Definitions and symptoms of the post-COVID syndrome: an updated systematic umbrella review.

Post-COVID syndrome (PCS) describes a persistent complex of symptoms following a COVID-19 episode, lasting at least 4 to 12 weeks, depending on the specific criteria used for its definition. It is often associated with moderate to severe impairments of daily life and represents a major burden for many people worldwide. However, especially during the first two years of the COVID-19 pandemic, therapeutic and diagnostic uncertainties were prominent due to the novelty of the disease and non-specific definitions that overlooked functional deficits and lacked objective assessment. The present work comprehensively examines the status of PCS definitions as depicted in recent reviews and meta-analyses, alongside exploring associated symptoms and functional impairments. We searched the database Pubmed for reviews and meta-analysis evaluating PCS in the period between May 31, 2022, to December 31, 2023. Out of 95 studies, 33 were selected for inclusion in our analyses. Furthermore, we extended upon prior research by systematically recording the symptoms linked with PCS as identified in the studies. We found that fatigue, neurological complaints, and exercise intolerance were the most frequently reported symptoms. In conclusion, over the past eighteen months, there has been a notable increase in quantity and quality of research studies on PCS. However, there still remains a clear need for improvement, particularly with regard to the definition of the symptoms necessary for diagnosing this syndrome. Enhancing this aspect will render future research more comparable and precise, thereby advancing and understanding PCS.

45 years German Society of Biological Psychiatry (DGBP).

The foundation of a German Society of Biological Psychiatry (DGBP) was initiated at the Second World Congress of Biological Psychiatry of the WFSBP in Barcelona in 1978. Its mission was and is to promote interdisciplinary research on the biology of mental disorders and to translate results of biological research into clinical practice. During the presidency of Peter Falkai, its tasks were defined to improve the quality and support of biologically oriented research in Germany by the DFG (Deutsche Forschungsgemeinschaft; German Research Foundation), BMBF (Bundesministerium für Bildung und Forschung) and EU (European Union), to promote young researchers doing biologically oriented research, to improve on the diagnosis and therapy of mental disorders and to advise policy makers by taking part in legal processes. The DGBP has been a corporate member of the WFSBP from its beginning, became a cooperative member of the DGPPN (Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde), later of the German Brain Council, and fostered relationships with other scientific societies. Over the past 45 years, more than twenty congresses were held in Germany and neighboring countries. Emerging from the pandemic, the DGBP is ready to continue its mission to promote interdisciplinary research on the biology of mental disorders with a focus on the development of young scientists and to translate results of biological research into clinical practice, with regard to pharmacotherapy in close cooperation with the Arbeitsgemeinschaft Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP). In this sense, this article also aims to stimulate the cooperation of the society with other national and international partners and to foster new relationships with young scientists and professionals interested in the aims and goals of the DGBP.

A major role for common genetic variation in anxiety disorders.

Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (ncase = 25 453, ncontrol = 58 113) and an additional analysis of Current Anxiety Symptoms (ncase = 19 012, ncontrol = 58 113). The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant positive genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.

Influence of two functional polymorphisms in NOS1 on baseline cortisol and working memory in healthy subjects.

INTRODUCTION: The neuronal isoform of the nitric oxide synthase (NOS-I) encoded by NOS1 is the main source of nitric oxide (NO) in the brain. Reduced NO signaling in the prefrontal cortex has been linked to schizophrenia and cognitive processes while reduced striatal NOS1 expression has been associated with impulsive behavior. METHODS: To evaluate the effect of two functional polymorphisms in alternative first exons of NOS1, ex1f-VNTR and ex1c-SNP rs41279104, on the HPA stress axis and neurocognitive abilities, 280 healthy subjects were genotyped, had their salivary cortisol levels measured and were assessed in verbal memory, verbal fluency, working memory and verbal IQ by using the California Verbal Learning Test (CVLT), the Regensburger test of verbal fluency (RWT), a n-back task and subscales of the Wechsler Adult Intelligence Scale III (WAIS-III). RESULTS: Schizophrenia risk (A)-allele carriers of NOS1 ex1c-SNP rs41279104 displayed significantly lower baseline cortisol levels (p = 0.004). NOS1 ex1f-VNTR genotype carriers showed differences in working memory performance (p = 0.05) in a gene-dose effect manner, with homozygous carriers of the short impulsivity-risk allele committing most commission errors. Finally, A-allele carriers of the NOS1 ex1c-SNP rs41279104 tended to react faster during the working memory task (p = 0.065). CONCLUSION: For the first time, we demonstrated an influence of the NOS1 ex1c-SNP rs41279104 on salivary cortisol levels and additionally implicate the A-allele in an enhanced reaction time during a working memory task. Regarding the NOS1 ex1f-VNTR our study supports the previously reported influence on impulsivity, lending further support to the hypothesis that this genetic variant underlies impulsive behavior.

