Individualized, connectome-based, non-invasive stimulation of OCD deep-brain targets: A proof-of-concept.

Treatment-resistant obsessive-compulsive disorder (OCD) generally improves with deep-brain stimulation (DBS), thought to modulate neural activity at both the implantation site and in connected brain regions. However, its invasive nature, side-effects, and lack of customization, make non-invasive treatments preferable. Harnessing the established remote effects of cortical transcranial magnetic stimulation (TMS), connectivity-based approaches have emerged for depression that aim at influencing distant regions connected to the stimulation site. We here investigated whether effective OCD DBS targets (here subthalamic nucleus [STN] and nucleus accumbens [NAc]) could be modulated non-invasively with TMS. In a proof-of-concept study with nine healthy individuals, we used 7T magnetic resonance imaging (MRI) and probabilistic tractography to reconstruct the fiber tracts traversing manually segmented STN/NAc. Two TMS targets were individually selected based on the strength of their structural connectivity to either the STN, or both the STN and NAc. In a sham-controlled, within-subject cross-over design, TMS was administered over the personalized targets, located around the precentral and middle frontal gyrus. Resting-state functional 3T MRI was acquired before, and at 5 and 25 min after stimulation to investigate TMS-induced changes in the functional connectivity of the STN and NAc with other regions of the brain. Static and dynamic seed-to-voxel correlation analyses were conducted. TMS over both targets was able to modulate the functional connectivity of the STN and NAc, engaging both overlapping and distinct regions, and unfolding following different temporal dynamics. Given the relevance of the engaged connected regions to OCD pathology, we argue that a personalized, connectivity-based procedure is worth investigating as potential treatment for refractory OCD.

Eye movement desensitization and reprocessing (EMDR) therapy or supportive counseling prior to exposure therapy in patients with panic disorder: study protocol for a multicenter randomized controlled trial (IMPROVE).

BACKGROUND: Exposure-based therapy is the treatment of choice for anxiety disorders, but many patients do not benefit sufficiently from it. Distressing images of threat related to the future or past may maintain the anxiety symptomatology or impede exposure therapy. An intervention that targets threat-related imagery is eye movement desensitization and reprocessing (EMDR) therapy. The main goal of this multicenter randomized controlled trial is to investigate whether EMDR therapy plus exposure therapy, relative to supportive counseling plus exposure therapy, improves treatment efficacy, tolerability, and adherence in patients with panic disorder. In addition, we will examine potential predictors of optimal treatment allocation, mechanisms of change as well as the long term effects of treatment. Finally, we will assess cost-effectiveness. METHODS: A multicenter randomized controlled trial mixed design will be conducted. Participants will be 50 patients, aged ≥ 18, diagnosed with a panic disorder. They will be randomly assigned to one of two conditions: EMDR therapy (i.e., flashforward strategy) or supportive counseling (each consisting of four weekly sessions of 90 min each) prior to exposure therapy (consisting of eight weekly sessions of 90 min each). Assessments will be made pre-treatment (T1), between-treatments (T2), post-treatment (T3), one month post-treatment (FU1) and six months post-treatment (FU2) by an assessor blind to treatment condition. The primary outcome measure is severity of panic-related symptoms. Secondary outcome measures are: tolerability of exposure therapy (initial avoidance, willingness to start exposure therapy, considered drop-out; no-show and drop-out), related symptomatology (generalized anxiety, depression), and functional impairment. DISCUSSION: The primary goals of this research are to compare the efficacy, tolerability, and adherence of EMDR therapy plus exposure therapy and supportive counseling plus exposure therapy and to identify predictors, moderators, and mediators for treatment success. This multi-center research aims to make a significant contribution to our understanding as to how treatment for patients with anxiety disorders can be optimized, and elucidate who can benefit most from this novel approach. TRIAL REGISTRATION: ISRCTN-ISRCTN29668369: Improving anxiety treatment by modifying emotional memories before real-life exposure. Registered 27 June 2022-retrospectively registered. ISRCTN-ISRCTN29668369.

