Therapeutic Drug Monitoring of Long-Acting Injectable Antipsychotic Drugs.

BACKGROUND: The use of therapeutic drug monitoring (TDM) to guide treatment with long-acting injectable (LAI) antipsychotics, which are increasingly prescribed, remains a matter of debate. The aim of this review was to provide a practical framework for the integration of TDM when switching from an oral formulation to the LAI counterpart, and in maintenance treatment. METHODS: The authors critically reviewed 3 types of data: (1) positron emission tomography data evaluating dopamine (D2/D3) receptor occupancy related to antipsychotic concentrations in serum or plasma; D2/D3 receptors are embraced as target sites in the brain for antipsychotic efficacy and tolerability, (2) pharmacokinetic studies evaluating the switch from oral to LAI antipsychotics, and (3) pharmacokinetic data for LAI formulations. Based on these data, indications for TDM and therapeutic reference ranges were considered for LAI antipsychotics. RESULTS: Antipsychotic concentrations in blood exhibited interindividual variability not only under oral but also under LAI formulations because these concentrations are affected by demographic characteristics such as age and sex, genetic peculiarities, and clinical variables, including comedications and comorbidities. Reported data combined with positron emission tomography evidence indicated a trend toward lower concentrations under LAI administration than under oral medications. However, the available evidence is insufficient to recommend LAI-specific therapeutic reference ranges. CONCLUSIONS: Although TDM evidence for newer LAI formulations is limited, this review suggests the use of TDM when switching an antipsychotic from oral to its LAI formulation. The application of TDM practice is more accurate for dose selection than the use of dose equivalents as it accounts more precisely for individual characteristics.

[Therapeutic drug monitoring in neuropsychopharmacology : Summary of the consensus guidelines 2017 of the TDM task force of the AGNP]. / Therapeutisches Drug-Monitoring in der Neuropsychopharmakologie : Zusammenfassung der Konsensusleitlinien 2017 der TDM-Arbeitsgruppe der AGNP.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood serum or plasma to optimize pharmacological therapy. TDM is an instrument with which the high interindividual variability of pharmacokinetics of patients can be identified and therefore enables a personalized pharmacotherapy. In September 2017 the TDM task force of the Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update of the consensus guidelines on TDM published in 2011. This article summarizes the essential statements for the clinical practice in psychiatry and neurology.

α2A -Adrenergic receptor polymorphisms and mRNA expression levels are associated with delay discounting in cocaine users.

Cocaine users characteristically display preferences for smaller immediate rewards over larger delayed rewards, and this delay discounting (DD) has been proposed as an endophenotype of cocaine addiction. Recent evidence suggests that the norepinephrine system and more specifically the α2A -adrenergic receptor (ADRA2A) are impacted by chronic cocaine use while also being potentially involved in the neural mechanisms underlying DD. Hence, we investigated the effects of ADRA2A polymorphisms and ADRA2A mRNA expression levels on DD of cocaine users and stimulant-naïve controls. Two hundred and twenty-three participants (129 cocaine users and 94 stimulant-naïve healthy controls) completed a computerized DD paradigm and were genotyped for three single nucleotide polymorphisms (SNPs; rs1800544, rs521674 and rs602618) in the ADRA2A gene, while their peripheral ADRA2A mRNA expression was quantified in whole blood samples. The three SNPs were in near-perfect linkage disequilibrium. Accordingly, significant group*genotype interactions were found for all three ADRA2A variants revealing steeper DD in cocaine users (but not in controls) carrying the G-allele of SNP rs1800544, the T-allele of rs521674 and the C-allele of rs602618. Similarly, high ADRA2A mRNA expression levels were significantly associated with a reduced tendency to choose smaller more immediate rewards (over larger delayed rewards) in cocaine users but not in controls. As the relationship between DD and cocaine use was moderated by ADRA2A SNPs and by peripheral ADRA2A gene expression, we propose that the norepinephrine system is involved in DD deficits observed in cocaine using individuals. Consequently, pharmacological compounds targeting ADRA2As might be considered for the symptom-specific treatment of delay aversion in stimulant addiction.

Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia.