CRP genetic variants are associated with mortality and depressive symptoms in chronic heart failure patients.

OBJECTIVE: Heart failure (HF) is a complex medical condition with a multitude of genetic and other factors being involved in the pathogenesis. Emerging evidence points to an involvement of inflammatory mechanisms at least in subgroups of patients. The same is true for depression and depressive symptoms, which have a high prevalence in HF patients and are risk factors for the development and outcomes of cardiovascular disease. METHODS: In 936 patients of the Interdisciplinary Network Heart Failure (INH) program, CRP and IL-6 protein blood levels were measured and genetic variants (single nucleotide polymorphisms) of the CRP and IL6 gene analyzed regarding their influence on mortality. RESULTS: Less common recessive genotypes of two single nucleotide polymorphisms in the CRP gene (rs1800947 and rs11265263) were associated with significantly higher mortality risk (p < 0.006), higher CRP levels (p = 0.029, p = 0.006) and increased depressive symptoms in the PHQ-9 (p = 0.005, p = 0.003). Variants in the IL-6 gene were not associated with mortality. CONCLUSION: Our results hint towards an association of less common CRP genetic variants with increased mortality risk, depressive symptoms and peripheral CRP levels in this population of HF patients thereby suggesting a possible role of the inflammatory system as link between poor prognosis in HF and depressive symptoms.

GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

[Pharmacogenetics in psychiatry: state of the art]. / Pharmakogenetik in der Psychiatrie: eine Standortbestimmung.

In this article, the current literature on pharmacogenetics of antidepressants, antipsychotics and lithium are summarized by the section of Neurobiology and Genetics of the German Society of Psychiatry, Psychotherapy and Neurology (DGPPN). The publications of international expert groups and regulatory authorities are reviewed and discussed. In Germany, a statement on pharmacogenetics was also made by the gene diagnostics committee of the Ministry of Health. The DGPPN supports two recommendations: 1) to perform CYP2D6 genetic testing prior to prescription of tricyclic antidepressants and 2) to determine the HLA-B*1502 genotype in patients of Asian origin before using carbamazepine. The main obstacle for a broad application of pharmacogenetic tests in psychiatry remains the lack of large prospective studies, for both single gene-drug pair and cobinatorial pharmacogenetic tests, to evaluate the benefits of genetic testing. Psychiatrists, geneticists and funding agencies are encouraged to increase their efforts for the future benefit of psychiatric patients.

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing.

Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic-pituitary-adrenal axis. Binding to its receptor CRHR1 triggers the downstream release of the stress response-regulating hormone cortisol. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here we aimed to evaluate CRHR1 as a risk factor for panic disorder (PD). Allelic variation of CRHR1 was captured by 9 single-nucleotide polymorphisms (SNPs), which were genotyped in 531 matched case/control pairs. Four SNPs were found to be associated with PD, in at least one sub-sample. The minor allele of rs17689918 was found to significantly increase risk for PD in females after Bonferroni correction and furthermore decreased CRHR1 mRNA expression in human forebrains and amygdalae. When investigating neural correlates underlying this association in patients with PD using functional magnetic resonance imaging, risk allele carriers of rs17689918 showed aberrant differential conditioning predominantly in the bilateral prefrontal cortex and safety signal processing in the amygdalae, arguing for predominant generalization of fear and hence anxious apprehension. Additionally, the risk allele of rs17689918 led to less flight behavior during fear-provoking situations but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus reduced gene expression driven by CRHR1 risk allele leads to a phenotype characterized by fear sensitization and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder.

[Guideline-oriented inpatient psychiatric psychotherapeutic/psychosomatic treatment of anxiety disorders : How many personnel are need?]. / Leitliniengerechte stationäre psychiatrisch-psychotherapeutische/psychosomatische Behandlung von Angsterkrankungen : Wieviel Personal ist erforderlich?

