Anna Schuhmacher

DNA sequence variants of the FKBP5 gene are associated with unipolar depression

FKBP5 is a glucocorticoid receptor-regulating co-chaperone of hsp-90 and, therefore, is suggested to play a role in the regulation of the hypothalamic-pituitary-adrenocortical system and the pathophysiology of depression. Previously, three studies identified single nucleotide polymorphisms (SNPs) in the FKBP5 gene associated with response to antidepressants, and one study found an association with diagnosis of depression. We selected five markers from the region of interest. A case-control sample comprising 268 German in-patients with recurrent unipolar depression, and 284 German controls recruited from the general population were available. Association of the selected FKBP5 sequence variants with clinical depression were analysed. In addition, we explored association with treatment response by (a) the Hamilton Depression Rating Scale and (b) the dexamethasone/corticotrophin-releasing hormone (Dex/CRH) test, as well as association with hippocampal volumes in a subpopulation of 110 patients. For three of the five investigated SNPs we were able to show association with the diagnosis of depression. In the subpopulation of 110 patients, diagnosis-related alleles were also associated with the reduction of cortisol secretion in the Dex/CRH test during a 4-wk treatment period, while psychopathological changes were not associated. Furthermore, diagnosis-related alleles were associated with reduction of the hippocampal volume. This study extends the replicated association of a promoter SNP with antidepressant response on a biological level by demonstrating normalization of the cortisol response under Dex/CRH stimulation during treatment. Furthermore, several of the investigated SNPs were associated with the disease status and the intermediate phenotype of hippocampal volume.

Functional serotonin 1A receptor variant influences treatment response to atypical antipsychotics in schizophrenia

The serotonin (5-HT) 1A receptor has been found to be dysregulated in prefrontal cortex and other brain regions in schizophrenia, and 5-HT1A receptor levels in the amygdala have been related to negative schizophrenia symptoms. We have assessed the impact of the functional C-1019G variant of the 5-HT1A receptor on the response to risperidone or haloperidol in a prospective, randomized, double-blind study. Patients were treated for 4 weeks and negative symptoms assessed weekly. The variant influenced the response to risperidone: improvement of negative symptoms by 4.38 points for carriers of the C allele, compared with the GG genotype (1.22 points, P=0.046). In a second independent study of 130 schizophrenia patients treated with atypical antipsychotics, this effect was confirmed (P=0.003). The functional variant of the 5-HT1A receptor thus influences the response of schizophrenia patients to atypical antipsychotics and may be useful in the future to predict the pharmacogenetics of negative symptoms.

Unipolar depression and hippocampal volume: Impact of DNA sequence variants of the glucocorticoid receptor gene†

Glucocorticoid receptor (GR) plays a major role in regulation of the hypothalamic–pituitary–adrenocortical (HPA) system; HPA dysregulation represents the most consistent biological pattern of depression. Multiple functional polymorphisms are known for the GR gene, which might influence the development of unipolar depression. Previous studies reported associations to some variants in this gene but not consistently so. We investigated seven genetic polymorphisms in the GR gene (NR3C1) located in the putative promoter, exon 2 and intron 2 region. Study populations were 322 German inpatients with recurrent unipolar depression, and 298 German controls recruited from the general population. The relationships between intermediate phenotypes (hippocampal and amygdala volumes) and NR3C1 DNA sequence variants were additionally explored in a subpopulation of patients. We found association between the diagnosis of depression and DNA sequence variants in intron 2 as well as in the 5′ region of the NR3C1 gene but not for the previously studied exon 2 and putative promoter variants (global test after control of multiple testing, P = 0.02). In patients, diagnosis‐related alleles were also associated to hippocampal volume reduction and amygdala volume variation. Unipolar depression is associated with DNA variants of the NR3C1 gene in our population. Neurobiological underpinnings of depression as volumetric reductions of the hippocampus may also be mediated by variants in this gene.

