Serum C-reactive protein level and sleep characteristics in obstructive sleep apnea syndrome comorbid with panic disorder: a preliminary study.

OBJECTIVE: Investigate the sleep characteristics of patients with obstructive sleep apnea syndrome (OSAS) comorbidity with panic disorder (PD), exploring its potential association with serum C-reactive protein (CRP) levels. PATIENTS AND METHODS: Fifty-four patients (25 OSAS patients with PD and 29 without PD) and 25 healthy controls (HCs) were included. The Self-rating anxiety scale (SAS), self-rating depression scale (SDS), and Pittsburgh sleep quality index (PSQI) were used to assess the mood and sleep quality of the subjects. All patients had circulating CRP levels and polysomnography was performed. RESULTS: OSAS with PD had higher SAS, SDS, PSQI than the OSAS without PD. Compared to OSAS without PD, OSAS with PD had higher percentage of non- rapid eye movement sleep 1 and 2 (N1 and N2%), sleep latency, and a lower percentage of rapid eye movement sleep (REM%). Respiratory-related microarousal index, AHI, and time below 90% oxygen saturation (T90) were low, and the lowest oxygen saturation (LO2) was high. Serum CRP levels in OSAS patients with PD were lower than that in OSAS patients without PD, but higher than that in HCs. In OSAS patients with PD, serum CRP levels were negatively correlated with wake time after sleep onset and SAS scores but positively correlated with sleep efficiency and N2%. Serum CRP levels were positively correlated with T90 and negatively correlated with LO2. CONCLUSION: OSAS patients with PD had worse sleep quality, less severe OSAS, and low serum CRP levels. Serum CRP levels in OSAS patients with PD were associated with poorer sleep quality and duration of hypoxia rather than AHI.

Understanding importance of clinical biomarkers for diagnosis of anxiety disorders using machine learning models.

Anxiety disorders are a group of mental illnesses that cause constant and overwhelming feelings of anxiety and fear. Excessive anxiety can make an individual avoid work, school, family get-togethers, and other social situations that in turn might amplify these symptoms. According to the World Health Organization (WHO), one in thirteen persons globally suffers from anxiety. It is high time to understand the roles of various clinical biomarker measures that can diagnose the types of anxiety disorders. In this study, we apply machine learning (ML) techniques to understand the importance of a set of biomarkers with four types of anxiety disorders-Generalized Anxiety Disorder (GAD), Agoraphobia (AP), Social Anxiety Disorder (SAD) and Panic Disorder (PD). We used several machine learning models and extracted the variable importance contributing to a type of anxiety disorder. The study uses a sample of 11,081 Dutch citizens' data collected by the Lifelines, Netherlands. The results show that there are significant and low correlations among GAD, AP, PD and SAD and we extracted the variable importance hierarchy of biomarkers with respect to each type of anxiety disorder which will be helpful in designing the experimental setup for clinical trials related to influence of biomarkers on type of anxiety disorder.

Blood endocannabinoid levels in patients with panic disorder.

BACKGROUND: The development and maintenance of anxiety disorders is not fully understood. There is consensus in the literature that in addition to genetic factors, social, psychological and neurobiological factors are of crucial importance. The present exploratory study investigates the influence of the endocannabinoids (EC) and related N-acylethanolamines (NA) on the maintenance of panic disorder (PD). METHODS: A total of n = 36 PD and n = 26 healthy controls (HC) were included in the study. Baseline characteristics showed no differences between the two groups. The participants were exposed to the Trier Social Stress Test (TSST) for reliable laboratory stress induction. Blood samples were taken during the TSST by an intravenous catheter to examine the endocannabinoid (EC) stress response. Repeated measures ANOVA was conducted to test for main effects of time and group as well as the respective interaction. RESULTS: Participants with PD consistently had significantly higher EC and NA blood levels than HC. The consistently high EC and NA levels barely showed any reactivity as indicated by a lack of statistical variance. In line with these findings no reaction to the psychosocial stressor TSST could be detected. CONCLUSION: Our main results show significant differences in EC concentrations between participants with PD and HC. These findings suggest that an imbalance in the ECS contributes to the maintenance of PD. Increased endocannabinoid levels may have important implications for organic diseases such as cardiovascular disorders. The limitations of the study as well as implications for further investigations are discussed.

