Svenja Schulze-Rauschenbach

High neuroticism and depressive temperament are associated with dysfunctional regulation of the hypothalamic–pituitary–adrenocortical system in healthy volunteers

Objective:  Elevated neuroticism, depressive temperament and dysfunctional regulation of the hypothalamic–pituitary–adrenocortical (HPA) system are considered as risk factors for unipolar depression. An interaction of these vulnerability factors was suggested, but controversially discussed. In absence of other informative studies we set out for a replication test and for elucidation of the underlying mechanism.

Impairment of inhibitory control of the hypothalamic pituitary adrenocortical system in epilepsy

Abstract.Excess comorbidity between depression and epilepsy proposes common pathophysiological patterns in both disorders. Neuroendocrine abnormalities were often observed in depression as well as in epilepsy. Lack of inhibitory control of the hypothalamic pituitary adrenocortical (HPA) system is a core feature of depression; main relay stations of this system are located in the amygdala and hippocampus, which are key regions for both disorders. Therefore we explored the feedback mechanism of the HPA system in epilepsy. In order to control for the impact of depression we focused on epilepsies without depression. We compared patients with epilepsy (subdivided by medication with or without hepatic enzyme inducing antiepileptic medication) with 16 healthy controls and 16 patients with unipolar major depression but without epilepsy. We observed a lack of inhibitory control of the HPA system in patients with epilepsy, also in the absence of enzyme inducing medication. An impact of the temporal lobe location of the epileptic focus could not be observed. Thus, epilepsies share with depression the deficiencies in the feedback mechanism of the HPA system, proposing common pathophysiological features of up to now unknown nature.

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.

Early onset of obsessive–compulsive disorder and associated comorbidity

Background: Previous studies have aimed to identify subtypes of obsessive–compulsive disorder (OCD) based on their age of onset (AOO). Obsessive–compulsive spectrum disorders (OCS disorders) such as tic disorders have been particularly associated with an early onset in some studies. However, subtypes of early‐ and late‐onset OCD are unevenly determined, and the biological and the clinical validity of these subtypes are unknown. This study was undertaken to discriminate the subtypes of OCD in different AOO levels and to test the hypothesis that different AOO bands are associated with a differential pattern of comorbidity. Methods: Two hundred fifty‐two patients with OCD were interviewed directly with the German version of the Schedule for Affective Disorders and Schizophrenia—Lifetime Anxiety Version, which provides DSM‐IV diagnosis. Subgroups with different ages of onset were investigated (cut‐off levels of 10, 15, and 18 years). Results: Subjects with an early AOO (onset ≤10 years) were significantly more likely to have OCS disorders (odds ratio [OR]=3.46; P=.001; 95% confidence interval [CI]: 1.72–6.96), in particular tic/Tourettes disorders (OR=4.63; P=.002; 95% CI: 1.78–12.05), than were late‐onset subjects. Conclusions: For most mental disorders (e.g., anxiety and mood disorders), no associations with AOO of OCD were identified. However, subjects in the early‐onset group (≤10 years) had a significant increase in comorbid tic and Tourettes disorders. Future research should examine potential neurobiological features associated with early‐onset presentations of OCD. Early detection and management of comorbidities may offset impairments later in life. Depression and Anxiety 26:1012–1017, 2009.

Neurocognitive impairments in non‐deprived smokers—results from a population‐based multi‐center study on smoking‐related behavior

The aim of the present study was to examine neurocognitive function associated with chronic nicotine use. A total of 2163 healthy participants (1002 smokers, 1161 never‐smoking controls) participated in a population‐based case‐control design. The main outcome measures were six cognitive domain factors derived from a neuropsychological test battery. In smokers, the battery was administered after controlled smoking of one cigarette. Analyses included age, sex and education as covariates. Results demonstrated small, but significant deficits in smokers for visual attention (P < 0.001) and cognitive impulsivity (P < 0.006), while verbal episodic memory, verbal fluency, verbal working memory, and Stroop‐interference did not differ between groups. These attention/impulsivity deficits were also present in smokers with only a low amount of cigarette consumption. Lifetime nicotine use (pack‐years) was not correlated with cognition in smokers. In conclusion, this study confirmed subtle and specific cognitive deficits in non‐deprived smokers. The independence of these deficits from consumption intensity may argue for an a priori deficit of some cognitive abilities in smokers. These specific deficits may constitute intermediate phenotypes for genetic research on nicotine use.