In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional consequences of such single-nucleotide polymorphisms (SNPs) in the affected genes or their regulatory regions. The Global Test was applied to detect schizophrenia-associated pathways using discovery and replication datasets comprising 5,040 and 5,082 individuals of European ancestry, respectively. Information concerning functional gene-sets was retrieved from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and the Molecular Signatures Database. Fourteen of the gene-sets or pathways identified in the discovery dataset were confirmed in the replication dataset. These include functional processes involved in transcriptional regulation and gene expression, synapse organization, cell adhesion, and apoptosis. For two genes, i.e. CTCF and CACNB2, evidence for association with schizophrenia was available (at the gene-level) in both the discovery study and published data from the Psychiatric Genomics Consortium schizophrenia study. Furthermore, these genes mapped to four of the 14 presently identified pathways. Several of the SNPs assigned to CTCF and CACNB2 have potential functional consequences, and a gene in close proximity to CACNB2, i.e. ARL5B, was identified as a potential gene of interest. Application of the present hierarchical approach thus allowed: (1) identification of novel biological gene-sets or pathways with potential involvement in the etiology of schizophrenia, as well as replication of these findings in an independent cohort; (2) detection of genes of interest for future follow-up studies; and (3) the highlighting of novel genes in previously reported candidate regions for schizophrenia.

Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating.

Several polymorphisms of the transcription factor 4 (TCF4) have been shown to increase the risk for schizophrenia, particularly TCF4 rs9960767. This polymorphism is associated with impaired sensorimotor gating measured by prepulse inhibition--an established endophenotype of schizophrenia. We therefore investigated whether TCF4 polymorphisms also affect another proposed endophenotype of schizophrenia, namely sensory gating assessed by P50 suppression of the auditory evoked potential. Although sensorimotor gating and sensory gating are not identical, recent data suggest that they share genetic fundamentals. In a multicenter study at six academic institutions throughout Germany, we applied an auditory P50 suppression paradigm to 1,821 subjects (1,023 never-smokers, 798 smokers) randomly selected from the general population. Samples were genotyped for 21 TCF4 polymorphisms. Given that smoking is highly prevalent in schizophrenia and affects sensory gating, we also assessed smoking behavior, cotinine plasma concentrations, exhaled carbon monoxide, and the Fagerström Test (FTND). P50 suppression was significantly decreased in carriers of schizophrenia risk alleles of the TCF4 polymorphisms rs9960767, rs10401120rs, rs17597926, and 17512836 (P < 0.0002-0.00005). These gene effects were modulated by smoking behavior as indicated by significant interactions of TCF4 genotype and smoking status; heavy smokers (FTND score ≥ 4) showed stronger gene effects on P50 suppression than light smokers and never-smokers. Our finding suggests that sensory gating is modulated by an interaction of TCF4 genotype with smoking, and both factors may play a role in early information processing deficits also in schizophrenia. Consequently, considering smoking behavior may facilitate the search for genetic risk factors for schizophrenia.

Investigation of the role of TCF4 rare sequence variants in schizophrenia.

Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci and is supported by several genetic and functional lines of evidence. While numerous studies have implicated common genetic variation at TCF4 in schizophrenia risk, the role of rare, small-sized variants at this locus-such as single nucleotide variants and short indels which are below the resolution of chip-based arrays requires further exploration. The aim of the present study was to investigate the association between rare TCF4 sequence variants and schizophrenia. Exon-targeted resequencing was performed in 190 German schizophrenia patients. Six rare variants at the coding exons and flanking sequences of the TCF4 gene were identified, including two missense variants and one splice site variant. These six variants were then pooled with nine additional rare variants identified in 379 European participants of the 1000 Genomes Project, and all 15 variants were genotyped in an independent German sample (n = 1,808 patients; n = 2,261 controls). These data were then analyzed using six statistical methods developed for the association analysis of rare variants. No significant association (P < 0.05) was found. However, the results from our association and power analyses suggest that further research into the possible involvement of rare TCF4 sequence variants in schizophrenia risk is warranted by the assessment of larger cohorts with higher statistical power to identify rare variant associations.