DNA methylation of IL-4 gene and the association with childhood trauma in panic disorder.

Increasing evidence suggests that aberrations in the immune-inflammatory pathways contribute to the pathophysiology of panic disorder (PD). We aimed to investigate whether an aberrant DNA methylation of the inflammation-related genes in the development of PD, including CCL3, CRP, CSF2, CXCL8, IFNG, IL12B, IL1A, IL-4, IL-6, TNF. Then, the effect of childhood trauma(CT) on methylation levels of  inflammation-related genes and the severity of PD was also investigated. We compared the methylation levels of the inflammation-related genes between 113 patients with PD and 130 matched healthy controls using MethylTarget approach. In addition, the Hamilton Anxiety Rating Scale (HAMA), Panic Disorder Severity Scale (PDSS) and Childhood Trauma Questionnaire-28 item Short Form (CTQ-28) were respectively assessed to all subjects. The result found that the methylation levels of IL-4 gene was significantly higher in PD patients than controls. ROC results found that the IL-4 gene had a sensitivity of 52.3% and a specificity of 74.6%. The methylation levels of IL-4 gene was significantly positively related to the severity of panic and anxiety. Finally, the hypermethylation of CSF2, CXCL8 and IL-4 genes was significantly associated with higher CT.

Differences in cytokines between patients with generalised anxiety disorder and panic disorder.

OBJECTIVE: The purpose of this study was to evaluate the differences among panic disorder (PD), generalised anxiety disorder (GAD) and controls in inflammatory cytokines. We also analysed the correlation between inflammatory cytokines and response to escitalopram in PD and GAD patients. METHODS: Eighty-six patients with PD, 86 patients with GAD and 86 healthy controls were recruited for this study. All participants were, respectively, assessed for severity of anxiety and panic symptoms using the Hamilton Anxiety Rating Scale (HAMA) and the Panic Disorder Severity Scale (PDSS); all patients in the study were also assessed after 4 weeks of treatment. The serum levels of cytokines were measured using a flow fluorescence microsphere assay. RESULTS: Both PD and GAD patients had higher serum levels of interleukin 6 (IL-6) than controls, and patients with PD showed significantly higher IL-6 than GAD patients. Significant positive correlations were found between the IFN-γ levels and the severity of anxiety in GAD patients. Higher level of IL-6 was associated with better response to escitalopram treatment in PD patients. However, the baseline levels of cytokines were not associated with treatment responses in GAD patients. CONCLUSION: The present findings suggest that patients with PD may have higher levels of IL-6 than GAD, and higher baseline levels of IL-6 may be a better response to escitalopram in the treatment of PD.

Changes in mean platelet volume and hematologic indices in patients with panic disorder due to oxidative stress.

OBJECTIVE: Cardiovascular disorders are common in patients with panic disorder (PD), usually mediated by platelets. The present study was conducted to evaluate oxidative stress conditions and complete analysis of blood cells in patients with PD. SETTING AND SAMPLE POPULATION: Sixty healthy individuals and 60 patients were included in the study. Whole blood and serum samples were obtained from patients and controls. MATERIALS & METHOD: Hematological studies, including blood cells count, hemoglobin, and hematocrit, were carried out on whole blood samples. In addition, oxidative stress indices including total antioxidant capacity, free oxygen species, and malondialdehyde concentration were measured in serum samples. RESULTS: Results showed that patients with PD had a significant increase in mean platelet volume index (MPV), platelet distribution width (PDW), red blood cell distribution width (RDW), and mean corpuscular hemoglobin concentration (MCHC) compared with healthy subjects (p < .05). Also, oxidative stress indices were significantly elevated in patients with PD compared with control group (p < .05). CONCLUSION: Elevated MPV is a hematologic indicator for patients with PD. This disorder may be caused by impaired serotonin metabolism, resulting in increased oxidative stress, as well as in platelet serotonin transporters. Regarding elevated oxidative stress, the risk of cardiovascular complications is high in patients with PD.