Abnormal white-matter rich-club organization in obsessive-compulsive disorder.

Rich-club organization is key to efficient global neuronal signaling and integration of information. Alterations interfere with higher-order cognitive processes, and are common to several psychiatric and neurological conditions. A few studies examining the structural connectome in obsessive-compulsive disorder (OCD) suggest lower efficiency of information transfer across the brain. However, it remains unclear whether this is due to alterations in rich-club organization. In the current study, the structural connectome of 28 unmedicated OCD patients, 8 of their unaffected siblings and 28 healthy controls was reconstructed by means of diffusion-weighted imaging and probabilistic tractography. Topological and weighted measures of rich-club organization and connectivity were computed, alongside global and nodal measures of network integration and segregation. The relationship between clinical scores and network properties was explored. Compared to healthy controls, OCD patients displayed significantly lower topological and weighted rich-club organization, allocating a smaller fraction of all connection weights to the rich-club core. Global clustering coefficient, local efficiency, and clustering of nonrich club nodes were significantly higher in OCD patients. Significant three-group differences emerged, with siblings displaying highest and lowest values in different measures. No significant correlation with any clinical score was found. Our results suggest weaker structural connectivity between rich-club nodes in OCD patients, possibly resulting in lower network integration in favor of higher network segregation. We highlight the need of looking at network-based alterations in brain organization and function when investigating the neurobiological basis of this disorder, and stimulate further research into potential familial protective factors against the development of OCD.

Anxiety and depression in small fiber neuropathy.

Psychiatric comorbidity is common in patients with chronic pain. In peripheral neuropathic pain, particularly anxiety and mood disorders are frequently present and associated with a high level of catastrophizing. Small fiber neuropathy (SFN) is a peripheral neuropathy dominated by pain. This study aimed to investigate the prevalence of and factors associated with anxiety and depressive symptoms in SFN. All consecutive patients diagnosed with SFN at Maastricht University Medical Center+, between September 2016 and October 2021, were included (n = 1310). Data on demographics, medical history, diagnostic tests, and questionnaires about pain, SFN-specific symptoms, and mental health were collected once. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety and depression and the Pain Catastrophizing Scale (PCS) to measure the degree of catastrophizing. One-third of the patients had an abnormal HADS score (≥11) on the subscales anxiety and/or depression (26.5% anxiety and 23.0% depression) indicating clinical relevance. Regression analysis showed that higher pain intensity, catastrophizing, and more SFN-related complaints were significantly associated with an abnormal HADS-score. In conclusion, the prevalence of reported anxiety or depressive symptoms in SFN is 36.3%. A multidisciplinary approach, not only focusing on pain relief, is therefore essential for the treatment of SFN.

Cognitive Outcome After Deep Brain Stimulation for Refractory Obsessive-Compulsive Disorder: A Systematic Review.

INTRODUCTION: Deep brain stimulation (DBS) is an effective treatment for refractory obsessive-compulsive disorder (OCD). Neuropsychological assessment contributes to DBS treatment in several ways: it monitors the cognitive safety of the treatment, identifies beneficial or detrimental cognitive side effects, and it could aid to explain variability in treatment outcome, and possibly the treatment's working mechanism(s). BACKGROUND: This systematic review assessed the cognitive safety of DBS for OCD and explored whether changes in cognitive function may help explain its working mechanism(s). MATERIALS AND METHODS: EMBASE, PubMed/Medline, Psycinfo, and the Cochrane Library were systematically searched for studies reporting cognitive outcomes following DBS for OCD. Searches were completed in November 2020. Included studies were appraised for study design and quality according to National Heart, Lung, and Blood Institute (NHLBI) quality assessment tools. RESULTS: Five randomized controlled trials and ten observational studies comprising a total of 178 patients were analyzed collectively. Variable outcomes of DBS were observed in the domains of attention, memory, executive functioning, and in particular, cognitive flexibility. CONCLUSION: Although individual studies generally do not report cognitive deterioration after DBS for OCD, the variability of study designs and the multitude of cognitive measures used precluded a meta-analysis to confirm its safety and recognition of a cognitive pattern through which the efficacy of DBS for OCD might be explained. In the future, prospective studies should preferably include a standardized neuropsychological assessment battery specifically addressing executive functioning and have a longer-term follow-up in order to demonstrate the cognitive safety of the procedure. Such prospective and more uniform data collection may also contribute to our understanding of the working mechanisms of DBS in OCD.