Investigation of the involvement of MIR185 and its target genes in the development of schizophrenia.

BACKGROUND: Schizophrenia is a complex neuropsychiatric disorder of unclear etiology. The strongest known genetic risk factor is the 22q11.2 microdeletion. Research has yet to confirm which genes within the deletion region are implicated in schizophrenia. The minimal 1.5 megabase deletion contains MIR185, which encodes microRNA 185. METHODS: We determined miR-185 expression in embryonic and adult mouse brains. Common and rare variants at this locus were then investigated using a human genetics approach. First, we performed gene-based analyses for MIR185 common variants and target genes using Psychiatric Genomics Consortium genome-wide association data. Second, MIR185 was resequenced in German patients (n = 1000) and controls (n = 500). We followed up promising variants by genotyping an additional European sample (patients, n = 3598; controls, n = 4082). RESULTS: In situ hybridization in mice revealed miR-185 expression in brain regions implicated in schizophrenia. Gene-based tests revealed association between common variants in 3 MIR185 target genes (ATAT1, SH3PXD2A, NTRK3) and schizophrenia. Further analyses in mice revealed overlapping expression patterns for these target genes and miR-185. Resequencing identified 2 rare patient-specific novel variants flanking MIR185. However, follow-up genotyping provided no further evidence of their involvement in schizophrenia. LIMITATIONS: Power to detect rare variant associations was limited. CONCLUSION: Human genetic analyses generated no evidence of the involvement of MIR185 in schizophrenia. However, the expression patterns of miR-185 and its target genes in mice, and the genetic association results for the 3 target genes, suggest that further research into the involvement of miR-185 and its downstream pathways in schizophrenia is warranted.

Neural correlates of stress-reactive rumination in depression - The role of childhood trauma and social anxiety.

Recent work showed an association of prefrontal dysfunctions in patients with Major Depressive Disorder (MDD) and social stress induced rumination. However, up to date it is unclear which etiological features of MDD might cause prefrontal dysfunctions. In the study at hand, we aimed to replicate recent findings, that showed prefrontal activation alterations during the Trier Social Stress Test (TSST) and subsequently increased stress-reactive rumination in MDD compared to healthy controls. Moreover, we aimed to explore the role of adverse childhood experiences and other clinical variables in this relationship. N = 55 patients currently suffering from MDD and n = 42 healthy controls (HC) underwent the TSST, while cortical activity in areas of the Cognitive Control Network (CCN) was measured via functional near-infrared spectroscopy (fNIRS). The TSST successfully induced a stress reaction (physiologically, as well as indicated by subjective stress ratings) and state rumination in all subjects with moderate to large effect sizes. In comparison to HC, MDD patients showed elevated levels of state rumination with large effect sizes, as well as a typical pattern of reduced cortical oxygenation during stress in the CCN with moderate effect sizes. Self-reported emotional abuse and social anxiety were moderately positively associated with increased stress-reactive rumination. Within the MDD sample, emotional abuse was negatively and social anxiety positively associated with cortical oxygenation within the CCN with moderate to large effect sizes. In conclusion, our results replicate previous findings on MDD-associated prefrontal hypoactivity during stress and extends the research toward specific subtypes of depression.

A variant of the neuronal amino acid transporter SLC6A15 is associated with ACTH and cortisol responses and cognitive performance in unipolar depression.

Major depressive disorder (MDD) is accompanied by both cognitive impairments and a hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system, resulting in an enhanced glucocorticoid secretion. Cortisol acts via mineralocorticoid and glucocorticoid receptors densely located in the hippocampus, a brain area that is important regarding cognitive functions and especially memory functions. Recently, a variant (rs1545843) affecting transcription of the human SLC6A15 gene has been associated with depression in a genome-wide association study. In an animal model, the neuronal amino acid transporter SLC6A15 was found to be decreased in stress-susceptible mice. Against the background of stress impacting on the activity of the HPA axis, we have investigated alterations of adrenocorticotropic hormone (ACTH) and cortisol secretion in the combined dexamethasone/corticotrophin-releasing hormone (Dex/CRH) test as well as memory and attention performance in a sample of 248 patients with unipolar depression and 172 healthy control subjects genotyped for rs1545843. MDD patients carrying the depression-associated AA genotype showed enhanced maximum and area under the curve ACTH and cortisol answers (p = 0.03) as well as an impaired memory and impaired sustained attention performance (p = 0.04) compared to carriers of at least one G allele. No effects of the SLC6A15 variant were found in the healthy control group. Our findings argue for a role of the SLC6A15 gene in ACTH and cortisol secretion during the Dex/CRH test and furthermore in the occurrence of cognitive impairments in unipolar depression.