Pre-treatment peripheral biomarkers associated with treatment response in panic symptoms in patients with major depressive disorder and panic disorder: A 12-week follow-up study.

OBJECTIVE: Peripheral biomarkers have been studied to predict treatment response of panic symptoms. We hypothesized that depressive disorder (MDD) vs. panic disorder (PD) would exhibit different peripheral biomarkers, and their correlation with severity of panic attacks (PA) would also differ. METHODS: Forty-one MDD patients, 52 PD patients, and 59 healthy controls were followed for 12 weeks. We measured peripheral biomarkers along with the Panic Disorder Severity Scale (PDSS) at each visit-pre-treatment, 2, 4, 8, and 12 weeks on a regular schedule. Peripheral biomarkers including serum cytokines, plasma and serum brain-derived neurotrophic factor (BDNF), leptin, adiponectin, and C-reactive protein (CRP) were quantified using enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with MDD and PD demonstrated significantly higher levels of pre-treatment IL-6 compared to controls, but no differences were seen in plasma and serum BDNF, leptin, adiponectin, and CRP. Pre-treatment leptin showed a significant clinical correlation with reduction of panic symptoms in MDD patients at visit 5 (p=0.011), whereas pre-treatment IL-6 showed a negative correlation with panic symptom reduction in PD patients (p=0.022). An improvement in three panic-related items was observed to be positively correlated with pre-treatment leptin in MDD patients: distress during PA, anticipatory anxiety, and occupational interference. CONCLUSION: Higher pre-treatment leptin was associated with better response to treatment regarding panic symptoms in patients with MDD, while higher IL-6 was associated with worse response regarding panic symptoms in PD patients. Different predictive peripheral biomarkers observed in MDD and PD suggest the need for establishing individualized predictive biomarkers, even in cases of similar symptoms observed in different disorders.

Copeptin in CCK-4-induced panic in healthy man: Sexual dimorphisms in secretion pattern and panic response, but no correlation of copeptin with panic symptoms.

Copeptin, the C-terminal part of the hypothalamic arginine vaspopressin (AVP) precursor, closely mirrors the production of AVP and was proposed as an easily measured novel marker of the individual stress level in man. First data in male volunteers proposed copeptin as a potential endocrine surrogate marker of cholecystokinin-tetrapeptide (CCK-4)-induced panic. We tried to replicate these pilot data and to extend them to the other sex. 46 healthy human subjects (29 men, 17 women) were given an intravenous bolus of 50 µg CCK-4. Basal and stimulated plasma copeptin was measured and panic symptoms were assessed using the Acute Panic Inventory (API). Basal copeptin was significantly lower in women vs. men, while men showed a significantly higher CCK-4-induced increase of copeptin. In contrast, female subjects displayed a signifcantly higher increase of API ratings by CCK-4. No significant correlations of panic symptoms and copeptin release induced by CCK-4 could be found, neither in man, nor in women, nor in the total sample. A sexual dimorphism in copeptin secretion and in panic response was demonstrated. Prior unexpected findings of copeptin release as an objective read-out of panic could not be replicated. The role of the vasopressinergic system in panic anxiety needs further study in panic patients and in healthy man, using also other panic provocation paradigms.

Ratio of plasma BDNF to leptin levels are associated with treatment response in major depressive disorder but not in panic disorder: A 12-week follow-up study.