Alexithymia in Obsessive-Compulsive Disorder – Results from a Family Study

Background: Previous studies have suggested an association between alexithymia and obsessive-compulsive disorder (OCD). However, it is unclear to which extent alexithymic traits in OCD patients reflect familial deficits in cognitively processing and communicating feelings that are also present in their first-degree relatives. This study investigates the hypotheses of an elevated level of alexithymia in subjects with OCD and their first-degree relatives compared to controls and their first-degree relatives. Methods: 82 cases with OCD and 169 first-degree relatives were compared to 76 controls and 144 first-degree relatives from a German family study on OCD (GENOS). All subjects completed the 20-item Toronto Alexithymia Scale (TAS-20). Direct or family informant interviews were carried out with the German version of the Schedule for Affective Disorders and Schizophrenia – lifetime version for anxiety disorders (DSM-IV). Results: OCD was associated with significantly higher scores of alexithymia. However, first-degree relatives of OCD cases and of controls did not differ in TAS-20 scores. In linear regression analyses, the TAS-20 total score showed significant intrafamilial associations within the families of control subjects but not within families of OCD cases. Conclusion: OCD is a severe mental disorder that is associated independently from other current comorbid axis I disorders with deficits in identifying and expressing feelings. However, alexithymia does not represent a familial risk factor for OCD.

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.

Evidence for specific cognitive deficits in visual information processing in patients with OCD compared to patients with unipolar depression.

OBJECTIVE Neuropsychological studies comparing cognitive performance in patients suffering from Obsessive-Compulsive Disorder (OCD) or Major Depressive Disorder (MDD) revealed deficits in the domains of verbal fluency and viso-motor speed/set shifting in both groups. Spatial working memory deficits, however, have been identified as specific markers of OCD. As yet, it has not been substantiated whether deficits in visual organization and complex visual memory are also specific to OCD and are not shared by MDD. METHOD Test performance in seven cognitive domains was assessed in 40 OCD patients, 20 MDD patients, and 40 healthy controls. Patient groups were matched according to severity of depressive symptoms. RESULTS Deficits shared by both patient groups, as compared to controls, were found in delayed spatial recall and verbal fluency while verbal memory was normal in both patient groups. Only patients with OCD, but not MDD patients were impaired in the domains visual memory, viso-motor speed/set shifting, visual organization, and problem solving. In addition, OCD patients differed significantly from MDD subjects in visual organization and problem solving. Visual organization scores correlated significantly with severity of current compulsions in the OCD group (r=-.324). CONCLUSIONS OCD patients demonstrate difficulties in visual organization and mental manipulation of complex visual material, which are not accounted for by depressive symptoms and which constitute a specific cognitive deficit of the disorder.

Obsessive-Compulsive Disorder and Posttraumatic Stress Disorder

Background: Previous studies suggested an association between exposure to trauma or stressful life events and obsessive-compulsive disorder (OCD). This study investigates the hypothesis that traumatic events and posttraumatic stress disorders (PTSD) precede the onset of OCD. Sampling and Methods: 210 cases with OCD from university treatment facilities were compared with 133 sex- and age-matched controls from the adult general population. The data were derived from a German family study on OCD (GENOS). Direct interviews were carried out with the German version of the Schedule for Affective Disorders and Schizophrenia – Lifetime Version for Anxiety Disorders (DSM-IV). Results: Severe traumatization occurred in 6.2% of the OCD cases and in 8.3% of the controls. The lifetime prevalence rates of traumatization, PTSD and acute stress disorder were not different between the subjects with OCD and controls (p > 0.05). In 6 cases, acute stress disorder, subclinical or full PTSD preceded the onset of OCD, in 3 cases the trauma-related disorders and OCD occurred within the same year, in 5 other cases, the trauma-related disorders started after the onset of OCD. Conclusion: There is no significant association of traumatization or PTSD with OCD compared with controls. Given the low rate of trauma-related disorders occurring before (2.9%) or within (1.5%) the same year as the onset of OCD other factors than severe traumatic events determine the onset of OCD in most of the cases.

Perceived parental rearing in subjects with obsessive―compulsive disorder and their siblings

Lennertz L, Grabe HJ, Ruhrmann S, Rampacher F, Vogeley A, Schulze‐Rauschenbach S, Ettelt S, Meyer K, Kraft S, Reck C, Pukrop R, John U, Freyberger HJ, Klosterkötter J, Maier W, Falkai P, Wagner M. Perceived parental rearing in subjects with obsessive–compulsive disorder and their siblings.