BACKGROUND/OBJECTIVES: The reimbursement of inpatient psychiatric psychotherapeutic/psychosomatic hospital treatment in Germany is regulated by the German personnel ordinance for psychiatric hospitals (Psych-PV), which has remained unchanged since 1991. The aim of this article was to estimate the personnel requirements for guideline-adherent psychiatric psychotherapeutic hospital treatment. METHODS: A normative concept for the required psychotherapeutic "dose" for anxiety disorders was determined based on a literature review. The required staffing contingent was compared to the resources provided by the Psych-PV based on category A1. RESULTS: According to the German policy guidelines for outpatient psychotherapy, a quota of 25 sessions of 50 min each (as a rule plus 5 probatory sessions) is reimbursed. This approach is supported by studies on dose-response relationships. As patients undergoing inpatient treatment for anxiety disorders are usually more severely ill than outpatients, a contingent of 30 sessions for the average treatment duration of 5 weeks seems appropriate in order to fully exploit the costly inpatient treatment time (300 min per patient and week). In contrast, only 70 min are reimbursed according to the Psych-PV. The total personnel requirement for the normative concept is 624 min per patient and week. The Psych-PV only covers 488 min (78 %). CONCLUSION: Currently, the time contingents for evidence-based psychiatric psychotherapeutic/psychosomatic hospital care are nowhere near sufficient. In the development of future reimbursement systems this needs to be corrected.

Dimensional structure of bodily panic attack symptoms and their specific connections to panic cognitions, anxiety sensitivity and claustrophobic fears.

BACKGROUND: Previous studies of the dimensional structure of panic attack symptoms have mostly identified a respiratory and a vestibular/mixed somatic dimension. Evidence for additional dimensions such as a cardiac dimension and the allocation of several of the panic attack symptom criteria is less consistent. Clarifying the dimensional structure of the panic attack symptoms should help to specify the relationship of potential risk factors like anxiety sensitivity and fear of suffocation to the experience of panic attacks and the development of panic disorder. METHOD: In an outpatient multicentre study 350 panic patients with agoraphobia rated the intensity of each of the ten DSM-IV bodily symptoms during a typical panic attack. The factor structure of these data was investigated with nonlinear confirmatory factor analysis (CFA). The identified bodily symptom dimensions were related to panic cognitions, anxiety sensitivity and fear of suffocation by means of nonlinear structural equation modelling (SEM). RESULTS: CFA indicated a respiratory, a vestibular/mixed somatic and a cardiac dimension of the bodily symptom criteria. These three factors were differentially associated with specific panic cognitions, different anxiety sensitivity facets and suffocation fear. CONCLUSIONS: Taking into account the dimensional structure of panic attack symptoms may help to increase the specificity of the associations between the experience of panic attack symptoms and various panic related constructs.

MAOA and mechanisms of panic disorder revisited: from bench to molecular psychotherapy.

Panic disorder with agoraphobia (PD/AG) is a prevalent mental disorder featuring a substantial complex genetic component. At present, only a few established risk genes exist. Among these, the gene encoding monoamine oxidase A (MAOA) is noteworthy given that genetic variation has been demonstrated to influence gene expression and monoamine levels. Long alleles of the MAOA-uVNTR promoter polymorphism are associated with PD/AG and correspond with increased enzyme activity. Here, we have thus investigated the impact of MAOA-uVNTR on therapy response, behavioral avoidance and brain activity in fear conditioning in a large controlled and randomized multicenter study on cognitive behavioral therapy (CBT) in PD/AG. The study consisted of 369 PD/AG patients, and genetic information was available for 283 patients. Carriers of the risk allele had significantly worse outcome as measured by the Hamilton Anxiety scale (46% responders vs 67%, P=0.017). This was accompanied by elevated heart rate and increased fear during an anxiety-provoking situation, that is, the behavioral avoidance task. All but one panic attack that happened during this task occurred in risk allele carriers and, furthermore, risk allele carriers did not habituate to the situation during repetitive exposure. Finally, functional neuroimaging during a classical fear conditioning paradigm evidenced that the protective allele is associated with increased activation of the anterior cingulate cortex upon presentation of the CS+ during acquisition of fear. Further differentiation between high- and low-risk subjects after treatment was observed in the inferior parietal lobes, suggesting differential brain activation patterns upon CBT. Taken together, we established that a genetic risk factor for PD/AG is associated with worse response to CBT and identify potential underlying neural mechanisms. These findings might govern how psychotherapy can include genetic information to tailor individualized treatment approaches.