BACKGROUND: A link between brain-derived neurotrophic factor (BDNF) expression and the mood regulatory effect of leptin has been suggested in the pathophysiology of major depressive disorder (MDD). We investigated treatment response and pre-treatment leptin and BDNF in patients with MDD and with panic disorder (PD). METHODS: We recruited 41 patients with MDD, 52 patients with PD, and 59 matched healthy controls. All subjects completed five visits (at baseline, 2, 4, 8, and 12 weeks), and both MDD and PD patients were treated with standard pharmacotherapy for 12 weeks. Plasma BDNF (pBDNF) and blood leptin levels were obtained along with a 17-item Hamilton Depression Scale rating (HDRS-17) score at every visit. RESULTS: The ratio of pre-treatment pBDNF to leptin was significantly lower in patients with MDD and PD compared to healthy controls (p = 0.024), but was not associated with severity of depressive or anxiety symptoms. Pre-treatment pBDNF:leptin ratio was significantly higher in treatment responders than in non-responders (p = 0.012) in MDD but not in PD. This difference was larger in MDD patients with appetite loss (p = 0.034). In multivariate analysis, pre-treatment pBDNF:leptin ratio was significantly associated with treatment responsiveness (Adjusted Odds Ration [AOR] = 2.50, 95% CI 1.02-6.14) in MDD. LIMITATION: small sample size; limited information on detailed pharmacological effects. CONCLUSIONS: A relatively higher ratio of pre-treatment pBDNF to leptin was associated with greater treatment response in MDD but not in PD. Further research should focus on exploration of a link between BDNF and leptin underlying neuronal plasticity in depression.

Exposure-induced changes of plasma metabolome and gene expression in patients with panic disorder.

BACKGROUND: Anxiety disorders including panic disorder (PD) are the most prevalent psychiatric diseases leading to high disability and burden in the general population. Acute panic attacks are distinctive for PD but also frequent in other anxiety disorders. The neurobiology or specific molecular changes leading to and present during panic attacks are insufficiently known so far. METHODS: In the present pilot study, we investigated dynamic metabolomic and gene expression changes in peripheral blood of patients with PD (n = 25) during two exposure-induced acute panic attacks. RESULTS: The results show that the metabolite glyoxylate was dynamically regulated in peripheral blood. Additionally, glyoxylate levels were associated with basal anxiety levels and showed gender-related differences at baseline. As glyoxylate is part of the degradation circuit of cholecystokinin, this suggests that this neuropeptide might be directly involved in exposure-induced panic attacks. Only gene expression changes of very small magnitude were observed in this experimental setting. CONCLUSIONS: From this first metabolome and gene expression study in exposure-induced acute panic attacks in PD we conclude that metabolites can potentially serve as dynamic markers for different anxiety states. However, these findings have to be replicated in cohorts with greater sample sizes.

Elevated peripheral kynurenine/tryptophan ratio predicts poor short-term auditory memory in panic disorder patients.

Abnormalities in the kynurenine pathway (KP) have been implicated in the cognitive deficits of psychiatry disorders, possibly through cytokines that increase the activity of indoleamine-2,3 dioxygenase (IDO), a key enzyme for tryptophan-to-kynurenine conversion. Some studies on panic disorder (PD) have detected elevated cytokines in blood. We aimed to determine the extent to which elevated peripheral cytokine levels and kynurenine/tryptophan (kyn/tryp) ratio (1) are biological markers for PD patients and (2) are related to cognition in PD. Seventy-eight PD patients and matched healthy controls were assessed for peripheral serum levels of interleukin (IL)-2R, IL-1ß, IL-10, kynurenine and tryptophan. The subjects were evaluated for episodic and short-term memory, selective attention and cognitive flexibility. In patients, IL-2R levels, which are involved in the regulation of IDO, were significantly associated with levels of kynurenine (p = .029), but this association was not observed in controls. Importantly, an elevated kyn/tryp ratio significantly predicted poor digit span forward (p = .004) and total (p = .004) scores in individuals with PD. This study is the first to link blood biomarkers of infiammation and the KP with cognitive deficits in PD subjects, suggesting that those with an elevated kyn/tryp ratio might have short-term auditory memory impairment. These findings indicate that treatments targeting the KP may ameliorate cognitive abnormalities in PD patients.

