Effect of serotonin transporter genotype on carbon dioxide-induced fear-related behavior in mice.

BACKGROUND: Inhaling 35% carbon dioxide induces an emotional and symptomatic state in humans closely resembling naturally occurring panic attacks, the core symptom of panic disorder. Previous research has suggested a role of the serotonin system in the individual sensitivity to carbon dioxide. In line with this, we previously showed that a variant in the SLC6A4 gene, encoding the serotonin transporter, moderates the fear response to carbon dioxide in humans. To study the etiological basis of carbon dioxide-reactivity and panic attacks in more detail, we recently established a translational mouse model. AIM: The purpose of this study was to investigate whether decreased expression of the serotonin transporter affects the sensitivity to carbon dioxide. METHODS: Based on our previous work, wildtype and serotonin transporter deficient (+/-, -/-) mice were monitored while being exposed to carbon dioxide-enriched air. In wildtype and serotonin transporter +/- mice, also cardio-respiration was assessed. RESULTS: For most behavioral measures under air exposure, wildtype and serotonin transporter +/- mice did not differ, while serotonin transporter -/- mice showed more fear-related behavior. Carbon dioxide exposure evoked a marked increase in fear-related behaviors, independent of genotype, with the exception of time serotonin transporter -/- mice spent in the center zone of the modified open field test and freezing in the two-chamber test. On the physiological level, when inhaling carbon dioxide, the respiratory system was strongly activated and heart rate decreased independent of genotype. CONCLUSION: Carbon dioxide is a robust fear-inducing stimulus. It evokes inhibitory behavioral responses such as decreased exploration and is associated with a clear respiratory profile independent of serotonin transporter genotype.

Transcranial magnetic stimulation in the treatment of obsessive-compulsive disorder: current perspectives.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neurostimulation technique receiving increasing attention in the treatment of different psychiatric disorders. Evidence for rTMS use in obsessive-compulsive disorder (OCD) is accumulating and informing further developments in the neurostimulation field, the latest being deep transcranial magnetic stimulation (dTMS). dTMS allows direct stimulation of deeper subcortical structures and larger brain volume than conventional rTMS. Underlying neurobiological mechanisms related to transcranial magnetic stimulation are still under evaluation, but appear to offer a novel "third" way of addressing symptoms via localized electrical stimulation compared to pharmacotherapy and psychotherapy approaches. This systematic review focuses on the effects of rTMS and dTMS stimulation on different brain targets in OCD. Brain areas included are the dorsolateral prefrontal cortex, supplementary motor area, orbitofrontal cortex/medial prefrontal cortex, and anterior cingulate cortex (ACC). Improved understanding of the therapeutic effects of rTMS in OCD will support fine-tuning of the method and help determine how we can best optimize the approach via rTMS or dTMS to achieve clinically relevant results.

Amiloride-sensitive cation channel 2 genotype affects the response to a carbon dioxide panic challenge.

Until recently, genetic research into panic disorder (PD) has had only limited success. Inspired by rodent research, demonstrating that the acid-sensing ion channel 1a (ASIC1a) is critically involved in the behavioral fear response to carbon dioxide (CO2) exposure, variants in the human homologue gene amiloride-sensitive cation channel 2 (ACCN2) were shown to be associated with PD. However, the relationship between changes in brain pH and ACCN2, as done in rodents by CO2 exposure, has not been investigated yet in humans. Here, we examined this link between the ACCN2 gene and the response to CO2 exposure in two studies: in healthy volunteers as well as PD patients and using both behavioral and physiological outcome measures. More specifically, 107 healthy volunteers and 183 PD patients underwent a 35% CO2 inhalation. Negative affect was assessed using visual analogue scales and the panic symptom list (PSL), and, in healthy volunteers, cardiovascular measurements. The single nucleotide polymorphism rs10875995 was significantly associated with a higher emotional response in PD patients and with an increase in systolic as well as diastolic blood pressure in healthy subjects. In all measurements, subjects homozygous for the T-allele showed a heightened reactivity to CO2. Furthermore, a trend towards an rs685012 genotype effect on the emotional response was found in PD patients. We provide the first evidence that genetic variants in the ACCN2 are associated with differential sensitivity to CO2 in PD patients as well as healthy volunteers, further supporting ACCN2 as a promising candidate for future research to improve current treatment options.