Instrument-assisted soft tissue mobilization: effects on the properties of human plantar flexors.

The effect of instrument-assisted soft tissue mobilization (ISTM) on passive properties and inflammation in human skeletal muscle has not been evaluated. Passive properties of muscle, inflammatory myokines and subjective reporting of functional ability were used to identify the effects of ISTM on the plantar flexors. 11 healthy men were measured for passive musculotendinous stiffness (MTS), passive range of motion (PROM), passive resistive torque (PASTQ) and maximum voluntary contraction peak torque (MVCPT) for plantar flexor muscles of the lower leg. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were measured from muscle biopsies from the gastrocnemius, and subjective measurements of functional ability were taken using the perception of functional ability questionnaire (PFAQ). MTS, PROM, PRT and MVCPT were measured in the treatment leg (TL) and control leg (CL) before, immediately after, 24 h, 48 h and 72 h following IASTM. Biopsies for IL-6 and TNF-α and PFAQ responses were collected before as well as 24 h, 48 h and 72 h after IASTM. There were no significant differences in MTS, PROM, PASTQ, MVCPT, IL-6 and TNF-α between the TL or CL. A significant decrease in the perception of function and a significant increase in pain for the TL were found following IASTM.

[Resource use and financing of guideline-adherent psychotherapeutic inpatient care]. / Aufwand und Finanzierung leitliniengerechter, psychotherapeutischer Behandlung im Krankenhaus.

BACKGROUND: The financing of psychiatric psychotherapeutic care in Germany is determined by the German psychiatric staffing regulations which are unchanged since 1991. Psychotherapy was established after 1991 as an effective and indispensable treatment of mental and behavioral disorders. AIMS AND OBJECTIVES: The aim of this study was to empirically investigate the use of psychiatrists' and psychologists' working time for psychotherapy in guideline-adherent hospital care. A further aim was to compare these results to the resources defined by the German psychiatric staffing regulations and in the new prospective payment system for psychiatry and psychosomatics in Germany. MATERIAL AND METHODS: University hospitals for psychiatry and psychotherapy were asked to retrospectively provide data of patients for which guideline-adherent care was possible. Participating institutions provided both data describing the staff time utilization of psychotherapeutic services provided by psychiatrists and psychologists and patient classifications according to the German psychiatric staffing regulations and the new prospective payment system for psychiatry and psychosomatics. RESULTS: Resources defined by the German psychiatric staffing regulations covered a mean of only 71 min of psychotherapy per patient and week while the actual mean intensity of psychotherapeutic care provided by the participating hospitals was 194 min per patient and week. The associated use of staff time was 102 min per patient and week. Both figures increased during an inpatient episode. The resources defined by the German psychiatric staffing regulations covered only 70 % of medical and psychological personnel. The current configuration of the new prospective payment system for psychiatry and psychosomatics covered only 59 % of staff time. CONCLUSION: The results of this study provide another unambiguous recommendation to adjust the out-dated German psychiatric staffing regulations to the current evidence and S3 guidelines for psychiatric psychotherapeutic hospital care. In particular, more resources are required for the provision of psychotherapeutic care.

SLC6A2 and SLC6A4 variants interact with venlafaxine serum concentrations to influence therapy outcome.

OBJECTIVE: The effects of genetic variants in genes encoding the target structures of antidepressants on the therapeutic efficacy of antidepressant drugs have been investigated with unconclusive results. One possible confounding factor in most studies was the fact that drug serum concentrations had not been determined. METHODS: Within a clinical setting, 56 inpatients suffering from depressive episodes in the context of either major depressive disorder or bipolar affective disorder were studied. Response to venlafaxine was assessed after 4 weeks of treatment and correlated to serum concentration and functional variants in genes encoding the norepinephrine (SLC6A2; rs28386840) and the serotonin transporter (SLC6A4; [5-HTTLPR], rs25531). Symptom change was evaluated using the Clinical Global Impression-Improvement (CGI-I) scale. RESULTS: No association between therapeutic response, venlafaxine serum concentration (active moiety) and rs28386840 was found. In carriers of the high expressing SLC6A4 genotype (lAlA-), a poor response to venlafaxine was found significantly more often. In subsamples stratified for serum concentration this held true for patients with serum concentrations between 201 and 400 ng/mL (n=21), while in patients with sub- (≤ 200 ng/mL; n=12) and supra-recommended (> 400 ng/mL; n=23) concentrations, no significant differences were observed. DISCUSSION: The observed association is consistent with findings of some previous studies, whereas others showed differing results highlighting the need for further investigations.