Stress-induced pro- and anti-inflammatory cytokine concentrations in panic disorder patients.

BACKGROUND: An attenuated responsivity of the hypothalamus-hypophysis-adrenal (HPA) axis upon challenge and an increased risk for cardiac events are relatively consistent findings in panic disorder (PD) patients. Due to cytokine-HPA interactions, an altered HPA-axis responsivity may be accompanied by altered cytokine concentrations. Immunological reactions under stress might be considered the missing link for explaining an increased cardiac risk. This study analyzed stress-induced cytokine levels in PD patients. METHODS: A total of n = 32 PD patients and n = 32 healthy control individuals performed the Trier Social Test (TSST). Blood sample collection accompanied the TSST for the collection of cortisol and pro- (IL-6, TNF-α) and anti-inflammatory cytokines (IL-10). Established self-report questionnaires were handed out for the clinical characterization and the assessment of subjective levels of distress during testing. Repeated measures ANCOVA were conducted to evaluate main effects of time or group and time x group interaction effects. Additional ANCOVAS with disease severity as between-subjects factor (healthy, borderline, mild, moderate, severe) took global panic severity into account. Pearson correlation analyses were carried out to test for an association of panic specific symptoms and peak cytokine release. RESULTS: The TSST resulted in a significantly increased secretion of cortisol, IL-6 and IL-10. The data analysis further revealed a significant time x group interaction effect for cortisol and IL-10. Compared to the healthy volunteers, the PD patients showed significantly higher baseline and challenged IL-10 concentrations but lower challenged cortisol concentrations. Mildly and moderately affected patients showed the highest levels of IL-10 compared to the healthy individuals. There were no differential secretion patterns of IL-6 and TNF-α between both groups in the course of the TSST. The peak IL-6 release was found to be significantly associated with global disease severity. CONCLUSION: We found evidence for altered levels of cytokines with primarily anti-inflammatory properties in PD patients under baseline and a psychosocial stress condition. The results provide tentative evidence for a low-grade inflammatory process in PD patients, possibly representing a missing link factor between PD diagnosis and the increased risk for cardiac disease.

Respiratory subtype of panic disorder: Can serum phosphate levels be a possible outcome to group cognitive-behavior therapy?

OBJECTIVE: Panic disorder (PD) respiratory subtype (RS) was described in order to cluster patients according to their symptoms. These patients are characterized by experiencing a relatively high number of noticeable respiratory symptoms during a panic attack (PA) and a higher reactivity to CO2. In this study, we aimed to evaluate the clinical relevance of this diagnostic category, evaluating if there are different responses to cognitive-behavioral therapy in patients with panic disorder RS as compared to those with the non-respiratory subtype (NRS), using serum phosphate as a biological marker. METHODS: Patients were assessed by a clinical interview followed by a structured diagnostic interview (M.I.N.I) and classified as RS or NRS based on symptoms. The severity of PD was evaluated throughout the PDSS, CGI, HAM-A, STAI and the BDI rating scales. All patients underwent 12 structured sessions of group-CBT for PD and had their blood collected at baseline and after treatment to assess phosphate levels. RESULTS: One hundred and thirty-eight patients have been assessed, and 102 were included in this trial. Sixty-nine patients completed the treatment protocol, 42 were classified as RS and 27 as NRS. Both RS and NRS patients improved in all clinical scales (p < 0.001). The mean phosphate levels increased from 2.44 mg/dl ±â€¯0.49 at baseline to 3.38 mg/dl ±â€¯0.52 (p < 0.01) in the RS group as well as from 2.46 mg/dl ±â€¯0.64 at baseline to 3.46 mg/dl ±â€¯0.61 (p < 0.01) in the NSR group. LIMITATIONS: Small sample size and the lack of assessment of other clinical and physiological parameters, such as respiratory variables. CONCLUSION: Our findings suggest that both RS and NRS benefit from group CBT and that there was a change in phosphate levels after effective treatment in both groups. Our data support the idea that there is a reversal of the conditions that promote hypophosphatemia as chronic hyperventilation after CBT treatment, whereas it is in disagreement to the presence of two different PD subtypes based on phosphate levels once their rates did not differ at baseline and had a similar increase after effective treatment.