Surgical and Hardware-Related Adverse Events of Deep Brain Stimulation: A Ten-Year Single-Center Experience.

INTRODUCTION: Although deep brain stimulation (DBS) is effective for treating a number of neurological and psychiatric indications, surgical and hardware-related adverse events (AEs) can occur that affect quality of life. This study aimed to give an overview of the nature and frequency of those AEs in our center and to describe the way they were managed. Furthermore, an attempt was made at identifying possible risk factors for AEs to inform possible future preventive measures. MATERIALS AND METHODS: Patients undergoing DBS-related procedures between January 2011 and July 2020 were retrospectively analyzed to inventory AEs. The mean follow-up time was 43 ± 31 months. Univariate logistic regression analysis was used to assess the predictive value of selected demographic and clinical variables. RESULTS: From January 2011 to July 2020, 508 DBS-related procedures were performed including 201 implantations of brain electrodes in 200 patients and 307 implantable pulse generator (IPG) replacements in 142 patients. Surgical or hardware-related AEs following initial implantation affected 40 of 200 patients (20%) and resolved without permanent sequelae in all instances. The most frequent AEs were surgical site infections (SSIs) (9.95%, 20/201) and wire tethering (2.49%, 5/201), followed by hardware failure (1.99%, 4/201), skin erosion (1.0%, 2/201), pain (0.5%, 1/201), lead migration (0.52%, 2/386 electrode sites), and hematoma (0.52%, 2/386 electrode sites). The overall rate of AEs for IPG replacement was 5.6% (17/305). No surgical, ie, staged or nonstaged, electrode fixation, or patient-related risk factors were identified for SSI or wire tethering. CONCLUSIONS: Major AEs including intracranial surgery-related AEs or AEs requiring surgical removal or revision of hardware are rare. In particular, aggressive treatment is required in SSIs involving multiple sites or when Staphylococcus aureus is identified. For future benchmarking, the development of a uniform reporting system for surgical and hardware-related AEs in DBS surgery would be useful.

Pharmacokinetic Drug-Drug Interactions of Mood Stabilizers and Risperidone in Patients Under Combined Treatment.

BACKGROUND: The combination of anticonvulsant mood stabilizers with antipsychotic drugs may lead to clinically relevant drug-drug interactions. The objective of the study was to identify pharmacokinetic interactions of different mood stabilizers on the metabolism of risperidone (RIS) under natural conditions. METHODS: A large therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-hydroxy-RIS (9-OH-RIS) of 1,584 adult patients was analyzed. Four groups (n = 1,072) were compared: a control group without a potentially cytochrome interacting comedication (R0, n = 852), a group comedicated with valproate (VPA) (RVPA, n = 153), a group comedicated with lamotrigine (LMT) (RLMT, n = 46), and a group under concomitant medication with carbamazepine (CBZ) (RCBZ, n = 21). Dose-adjusted plasma concentrations (C/D ratio) for RIS, 9-OH-RIS and active moiety (AM) (RIS + 9-OH-RIS), as well as metabolic ratios (RIS/9-OH-RIS) were computed. RESULTS: Groups did not differ with regard to the daily dosage (P = 0.46). Differences were detected for the distributions of the C/D ratios for RIS, 9-OH-RIS and AM (P = 0.003, P < 0.001 and P < 0.001, respectively). Differences remained significant after conducting a Bonferroni correction (P = 0.0125). Pairwise comparisons of the concomitant medication groups with the control group revealed significant differences; RIS C/D ratios were significantly higher in the VPA and the LMT group than in the control group (P = 0.013; P = 0.021). However, these differences did not remain significant after Bonferroni correction. In contrast, CBZ-treated patients showed lower dose-adjusted plasma concentrations of 9-OH-RIS (P < 0.001) as well as the AM (P < 0.001) than the control group; this difference survived the Bonferroni correction. CONCLUSIONS: The data give evidence for pharmacokinetic interactions between RIS and different anticonvulsant mood stabilizers. Carbamazepine decreased serum concentrations of 9-OH-RIS and the AM when compared with the control group. In case of VPA and LMT, findings were less significant; hints for a weak RIS metabolism inhibition by LMT of unclear clinical significance were found.