Sensorimotor Gating of Schizophrenia Patients Is Influenced by 5-HT2A Receptor Polymorphisms

BACKGROUND Schizophrenia patients exhibit impairment in prepulse inhibition (PPI) of the acoustic startle response (ASR), suggesting a sensorimotor gating deficit. The serotonin-2A receptor (5-HT(2A)R) has been implicated in both the pathogenesis of schizophrenia and the PPI deficits of schizophrenia patients. Moreover, both schizophrenia and PPI are thought to be inheritable. We investigated the impact of three 5-HT(2A)R polymorphisms (A-1438G, T102C, H452Y) on PPI in schizophrenia patients. METHODS We analyzed the 5-HT(2A)R A-1438G, T102C, and H452Y polymorphisms and assessed startle reactivity, habituation, and PPI of ASR in 68 Caucasian schizophrenia inpatients. Patients were also examined with the Positive and Negative Syndrome Scale. RESULTS The 5-HT(2A)R A-1438G and T102C polymorphisms were in complete linkage disequilibrium. Patients carrying the T102C TT and the A-1438G AA allele show significantly higher PPI levels and a faster early habituation compared with all other variants. 5-HT(2A)R A-1438G and T102C genotype explained approximately 11% of the PPI and early habituation variance. In contrast, the 5-HT(2A)R H452Y polymorphism did not affect startle parameters. CONCLUSIONS Our findings suggest that PPI and habituation are modulated by 5-HT(2A)R A-1438G and T102C genotype in schizophrenia. Consequently, alterations within brain 5-HT(2A)Rs may contribute to the PPI deficits in schizophrenia.

The value of HMPAO SPECT in predicting treatment response to citalopram in patients with major depression

Alterations of regional cerebral blood flow (rCBF) in prefrontal cortex and the anterior cingulate cortex are conspicuous imaging findings in patients with major depression (MD). While these rCBF changes have been suggested as functional disease markers, data in large patient samples examining treatment response prediction to antidepressant therapy are limited. This study examined the predictive value of Tc-99m-HMPAO-SPECT for subsequent treatment response to antidepressant therapy with citalopram in an unprecedented large collective of patients. Ninety-three patients with MD were examined with Tc-99m-HMPAO-SPECT twice, at the beginning of citalopram-treatment (T1) and after 4 weeks of treatment (T2). To determine the impact of rCBF changes associated with treatment response, the patient sample was divided into two subgroups: responders (44 patients) and non-responders (49 patients). A two-sample t-test was used to determine group-specific rCBF-differences. Age, gender and initial Hamilton Rating Scale for Depression (HRSD) were treated as regressors of no interest. The responder group revealed significant relative rCBF increases at T1 in a large region en-compassing predominantly prefrontal and temporal cortices as well as subgenual cingulate cortex. No relative rCBF decreases were detected in this group. The comparison between T1 and T2 revealed trends of rCBF decreases in inferior frontal gyrus and rCBF increases in premotor cortex in the responder group. Our data show that rCBF measurements with TC-99M-HMPAO-SPECT provide a predictor estimate for subsequent treatment response in depressed patients undergoing antidepressant therapy with citalopram. This effect is highly significant and, most notably, independent of the initial HRSD score.

No association of the Val66Met polymorphism of the brain-derived neurotrophic factor with hippocampal volume in major depression.

Recently, an association of the Val66Met polymorphism of the brain-derived neurotrophic factor with hippocampal volume in patients with major depression has been reported. Here, we aimed at replicating this finding in an independent German sample. We included 79 patients with unipolar major depressive episodes and 84 healthy comparison participants. The brain-derived neurotrophic factor Val66Met polymorphism was determined in all participants. The volume of the hippocampus was manually traced on high-resolution magnetic resonance images. The hippocampal volumes of patients were significantly smaller than those of the comparison participants, confirming previous reports. There was, however, no Val66Met effect on hippocampal volume in either group. To conclude, we did not replicate the Val66Met effect on hippocampal volume in neither patients with major depression nor in healthy participants.

Further evidence for a functional role of the glutamate receptor gene GRM3 in schizophrenia.