Stress hormone response to the DEX-CRH test and its relation to psychotherapy outcome in panic disorder patients with and without agoraphobia.

This study tested whether the hormonal stress response to the DEX-CRH test may be predictive of the psychotherapy success for panic disorder (PD). Thirty-four patients diagnosed either with agoraphobia with PD or PD without agoraphobia were subjected to cognitive behavioural therapy (CBT). Patients (pre-therapy) and healthy volunteers were exposed to the DEX-CRH test. Blood samples were taken for cortisol and adrenocorticotropic hormone (ACTH) assessment. Established panic-specific questionnaires were handed out for the pre-therapy and post-therapy evaluation of disease severity (with reference to panic beliefs and agoraphobic cognitions, fear of bodily sensations, agoraphobic avoidance behaviour). Repeated measures ANCOVA were conducted for the analysis of the pre-therapy hormonal response, and Pearson's correlation analysis to test for associations with the psychotherapy outcome. Data analyses revealed large effect sizes for CBT in the clinical measures (η2 ≥ 0.321), main effects of time for cortisol and ACTH with no differences between both groups, and significant associations between cortisol release and agoraphobic cognitions for the patients. PD diagnosis had no impact on the hormonal response. However, those patients with higher cortisol release showed less improvement after CBT (significantly for agoraphobic cognitions). Clinical implications of these findings are the prediction of the therapy success from a potential endocrine correlate whose persistency (if assessed repeatedly) during the treatment may predict (non-)response to the current treatment, possibly representing a decision support for a change in treatment to avoid the continuation of an inefficient treatment.

Anxiety disorders and CRP in a population cohort study with 54,326 participants: The LifeLines study.

OBJECTIVES: Growing evidence indicates that inflammatory processes may play a role in the pathogenesis of anxiety disorders. Nevertheless, much remains to be learned about the involvement of inflammation, including C-reactive protein (CRP), in specific anxiety disorders. This study examines the relation between anxiety disorders and CRP. METHODS: Associations of serum CRP with anxiety disorders were determined in a large population study (n = 54,326 participants, mean age = 47 years; 59% female), the LifeLines cohort. Depressive and anxiety disorders (generalized anxiety disorder, social anxiety phobia, panic disorder with or without agoraphobia and agoraphobia without panic disorder) were assessed using the Mini-International Neuropsychiatric Interview. RESULTS: Anxiety disorders, with the exception of social anxiety disorder, were significantly associated with increased CRP. After adjusting for demographics, life style factors, health factors, medication use, depression, and psychological stressors, CRP remained significantly associated with panic disorder with agoraphobia (ß = 0.01, P = .013). Moreover, CRP levels were significantly higher in people with panic disorder with agoraphobia compared to other anxiety disorders, independent of all covariates (F = 3.00, df = 4, P = .021). CONCLUSIONS: Panic disorder with agoraphobia is associated with increased CRP, although the effect size of this association is small. This indicates that neuroinflammatory mechanisms may play a potential role in its pathophysiology.

Cytokine alterations in panic disorder: A systematic review.