Pharmacokinetic patterns of risperidone-associated adverse drug reactions.

PURPOSE: The aim of the study was to investigate a correlation between plasma concentrations of risperidone (RIS), its active metabolite 9-hydroxyrisperidone (9-OH-RIS) and the active moiety (AM) (RIS + 9-OH-RIS), and adverse drug reactions (ADRs) in a naturalistic sample. METHODS: Plasma concentrations of RIS, 9-OH-RIS, and AM in patients out of a therapeutic drug monitoring (TDM) database complaining ADRs were categorized according to the Udvalg for Kliniske Undersogelser side effect rating scales (UKU) (n = 97) and compared to patients without ADRs (n = 398). RESULTS: Patients in the ADR group received a significantly lower daily dosage of risperidone (trimmed mean 3.64 mg/day) than patients without ADRs (4.40 mg/day). No differences were found for active moiety plasma concentrations between the groups (p = 0.454). Differences were detected only in the case of dose-adjusted plasma concentration values (concentration-by-dose, C/D) for 9-OH-RIS, being higher in patients reporting ADRs (4.78 ng/mL/mg) than in patients without ADRs (4.3 ng/mL/mg) (p = 0.037 for Mann-Whitney U test). Note that differences for non-adjusted 9-OH-RIS plasma levels between groups failed to reach significance (p = 0.697). CONCLUSIONS: Our findings are consistent with previous data supporting a prominent role of 9-hydroxyrisperidone, but not of risperidone with regard to ADRs. When studying the various subgroups of reported ADRs separately, the size of these subsamples offers some plausible limitations by reducing the power of the analysis.

The role of the peripheral and central adrenergic system in the construction of the subjective emotional experience of panic.

RATIONALE: Although the study of emotions can look back to over 100 years of research, it is unclear which information the brain uses to construct the subjective experience of an emotion. OBJECTIVE: In the current study, we assess the role of the peripheral and central adrenergic system in this respect. METHODS: Healthy volunteers underwent a double inhalation of 35% CO2, which is a well-validated procedure to induce an intense emotion, namely panic. In a randomized, cross-over design, 34 participants received either a ß1-blocker acting selectively in the peripheral nervous system (atenolol), a ß1-blocker acting in the peripheral and central nervous system (metoprolol), or a placebo before the CO2 inhalation. RESULTS: Heart rate and systolic blood pressure were reduced in both ß-blocker conditions compared to placebo, showing effective inhibition of the adrenergic tone. Nevertheless, the subjective experience of the induced panic was the same in all conditions, as measured by self-reported fear, discomfort, and panic symptom ratings. CONCLUSIONS: These results indicate that information from the peripheral and central adrenergic system does not play a major role in the construction of the subjective emotion.

Network analysis in Gamma Knife capsulotomy for intractable obsessive-compulsive disorder.

