/T and Th1E47csT/G polymorphisms in a sample of 118 healthy, non-demented controls and 239 consecutively recruited gerontopsychiatric patients diagnosed as: Alzheimer's disease (N = 89), age mild cognitive impairment (N = 32), memory complainers without any cognitive deficit (N = 54) and depression/other psychiatric disorders (N = 64), to test whether the investigated polymorphisms have a high enough selectivity and specificity to distinguish between the different gerontopsychiatric disorders or to differentiate AD genetically from other forms of dementia, respectively. Also a possible association with the APOE epsilon 4 polymorphism was examined. We found a statistically significant association between the APOE epsilon 4 allele and Alzheimer's disease (p = 0.0001) and age associated memory impairment (p = 0.006). Our study failed to show an association between the promoter polymorphisms -491A/T and Th1E47csT/G in the APOE gene and gerontopsychiatric disorders either alone or in relationship to the APOE epsilon 4 polymorphism. However, if we combine our results with three previous published positive reports there seems to be an association between the -491A/T polymorphism and AD, though its size is less than found in the original publication.

There is increasing evidence that the neurodegenerative processes in Alzheimer's disease (AD) may be related to alterations in calcium homeostasis and that these metabolic changes are not necessarily restricted to the central nervous system. However, previous studies investigating [Ca2+]i in fibroblasts, lymphoblasts, platelets and lymphocytes of AD patients gave inconclusive results, since increase, decrease and no alteration in [Ca2+]i were found in AD patients compared with controls. With respect to the importance of establishing altered Ca2+ homeostasis in peripheral cells, we have investigated [Ca2+]i in circulating mononuclear cells of patients with AD, multi-infarct dementia, age-associated memory impairment and healthy controls. [Ca2+]i was evaluated using the fluorescent dye fura-2 before and during stimulation with phythaemagglutinin (PHA). In our study we failed to find major differences in resting [Ca2+]i and in response to stimulation with 25 micrograms/ml and 100 micrograms/ml PHA in cells of AD patients as compared with all other groups investigated. There was only a tendency towards a decrease in [Ca2+]i in AD after stimulation with PHA. Thus the present findings suggest that [Ca2+]i evaluation in mononuclear cells does not have diagnostic value in discriminating AD patients from other demented patients. However, there might be some difference in [Ca2+]i values between early- and late-onset AD, which could have pathophysiological importance.