BACKGROUND: Panic disorder (PD) occurs in 3.4-4.7% of the general population. Although accumulating evidence suggests that some inflammatory processes play a role in the pathophysiology of mental disorders, very few studies have evaluated cytokine levels in patients with PD. The aim of the present study was to systematically review the characteristic cytokine profile of PD patients and discuss some possibilities for future trials on this common and disabling disorder. METHODS: A comprehensive literature search was carried out in PubMed and Web of Science databases (search terms: "panic disorder" or "panic attacks" and IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, TNF-alpha and INF-gamma). RESULTS: Eleven studies involving measurements of cytokines in PD patients were included in this review article. Increased serum levels of some inflammatory markers such as IL-6, IL-1ß and IL-5 were reported in PD patients compared with control subjects. There are some conflicting results regarding IL-2, IL-12, and INF-γ in association with PD. LIMITATIONS: There are discrepant findings in the existing literature regarding PD and cytokines. A significant portion of the recognized heterogeneity may be attributable to variability in assay procedures. The discrepant findings may also have been due to differences in the study populations. CONCLUSIONS: Cytokines induce the production of acute-phase proteins and are linked to neurogenesis, modification of the HPA axis, microglial activation, tryptophan metabolism and an imbalance in excitatory and inhibitory neurotransmission. Investigation of inflammatory biomarkers in PD could contribute to understanding the pathophysiological mechanisms in this debilitating disorder.

Associations between severity of anxiety and clinical and biological features of major affective disorders.

Patients with major affective disorders (MAFD) with comorbid anxiety show a greater functional impairment than those without anxiety. The aim of this study is to delineate the associations between severity of anxiety in MAFD, namely bipolar disorder (BD) and major depression (MDD), and MAFD characteristics and serum high-density lipoprotein (HDL)-cholesterol levels. Recruited were 82 participants with anxiety disoders and 83 without anxiety disoders, including 101 MAFD patients and 51 healthy controls. We used the Hamilton Anxiety Rating Scale (HAM-A) to measure severity of anxiety and made the diagnoses of posttraumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), panic disorder (PD), generalized anxiety disorder (GAD) and phobias. The HAM-A score is significantly predicted by higher number of depressive episodes, GAD and phobias, childhood trauma, tobacco use disorder, metabolic syndrome and lowered HDL-cholesterol. Increased HAM-A scores are, independently from severity of depression, associated with lowered quality of life, increased disabilities and suicidal ideation. Lithium treatment significantly lowers HAM-A scores. It is concluded that severity of anxiety significantly worsens the phenomenology of MAFD. Therefore, treatments of MAFD should target increased severity of anxiety and its risk factors including low HDL-cholesterol, metabolic syndrome, childhood trauma and tobacco use disorder.

Cortisol stress response in post-traumatic stress disorder, panic disorder, and major depressive disorder patients.

BACKGROUND: Previous research has focussed extensively on the distinction of HPA-axis functioning between patient groups and healthy volunteers, with relatively little emphasis on a direct comparison of patient groups. The current study's aim was to analyse differences in the cortisol stress response as a function of primary diagnosis of panic disorder (PD), post-traumatic stress disorder (PTSD), and major depressive disorder (MDD). METHODS: A total of n=30 PD (mean age±SD: 36.07±12.56), n=23 PTSD (41.22±10.17), n=18 MDD patients (39.00±14.93) and n=47 healthy control (HC) individuals (35.51±13.15) participated in this study. All the study participants were female. The Trier Social Stress Test (TSST) was used for reliable laboratory stress induction. Blood sampling accompanied the TSST for cortisol and ACTH assessment. Panic-related, PTSD-specific questionnaires and the Beck Depression Inventory II were handed out for the characterisation of the study groups. Repeated measure ANCOVAs were conducted to test for main effects of time or group and for interaction effects. Regression analyses were conducted to take comorbid depression into account. RESULTS: 26.7% of the PD patients, 43.5% of the PTSD patients, 72.2% of the MDD patients and 80.6% of the HC participants showed a cortisol stress response upon the TSST. ANCOVA revealed a cortisol hypo-responsiveness both in PD and PTSD patients, while no significant group differences were seen in the ACTH concentrations. Additional analyses showed no impact of comorbid depressiveness on the cortisol stress response. MDD patients did not differ in the hormonal stress response neither compared to the HC participants nor to the PD and PTSD patients. CONCLUSION: Our main findings provide evidence of a dissociation between the cortisol and ACTH concentrations in response to the TSST in PTSD and in PD patients, independent of comorbid depression. Our results further support overall research findings of a cortisol hypo-responsiveness in PD patients. A hypo-response pattern was also seen in the PTSD patients agreeing with previous finding on the cortisol stress reactivity following TSST stress induction in these patients. Patients with a primary MDD diagnosis showed descriptively higher cortisol concentrations compared to the anxiety patients, and lower cortisol concentrations as the healthy individuals. The limitations of the study and implications for future studies will be discussed.