Introduction: Gamma-knife Ventral Capsulotomy (GVC) has been suggested as an efficacious treatment for a subset of patients with treatment refractory obsessive compulsive disorder (OCD). Research question: The goal of this study was to investigate neural correlates of GVC and investigate the predictive value of white matter tracts that are known to be associated with clinical outcome to Deep Brain Stimulation (DBS). Material and methods: MR images of 8 treatment-refractory OCD patients with a minimum follow-up of 3-years who underwent GVC were used to correlate lesion characteristics with symptom improvement. This exploratory study investigated relations between differences in cortical grey matter structure and subcortical structures before and after GVC for responding and non-responding patients (n â€‹= â€‹6). Normative diffusion MRI- based tractography was used to determine networks associated with successful lesions. Results: The mean total Y-BOCS reduction was 19.6 after three years, resulting in a response rate of 63%.The strongest correlation with symptom improvement was found for a decrease of the left ventral diencephalon volume (r â€‹= â€‹-0.83, p â€‹= â€‹0.039). Discriminative tractography suggest streamlines connecting the prefrontal cortex with the subthalamic nucleus to be associated with clinical response. However, results could not be validated either implicating interpatient anatomical variability or reflecting the relative small sample size as a limitation. Discussion/Conclusion: Taken together, the present study highlights the efficacy of GVC in patients with treatment-refractory OCD. Our results are suggestive of GVC treatment efficacy being mediated by the involvement of a subpart of the ALIC connecting the PFC and the STN.

Paroxetine augmentation in patients with generalised social anxiety disorder, non-responsive to mirtazapine or placebo.

OBJECTIVES: The aim of the study was to investigate if combination of mirtazapine with paroxetine causes a greater therapeutic effect and less sexual side effects than paroxetine monotherapy in social anxiety disorder (SAD). METHODS: Twenty one patients with generalised SAD, non-responsive to a 12 week trial with mirtazapine and 22 patients, non-responsive to placebo received paroxetine (20-40 mg) in addition to their double-blind treatment with mirtazapine or placebo for another 12 weeks. The Liebowitz Social Anxiety Scale (LSAS) and the Clinical Global Impression-Improvement (CGI-I) scale were used to measure efficacy. Sexual functioning was assessed by the Arizona Sexual Experiences Scale (ASEX). RESULTS: Both treatments showed a significant LSAS reduction and their response rates (based on LSAS reduction ≥ 40% and CGI-I ≤ 2) were similar (paroxetine and mirtazapine: 52.4%, paroxetine and placebo: 59.1%). Sexual dysfunction (based on ASEX ≥ 19) was found in half of patients treated with paroxetine and placebo, and in 38% of patients treated with paroxetine and mirtazapine. CONCLUSION: The present study did not find support for a greater efficacy of combination pharmacotherapy in SAD, however results suggest that combination of paroxetine with mirtazapine might cause less sexual dysfunction than treatment with paroxetine alone.

Therapygenetic effects of 5-HTTLPR on cognitive-behavioral therapy in anxiety disorders: A meta-analysis.

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy.

Negative affectivity in smokers applying to smoking cessation clinics: a case-control study.

OBJECTIVE: The objective of this study was to assess whether subjects applying to smoking cessation clinics display a higher level of affective symptoms than smokers recruited from the general population. METHODS: The study was conducted according to a cross-sectional, case-control design. Cases were smokers applying to public smoking cessation clinics for the first time and controls were smokers recruited from the general population. Socio-demographic data and clinical information were collected. Self- (Hospital Anxiety Depression Scale, Beck Depression Inventory, State-Trait Anxiety Inventory) and hetero-administered (Montgomery Asberg Depression Rating Scale, Hamilton Anxiety scale) rating scales were used to assess anxious and depressive symptoms. Nicotine dependence was measured via a self-administered questionnaire (Fagerström Tolerance Questionnaire). RESULTS: Sixty-eight cases were recruited, individually matched, and compared to controls. Overall, cases had significantly higher scores than controls when the rating scales assessing anxious and depressive symptoms were evaluated. CONCLUSIONS: Smokers applying to smoking cessation clinics for the first time have a higher level of negative affectivity than smokers from the general population. An evaluation of the level of negative affectivity could be introduced into clinical practice to have a complete assessment of the patient. We propose adding psychological or pharmacological support to complement the smoking cessation program.

Effects of experimental panic on neuroimmunological functioning.