In recent years, evidence has been accumulating indicating a major role of glutamate in the pathogenesis and pathophysiology of schizophrenia. Of particular importance in this regard are the metabotropic glutamate receptors (GRM). Thus, a recently published trial of the amino acid analogue LY2140023, which exerts its effects through the activation of the glutamate receptors GRM3/GRM2, showed an improvement of positive and negative symptoms comparable to treatment with olanzapine. A functional variant of GRM3 has been described which modulates synaptic glutamate levels. We assessed whether this functional variant rs6465084 is related to schizophrenia in a large sample of patients and controls. We found an increased frequency of the A allele (p=0.027) and the AA genotype (p=0.024) in schizophrenia patients. Moreover, in an assessment of schizophrenia endophenotypes, patients of the AA genotype performed poorly in the digit symbol test, a measure of attention (p=0.008). Our results provide further evidence for the potential importance of the glutamate receptor GRM3 in schizophrenia, and indicate that the novel antipsychotic LY2140023 may actually be targeting a pathogenic pathway of schizophrenia.

Novel Schizophrenia Risk Gene TCF4 Influences Verbal Learning and Memory Functioning in Schizophrenia Patients

Background: Recently, a role of the transcription factor 4 (TCF4) gene in schizophrenia has been reported in a large genome-wide association study. It has been hypothesized that TCF4 affects normal brain development and TCF4 has been related to different forms of neurodevelopmental disorders. Schizophrenia patients exhibit strong impairments of verbal declarative memory (VDM) functions. Thus, we hypothesized that the disease-associated C allele of the rs9960767 polymorphism of the TCF4 gene led to impaired VDM functioning in schizophrenia patients. Method: The TCF4 variant was genotyped in 401 schizophrenia patients. VDM functioning was measured using the Rey Auditory Verbal Learning Test (RAVLT). Results: Carriers of the C allele were less impaired in recognition compared to those carrying the AA genotype (13.76 vs. 13.06; p = 0.049). Moreover, a trend toward higher scores in patients with the risk allele was found for delayed recall (10.24 vs. 9.41; p = 0.088). The TCF4 genotype did not influence intelligence or RAVLT immediate recall or total verbal learning. Conclusion: VDM function is influenced by the TCF4 gene in schizophrenia patients. However, the elevated risk for schizophrenia is not conferred by TCF4-mediated VDM impairment.

The His452Tyr variant of the gene encoding the 5-HT2A receptor is specifically associated with consolidation of episodic memory in humans

Basic research has shown that serotonin plays an important role in memory formation. Accordingly, genetic variation of serotonin receptors can be expected to affect memory and to underlie, in part, the heritability of memory capacity. A study by de Quervain and colleagues found a highly significant association of the functional 5-HT2A receptor variant His452Tyr (rs6314) with long-term memory. We replicated this finding in a cohort of 133 adults (mean age 43.5 yr). Carriers of the Tyr allele showed poorer verbal delayed recall and recognition, while immediate recall and additional measures of attentional and executive function were not affected by the His452Tyr genotype. Results suggest a possible role of 5-HT2A receptors in memory consolidation. Serotonergic drugs may have the potential to improve memory.

Influence of 5-HT3 receptor subunit genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E on treatment response to antipsychotics in schizophrenia.

Objectives Among serotonin (5-HT) receptors, the 5-HT3 receptor is the only ligand-gated ion channel. 5-HT3 antagonists such as ondansetron and tropisetron may improve auditory gating and neurocognitive deficits in schizophrenic patients. Moreover, many antipsychotic drugs are antagonists at 5-HT3 receptors. However, the role of 5-HT3 receptor variants on response to antipsychotic drugs in schizophrenic patients is still unclear. Methods In a prospective, randomized, double-blind study, we have assessed six functional and coding variants of the subunit genes HTR3A, HTR3B as well as the novel HTR3C, HTR3D, and HTR3E subunits in the response to haloperidol or risperidone. Seventy patients were treated for 4 weeks and positive symptoms, negative symptoms, and general psychopathology were measured by the Positive and Negative Syndrome Scale (PANSS). Results HTR3E had an effect on the speed of response to antipsychotics. GG-allele carriers responded more quickly to treatment on the PANSS negative symptom subscale (P = 0.03) and on the total PANSS score (P = 0.04) irrespective of medication. In a second independent study of 144 schizophrenia patients treated with atypical antipsychotics, this effect could not be confirmed. Conclusion Our findings argue against a major effect of HTR3 variants in response to antipsychotics. Solely, the HTR3E and also the HTR3A variant could exert a weak effect on the speed of response to antipsychotics.