Effects of gender and age on serum concentrations of antidepressants under naturalistic conditions.

Therapeutic drug monitoring (TDM) data of antidepressant drugs are often evaluated using homogeneous samples of selected individuals without psychiatric or somatic comorbidity. These data may have limitations in transferability to everyday clinical practice. Hence, studies under naturalistic conditions are important to clarify the full clinical relevance of TDM of antidepressants. TDM analyses were retrospectively evaluated for a 3-year period from 2008 to 2010. The influence of gender and age on dose-corrected serum concentrations of antidepressants was examined in a standard clinical setting. 693 TDM analyses of amitriptyline and nortriptyline (AMI + NOR), 160 of citalopram (CIT), 152 of clomipramine and N-clomipramine (CLO + N-CLO), 272 of doxepine and N-doxepine (DOX + N-DOX), 359 of escitalopram (ESC), 198 of fluoxetine and N-fluoxetine (FLU + N-FLU), 92 of maprotiline (MAP), 888 of mirtazapine (MIR), and 77 of sertraline (SER) remained in the sample. Females had significantly higher dose-corrected serum concentrations of AMI + NOR (32 %), CIT (29 %), DOX + N-DOX (29 %), and MIR (20 %), and patients older than 60 years had significantly higher dose-corrected serum concentrations of AMI + NOR (21 %), CIT (40 %), DOX + N-DOX (48 %), MAP (46 %), MIR (24 %), and SER (67 %). Comparing the two extreme groups, females >60 years showed a remarkably higher dose-corrected serum concentration of AMI + NOR (52 %), CIT (78 %), DOX + N-DOX (86 %), and MIR (41 %) in contrast to males ≤60 years. Gender and age have a significant influence on the serum concentrations of different antidepressant drugs, and additive effects must be considered. TDM is recommended to reduce the risk of adverse effects due to supratherapeutic serum levels, also in a naturalistic clinical setting.

Neuropeptide S receptor gene -- converging evidence for a role in panic disorder.

Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn¹°7Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case-control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder. The more active NPSR rs324981 T allele was found to be associated with panic disorder in the female subgroup of patients in both samples as well as in a meta-analytic approach. The T risk allele was further related to elevated anxiety sensitivity, increased heart rate and higher symptom reports during a behavioral avoidance test as well as decreased activity in the dorsolateral prefrontal, lateral orbitofrontal and anterior cingulate cortex during processing of fearful faces in patients with panic disorder. The present results provide converging evidence for a female-dominant role of NPSR gene variation in panic disorder potentially through heightened autonomic arousal and distorted processing of anxiety-relevant emotional stimuli.

TMEM132D, a new candidate for anxiety phenotypes: evidence from human and mouse studies.

The lifetime prevalence of panic disorder (PD) is up to 4% worldwide and there is substantial evidence that genetic factors contribute to the development of PD. Single-nucleotide polymorphisms (SNPs) in TMEM132D, identified in a whole-genome association study (GWAS), were found to be associated with PD in three independent samples, with a two-SNP haplotype associated in each of three samples in the same direction, and with a P-value of 1.2e-7 in the combined sample (909 cases and 915 controls). Independent SNPs in this gene were also associated with the severity of anxiety symptoms in patients affected by PD or panic attacks as well as in patients suffering from unipolar depression. Risk genotypes for PD were associated with higher TMEM132D mRNA expression levels in the frontal cortex. In parallel, using a mouse model of extremes in trait anxiety, we could further show that anxiety-related behavior was positively correlated with Tmem132d mRNA expression in the anterior cingulate cortex, central to the processing of anxiety/fear-related stimuli, and that in this animal model a Tmem132d SNP is associated with anxiety-related behavior in an F2 panel. TMEM132D may thus be an important new candidate gene for PD as well as more generally for anxiety-related behavior.