OBJECTIVE: Psychoimmunological research in panic disorder (PD) so far focussed on single time point evaluation in resting conditions. No robust evidence for changes in the immune system was found using this method. However, PD is characterized by the occurrence of unexpected panic attacks (PAs). The current research focuses on cytokine and acute phase protein (APP) levels and mitogen-induced cytokine secretion following 35% CO(2) inhalation-induced panic. METHODS: Eighteen PD patients and 18 matched healthy control subjects underwent both a placebo and a 35% CO(2) inhalation on separate days. Blood samples for cytokine and APP determination were taken before and after the inhalation. In addition to serum determination, whole blood samples were cultured and stimulated with mitogens for assessment of the functional capacity of the immune system. RESULTS: The 35% CO(2) inhalation induced significantly higher levels of anxiety in PD patients as compared to the control subjects, but no differences in immune parameters were found, either in basal conditions or after experimental panic induction. CONCLUSION: In our sample we do not find any changes in serum levels or functional capacity of several immunological parameters in the experimentally provoked PAs. Similar results have been found in social phobia, whereas in other affective disorders such as depression and posttraumatic stress disorder, immune changes are evident. Changes seem to coincide with alterations in hypothalamic-pituitary-adrenal (HPA) axis function. Therefore, the bidirectional communication pathway between the immune system and the HPA axis might play a role in some affective disorders, but it does not specifically seem to be involved in the etiology of PD.

Amygdala hyperfunction in phobic fear normalizes after exposure.

BACKGROUND: The amygdala is implicated as a key brain structure in fear processing. Studies exploring this process using the paradigm of fear conditioning have implicated the amygdala in fear acquisition and in generating behavioral fear responses. As such, fear extinction could be expected to induce a reduction in amygdala activity. However, exposure in specific phobia has never been shown persistently to reduce amygdala activity. METHODS: By means of event-related functional magnetic resonance imaging, responses to phobia-related, general threat, and neutral pictures were measured before and 2 weeks after an intensive exposure session in 20 subjects with specific phobia for spiders and compared with healthy control subjects. RESULTS: Phobic subjects showed increased amygdala activity at baseline. This hyperactivity was significantly reduced 2 weeks after exposure therapy. Furthermore, a significant reduction of hyperactivity in anterior cingulate cortex and insula was found postexposure. CONCLUSIONS: To our knowledge, this is the first study demonstrating the effect of exposure on the amygdala in specific phobia. Our findings suggest that exposure therapy can have an effect on subcortical structures.

Pharmacokinetic considerations in antipsychotic augmentation strategies: How to combine risperidone with low-potency antipsychotics.

OBJECTIVES: To investigate in vivo the effect of low-potency antipsychotics on metabolism of risperidone (RIS). METHODS: A therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-OH-RIS of 1584 patients was analyzed. Five groups were compared; a risperidone group (n=842) and four co- medication groups; a group co-medicated with chlorprothixene (n=67), a group with levomepromazine (n=32), a group with melperone (n=46), a group with pipamperone (n=63) and a group with prothipendyl (n=24). Plasma concentrations, dose-adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS and active moiety (RIS+9-OH-RIS; AM) as well as the metabolic ratios (9-OH-RIS/RIS; MR) were computed. RESULTS: Differences in plasma concentrations were detected for AM and RIS. Pairwise comparisons revealed significant findings; RIS plasma concentrations were higher in co-medication groups than in monotherapy group. Chlorprothixene- and prothipendyl- medicated patients demonstrated no other differences. In the levomepromazine and melperone group plasma and C/D concentrations of AM and RIS were higher, while MRs were lower. For pipamperone, differences included higher C/D values of RIS and lower MRs. CONCLUSIONS: Alterations of risperidone metabolism suggest pharmacokinetic interactions for levomepromazine and melperone. In the pipamperone-group, lower MRs as well as higher plasma and C/D levels of RIS suggest potential interactions.

Risperidone-induced extrapyramidal side effects: is the need for anticholinergics the consequence of high plasma concentrations?