Associations of plasma leptin to clinical manifestations in reproductive aged female patients with panic disorder.

Preclinical studies suggest the implication of the adipocyte hormone leptin in anxiety and fear processes. We explored for potential differences regarding plasma leptin, cortisol and the ratio leptin/Body Mass Index (BMI) between 27 medication-free female patients with Panic Disorder (PD) and 42 age-matched female controls, and for potential associations between plasma leptin and psychometric evaluations including number of panic attacks during last week, Clinical Global Impression-Severity of Illness (CGI-S) and Symptoms Checklist-90-Revised (SCL-90-R). Cortisol levels showed no differences between patients and controls, or correlations to leptin or to any clinical features. Both groups demonstrated a strong positive correlation between leptin and BMI and similar leptin and leptin/BMI, despite patients' lower BMI. However, patients -but not controls- demonstrated significant negative correlations of leptin to the 'somatization', 'anxiety', and 'phobic anxiety' SCL-90-R subscales. Moreover, there was a significant negative correlation of leptin and of leptin/BMI ratio to the number of panic attacks during last week, while higher CGI-S was associated with lower leptin/BMI ratio. Our results, limited to PD female patients, suggest that lower leptin serum levels are significantly associated with greater severity of psychopathological manifestations, including number of panic attacks, symptoms of somatization, anxiety and phobic anxiety and overall clinical presentation.

Cytokine Levels in Panic Disorder: Evidence for a Dose-Response Relationship.

OBJECTIVE: Several studies have investigated possible biological correlates of mental disorders. Although some studies have consistently reported elevated levels of serum inflammatory markers in depression, very few have evaluated cytokine levels in patients with lifetime panic disorder (PD). METHODS: Seventy-eight adults (75% women) from an anxiety disorders outpatient unit were categorized according to their PD status: current or in remission. Serum levels of interleukin (IL)-6, tumor necrosis factor α, and IL-10 were evaluated using flow cytometry with enhanced sensitivity flex sets. Data on clinical comorbidity, lipid profile, fasting blood glucose, C-reactive protein, and PD severity were also obtained. RESULTS: Significantly higher mean levels of serum IL-6 (0.83 vs 0.60 pg/mL [95% confidence interval {CI}for the log-transformed mean difference, -0.41 to -0.57], p = .008) but not of tumor necrosis factor-α (0.18 vs 0.14 pg/mL [95% CI, -1.12 to 0.11]; p = 0.53) or IL-10 (0.21 vs 0.26 [95% CI, -0.20 to 0.44]; p = 0.16), were associated with current PD compared to remitted PD. Higher Panic Disorder Severity Scale (standardized ß = 0.36; p = .013), body mass index (standardized ß = 0.53, p < .001) and fasting blood glucose 5.6 mmol/L or greater (standardized ß = 0.23, p = .038) were significantly associated with higher levels of IL-6 in the multivariate linear regression model. CONCLUSIONS: Our findings support a proinflammatory state in patients with current PD that is independent of possible confounders. Although there are important implications of these findings, replication is required.