Nicotine enhances antisaccade performance in schizophrenia patients and healthy controls.

Nicotine has been proposed to be a cognitive enhancer, particularly in schizophrenia patients. So far, the published studies of nicotine effects on antisaccade performance in schizophrenia patients only tested participants who were deprived smokers. Thus, we aimed to test both smoking and non-smoking patients as well as healthy controls in order to extend previous findings. Moreover, we employed a paradigm using standard and delayed trials. We hypothesized that, if nicotine is a genuine cognitive enhancer, its administration would improve antisaccade performance both in smoking and non-smoking participants. A total of 22 patients with schizophrenia (12 smokers and 10 non-smokers) and 26 controls (14 smokers and 12 non-smokers) completed the study. The effects of a nicotine patch (14 mg for smokers, 7 mg for non-smokers) on antisaccade performance were tested in a randomized, double-blind, placebo-controlled, cross-over trial. Schizophrenia patients made significantly more antisaccade errors than controls (p = 0.03). Both patients and controls made fewer antisaccade errors in the delayed trials than in the standard trials (p < 0.0001). Nicotine significantly reduced antisaccade error rate in the standard trials, but not in the delayed trials (p = 0.02). Smoking status did not influence the nicotine effect on antisaccade error rate (p = 0.10) indicating an equal procognitive effect of nicotine in smokers and non-smokers. Overall the present findings indicate that beneficial effects of nicotine on antisaccade performance are not confined to smoking schizophrenia patients. Instead, the findings likely represent genuine nicotine-induced enhancement of cognitive performance.

The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) influences age at onset of obsessive-compulsive disorder.

Neuropeptide S (NPS) is a novel central acting neuropeptide that modulates several brain functions. NPS has shown strong anxiolytic-like effects and interactions with other central transmitter systems, including serotonin and glutamate. A coding variation (Asn107Ile) of the NPS receptor gene (NPSR1) was associated with panic disorder and schizophrenia. Based on these encouraging findings, the present study aimed at exploring a potential role of NPSR1 in obsessive­compulsive disorder (OCD). A sample of 232 OCD patients was successfully genotyped for the NPSR1 Asn107Ile variant (rs324981). Age at onset was taken into account to address the heterogeneity of the OCD phenotype. The NPSR1 genotype significantly affected age at onset of the OCD patients, with a mean age at onset approximately 4 yr earlier in homozygous carriers of the low-functioning Asn107 variant compared to patients with at least one Ile107 variant (p=0.032). Case­control analyses with 308 healthy control subjects reveal a highly significant association of the Asn107 variant with early onset OCD (odds ratio=2.36, p=0.0004) while late onset OCD or the OCD group as a whole were unrelated to the NPSR1 genotype. Based on our association finding relating NPSR1 genotype to early onset OCD, we suggest a differential role of the NPS system in OCD. In particular, the early onset OCD subtype seems to be characterized by a genetically driven low NPS tone, which might affect other OCD-related transmitter systems, including the serotonin and glutamate systems. In agreement with preclinical research, we suggest that NPS may be a promising pharmacological candidate with anti-obsessional properties.

In situ fNIRS measurements during cognitive behavioral emotion regulation training in rumination-focused therapy: A randomized-controlled trial.