Pharmacokinetic considerations in the treatment of hypertension in risperidone-medicated patients - thinking of clinically relevant CYP2D6 interactions.

BACKGROUND: Treatment of arterial hypertension in patients with severe mental illnesses often results in polypharmacy, potentially leading to drug-drug interactions. The objective of the study was to analyse the in vivo inhibitory potential of two antihypertensive drugs, amlodipine and metoprolol on CYP2D6 catalysed 9-hydroxylation of risperidone (RIS). METHODS: A therapeutic drug monitoring database with plasma concentrations of RIS and 9-hydroxyrisperidone (9-OH-RIS) of 1584 patients was analysed. Three groups were considered; a group of patients receiving RIS without a potentially cytochrome influencing co-medication (control group, R0, n=852), a group co-medicated with amlodipine (RA, n=27) and a group, co-medicated with metoprolol (RM, n=41). Plasma concentrations, concentration-to-dose ratios (C/Ds) of RIS, 9-OH-RIS and the active moiety (AM), as well as the metabolic ratios were computed and compared using the Kruskal-Wallis test, the Mann-Whitney U test and the Jonckheere-Terpstra test to determine the means and different patterns of distribution of plasma concentrations as well as the concentration-to-dose ratios. RESULTS: The median daily dosage of RIS did not differ between the groups (p=0.708). No differences were found in median plasma concentrations of RIS, 9-OH-RIS and AM. However, concentration-to-dose ratios for RIS, 9-OH-RIS and AM were significantly higher in the amlodipine group (p=0.025, p=0.048 and p=0.005). In the metoprolol group, the concentration-to-dose ratio for RIS was significantly higher than in the control group (p=0.017), while the C/D for 9-OH-RIS and AM was not. CONCLUSIONS AND LIMITATIONS: Our data show a potential pharmacokinetic interaction, most likely via CYP3A4 between amlodipine and RIS, reflected in significantly different C/Ds for RIS, 9-OH-RIS and AM. Although the interaction did not result in significantly higher plasma levels, changes in C/Ds and their distribution with regard to the median concentrations were observed.

The relation between depressive and obsessive-compulsive symptoms in obsessive-compulsive disorder: Results from a large, naturalistic follow-up study.

OBJECTIVE: Despite the frequent occurrence of depressive symptoms in obsessive-compulsive disorder (OCD), little is known about the reciprocal influence between depressive and obsessive-compulsive symptoms during the course of the disease. The aim of the present study is to investigate the longitudinal relationship between obsessive-compulsive and depressive symptoms in OCD patients. METHOD: We used the baseline and 1-year follow-up data of the Netherlands Obsessive Compulsive Disorder Association (NOCDA) study. In 276 patients with a lifetime diagnosis of obsessive-compulsive disorder, depressive and obsessive-compulsive symptoms were assessed at baseline and at one-year follow-up with the Beck Depression Inventory (BDI) and the Yale-Brown Obsessive Compulsive Symptom (Y-BOCS) scale. Relations were investigated using a cross-lagged panel design. RESULTS: The association between the severity of depressive symptoms at baseline and obsessive-compulsive symptoms at follow-up was significant (ß=0.244, p<0.001), while the association between the severity of obsessive-compulsive symptoms at baseline and depressive symptoms at follow-up was not (ß=0.097, p=0.060). Replication of the analyses in subgroups with and without current comorbid major depressive disorder (MDD) and subgroups with different sequence of onset (primary versus secondary MDD) revealed the same results. LIMITATIONS: There may be other factors, which affect both depressive and obsessive-compulsive symptoms that were not assessed in the present study. CONCLUSION: The present study demonstrates a relation between depressive symptoms and the course of obsessive-compulsive symptoms in OCD patients, irrespective of a current diagnosis of MDD and the sequence of onset of OCD and MDD.