Antipsychotic drugs can induce various undesirable adverse motor reactions, such as extrapyramidal side effects (EPS). A widely accepted pharmacodynamic mechanism underlying EPS includes an increase in striatal D2-receptor occupancy. However, less is known about the pharmacokinetic background of EPS. The aim of this study was to analyze in-vivo possible pharmacokinetic patterns underlying biperiden-treated EPS in risperidone (RIS)-medicated patients. A large therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-hydroxyrisperidone (9-OH-RIS) of 2293 adult inpatients and outpatients was analyzed. Two groups were compared: a group receiving RIS (n=772) and a group comedicated with biperiden (n=68). Plasma concentrations, dose-adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS, and active moiety (AM) (RIS+9-OH-RIS) as well as ratios of concentrations for metabolite to parent drug (9-OH-RIS/RIS) were computed. We compared the plasma concentrations of the different compounds between the two groups considering the prescription of biperiden as an indirect report of EPS. The daily dosage of RIS did not differ between groups. No differences were detected in case of plasma concentrations and C/D of RIS and active metabolite between the groups. However, plasma concentrations of the AM were significantly higher in the comedicated group (P=0.032) and showed a trend in terms of the active metabolite 9-OH-RIS (P=0.053). Data indicate enhanced AM plasma concentrations of RIS in patients comedicated with biperiden as an EPS treatment. This might underscore an association between higher plasma concentrations of the AM and treatment-requiring EPS.

Prevalence of respiratory disorders in first-degree relatives of panic disorder patients.

BACKGROUND: Panic Disorder (PD) patients often report a history of respiratory pathology, such as asthma. It is known that both PD and respiratory disorders, like asthma, run in families. A common diathesis for PD and some respiratory disorders may be present both in PD patients and their first-degree relatives. We examined whether the lifetime prevalence of respiratory disorders is higher in first-degree relatives of PD patients than in first-degree relatives of patients with other anxiety disorders. METHODS: The lifetime history of respiratory pathology was assessed in 379 first-degree relatives of patients with an anxiety disorder by means of a questionnaire. RESULTS: We found the first-degree relatives of PD patients to report more chronic obstructive pulmonary diseases (COPD) in general (24.8%) and asthma (10.5%) in particular than the comparison group (13.2% and 3.3%, respectively). LIMITATIONS: Our data rely on retrospective self-reports. CONCLUSIONS: Our findings are consistent with and extend previous studies suggesting a specific association between COPD, asthma in particular, and PD.

CO2 challenge results in hypothalamic-pituitary-adrenal activation in healthy volunteers.

The 35% CO(2) challenge is known to induce symptoms of a panic attack both in panic disorder (PD) patients and healthy volunteers. Although the challenge applies more to PD patients, studies in healthy volunteers provide the opportunity to isolate the physical symptoms from the disorder and to focus on the direct effect from the challenge on stress responsive systems. One of the main stress responsive systems is the hypothalamic-pituitary-adrenal (HPA) axis. It remains unclear whether panic symptoms are accompanied by HPA axis activation. Differences in design have hampered any comparison between studies. For example, both serum and salivary cortisol have been used to provide an index of HPA axis activation. Furthermore, indications for central HPA axis disturbance have been suggested. The current study aimed to study the HPA axis response following the induction of panic symptoms in healthy volunteers, both at the pituitary level and at the adrenal level. Furthermore, both serum and salivary cortisol levels were determined. Subjective feelings of anxiety and, correspondingly, cortisol and ACTH levels, were found to be significantly increased following the 35% CO(2) challenge. Cortisol and ACTH responses to CO(2) were also associated. A significant cortisol increase was observed in both serum and saliva samples, although these were more pronounced when considering the free fraction serum values. We conclude that the induction of panic symptoms results in HPA axis activation, both at the pituitary and adrenal level. The question remains as to whether positive responders to the 35% CO(2) inhalation (more specifically PD patients) show a more pronounced HPA axis response.