Repetitive negative thinking (RNT), including rumination, plays a key role in various psychopathologies. Although several psychotherapeutic treatments have been developed to reduce RNT, the neural correlates of those specific treatments and of psychotherapy in general are largely unknown. Functional near-infrared spectroscopy (fNIRS) offers the potential to investigate the neural correlates of psychotherapeutic techniques in situ. Therefore, in this study we investigated the efficacy and neural correlates of a fNIRS adapted Mindfulness-based Emotion Regulation Training (MBERT) for the treatment of depressive rumination in 42 subjects with major depressive disorder (MDD) in a cross-over designed randomized controlled trial. Using psychometric measures, subjective ratings and fNIRS, we analyzed in situ changes in depressive symptom severity, ruminative thoughts and cortical activity in the Cognitive Control Network (CCN). Our results show that MBERT is effective in treating depressive symptoms and rumination. On a neural level, we found consistently higher cortical activation during emotion regulation training compared to control trials in the bilateral inferior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC). Furthermore, cortical oxygenation decreased from session to session in the bilateral DLPFC. The relevance of the results for the psychotherapeutic treatment of MDD as well as further necessary investigations are discussed.

The schizophrenia risk allele C of the TCF4 rs9960767 polymorphism disrupts sensorimotor gating in schizophrenia spectrum and healthy volunteers.

In a large-scale meta-analysis, it has been recently shown that the transcription factor 4 (TCF4) gene is among the most prominent susceptibility genes for schizophrenia. Moreover, transgenic mice overexpressing TCF4 in the brain display a reduction of sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR). PPI is heritable and has been established as an important translational endophenotype of schizophrenia. We therefore investigated the impact of the schizophrenia susceptibility gene TCF4 (rs9960767) on sensorimotor gating of the ASR in healthy humans and in patients with a schizophrenia spectrum disorder. We assessed PPI, startle reactivity, and habituation of the ASR in two independent samples. The first sample consisted of 107 healthy volunteers from London, UK. The second sample was a schizophrenia spectrum group (n = 113) of 73 schizophrenia patients and 40 individuals at high risk for schizophrenia from Bonn, Germany (total sample n = 220). In both samples, PPI was strongly decreased in carriers of the schizophrenia risk allele C of the TCF4 gene (meta-analysis across both samples: p = 0.00002), whereas startle reactivity and habituation were unaffected by TCF4 genotype. Sensorimotor gating is modulated by TCF4 genotype, indicating an influential role of TCF4 gene variations in the development of early information-processing deficits in schizophrenia.

The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response.

Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development.

Association of amygdala volumes with cortisol secretion in unipolar depressed patients.

Major depressive disorder (MDD) is accompanied by morphological changes of brain structures which are of great importance in the neural circuitry mediating depression like the hippocampus and the amygdala. Hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system resulting in enhanced glucocorticoid secretion can often be observed during depression and has been thought to play an important role in inducing these morphological changes. We used magnetic resonance imaging to investigate alterations of amygdala and hippocampal volumes in 86 in-patients with unipolar depression and 87 healthy controls, and we then correlated amygdala and hippocampal volumes of 76 in-patients with the area under the curve of cortisol secretion in the dexamethasone/corticotropin releasing hormone (Dex/CRH) test at baseline and during short-term antidepressant therapy. In line with recently published studies both left and right amygdala volumes of patients in a first depressive episode were smaller than those of healthy controls. Patients with recurrent depressive episodes showed a reduction of hippocampal volumes, while amygdala volumes were normal. Larger left and right amygdala volumes correlated with a more pronounced reduction of HPA activity, measured by the cortisol secretion in the combined DEX/CRH test, during antidepressant therapy in patients with recurrent depressive episodes.

The schizophrenia risk gene ZNF804A influences the antipsychotic response of positive schizophrenia symptoms.

Genetic factors determining the response to antipsychotic treatment in schizophrenia are poorly understood. A new schizophrenia susceptibility gene, the zinc-finger gene ZNF804A, has recently been identified. To assess the pharmacogenetic importance of this gene, we treated 144 schizophrenia patients and assessed the response of positive and negative symptoms by PANSS. Patients homozygous for the ZNF804A risk allele for schizophrenia (rs1344706 AA) showed poorer improvement of positive symptoms (7.35 ± 0.46) compared to patients with a protective allele (9.41 ± 0.71, P = 0.022). This provides further evidence that ZNF804A is of functional relevance to schizophrenia and indicates that ZNF804A may be a novel target for pharmacological interventions.

A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis.

Mutations in postsynaptic scaffolding genes contribute to autism, thus suggesting a role in pathological processes in neurodevelopment. Recently, two de novo mutations in SHANK3 were described in schizophrenia patients. In most cases, abnormal SHANK3 genotype was also accompanied by cognitive disruptions. The present study queries whether common SHANK variants may also contribute to neuropsychological dysfunctions in schizophrenia. We genotyped five common coding or promoter variants located in SHANK1, SHANK2 and SHANK3. A comprehensive test battery was used to assess neuropsychological functions in 199 schizophrenia patients and 206 healthy control subjects. In addition, an independent sample of 77 subjects at risk for psychosis was analyzed for replication of significant findings. We found the T allele of the SHANK1 promoter variant rs3810280 to lead to significantly impaired auditory working memory as assessed with digit span (12.5 ± 3.6 vs. 14.8 ± 4.1, P < .001) in schizophrenia cases, applying strict Bonferroni correction for multiple testing. This finding was replicated for forward digit span in the at-risk sample (7.1 ± 2.0 vs. 8.3 ± 2.0, P = .044). Previously, altered memory functions and reduced dendritic spines and postsynaptic density of excitatory synapses were reported in SHANK1 knock-out mice. Moreover, the atypical neuroleptic clozapine was found to increase SHANK1 density in rats. Our findings suggest a role of SHANK1 in working memory deficits in schizophrenia, which may arise from neurodevelopmental changes to prefrontal cortical areas.

Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster.

Alcohol dependence (AD) is an important contributory factor to the global burden of disease. The etiology of AD involves both environmental and genetic factors, and the disorder has a heritability of around 50%. The aim of the present study was to identify susceptibility genes for AD by performing a genome-wide association study (GWAS). The sample comprised 1333 male in-patients with severe AD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and 2168 controls. These included 487 patients and 1358 controls from a previous GWAS study by our group. All individuals were of German descent. Single-marker tests and a polygenic score-based analysis to assess the combined contribution of multiple markers with small effects were performed. The single nucleotide polymorphism (SNP) rs1789891, which is located between the ADH1B and ADH1C genes, achieved genome-wide significance [P = 1.27E-8, odds ratio (OR) = 1.46]. Other markers from this region were also associated with AD, and conditional analyses indicated that these made a partially independent contribution. The SNP rs1789891 is in complete linkage disequilibrium with the functional Arg272Gln variant (P = 1.24E-7, OR = 1.31) of the ADH1C gene, which has been reported to modify the rate of ethanol oxidation to acetaldehyde in vitro. A polygenic score-based approach produced a significant result (P = 9.66E-9). This is the first GWAS of AD to provide genome-wide significant support for the role of the ADH gene cluster and to suggest a polygenic component to the etiology of AD. The latter result may indicate that many more AD susceptibility genes still await identification.

PCLO rs2522833 modulates HPA system response to antidepressant treatment in major depressive disorder.

Variant rs2522833 of the Piccolo-encoding gene PCLO has recently been found to be associated with major depressive disorder (MDD). PCLO encodes a presynaptic cytomatrix protein which influences monoamine neurotransmitter release. Piccolo could therefore play an important role in treatment response to antidepressant therapy and the improvement of alterations in HPA system reactivity. We investigated the influence of the coding variant rs2522833 in the PCLO gene on treatment response in 205 in-patients with unipolar depression. Treatment response was measured (1) at the level of psychopathology using the Hamilton Depression Rating Scale (HAMD) and (2) with the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, which is a refined tool for showing dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system, a neurobiological finding in depression. While we did not find an association between variation in PCLO and HAMD scores, HPA dysregulation was less pronounced in carriers of the AA genotype than in carriers of one or two C alleles. HPA activity of individuals with the AA genotype only marginally changed during 4-wk antidepressant treatment, whereas C allele carriers showed a higher hormonal secretion at admission than carriers of the AA genotype but lower responsivity to the Dex/CRH challenge after 4 wk. Our results point to a moderating role of PCLO SNP rs2522833 on HPA regulation during antidepressant treatment, which may represent a neurobiological feature of stability of clinical response.