The bidirectional relationship between anxiety disorders and circulating levels of inflammatory markers: Results from a large longitudinal population-based study.

BACKGROUND: Although there has been abundant research on chronic low-grade inflammation as a potential mechanism underlying the link between mood disorders and cardiovascular risk, less is known about the role of inflammatory factors and anxiety disorders. The aim of this paper is to evaluate the bi-directional associations between inflammatory markers including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and high sensitivity C-reactive protein (hsCRP) with anxiety disorders and its subgroups. METHODS: The sample consisted of 3,113 participants (53.7% women; mean age: 51.0, S.D. 8.8 years), randomly selected from the general population, who underwent comprehensive somatic and psychiatric evaluations at baseline and follow-up (mean follow-up duration = 5.5 years, S.D. 0.6). Anxiety disorders were assessed with semistructured diagnostic interviews. Inflammatory biomarkers were analyzed in fasting blood samples. RESULTS: After adjustment for potential confounders, current anxiety disorders (ß = 0.09, 95% CI 0.00-0.17) and agoraphobia (ß = 0.25, 95% CI: 0.07-0.43) at baseline were associated with a steeper increase of hsCRP levels over the follow-up period. Current posttraumatic stress disorder (PTSD) was associated with a lower increase of IL-6 levels over the follow-up period (ß = -0.52, 95% CI: -1.00/-0.04). There was no evidence for an association between inflammation markers at baseline and anxiety disorders at follow-up. CONCLUSIONS: The prospective association between agoraphobia at baseline and hsCRP levels over the follow-up period suggests that chronic low-grade inflammation may be a consequence of this condition. The decrease in IL-6 in PTSD also requires further investigation. No evidence was found for chronic low-grade inflammation as a predictor of future anxiety disorders.

Gender effect on the relationship between stress hormones and panic-agoraphobic spectrum dimensions in healthy subjects.

INTRODUCTION: Alterations of the hypothalamic-pituitary-adrenal (HPA) axis and of its peripheral indices have been reported in both normal and pathological anxiety with controversial findings. The aim of the present study was to investigate the possible correlations between serum cortisol and dehydroepiandrosterone-sulfate (DHEA-S) levels and DHEA-S/cortisol ratio, and panic-agoraphobic spectrum dimensions in a sample of healthy subjects. METHODS: Forty-two healthy subjects of both sexes, with no current or lifetime psychiatric disorders, were assessed by means of the Structured Clinical Interview for DSM-IV (SCID-I/P) and the so-called Panic Agoraphobic Spectrum-Self Report lifetime version (PAS-SR). RESULTS: Significant, negative correlations were found between cortisol levels and the total score of the separation sensitivity, panic-like symptoms, and medication/substance sensitivity PAS-SR domains. The PAS-SR total and the panic-like symptoms domain scores were positively related to the DHEAS/cortisol ratio. When the sample was divided in women and men, these correlations were present in women only. DISCUSSION: These findings, while indicating the presence of significant relationships between panic-agoraphobic traits and some indices of HPA axis functioning in healthy women, would suggest this as one of the factors explaining the greater vulnerability of women to cross the line between normal and pathological anxiety. CONCLUSIONS: Further studies are needed to explore gender differences in the relationships between HPA axis alterations and the panic-agoraphobic spectrum dimensions.

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.

Relative hyperhomocysteinemia in patients with panic disorder: a case-control study.

BACKGROUND: The aim of this work was to examine a possible association between a clinically relevant panic disorder and plasma total homocysteine concentration. METHODS: 23 patients with panic disorder with or without agoraphobia confirmed by a standardized clinical interview (Structural Clinical Interview for DSM-IV-German version) and 23 healthy controls matched for gender and age completed questionnaires (SCL-K9, STAI, ADS, STAXI) and had blood drawn after a 15 min rest. Plasma total homocysteine concentrations were measured by competitive enzyme immunoassay. Interfering variables such as age, gender, smoking status, comorbid depression and medication were controlled for. RESULTS: Patients with panic disorder had higher plasma homocysteine concentrations in comparison to the control group (mean value 11.00 vs. 9.14 mumol/l, p = 0.04 with age, gender, smoking status, comorbid depression and antidepressant medication being controlled for). Furthermore, homocysteine plasma concentration was positively correlated with Global Severity of Symptoms (SCL-K9, r(Pearson) = 0.41, p < 0.01). CONCLUSION: The findings of this study suggest a link between elevated plasma homocysteine levels and panic disorder. This raises a new hypothesis of another pathway to an increased risk of cardiovascular events in anxious individuals.

Elevated alpha-amylase but not cortisol in generalized social anxiety disorder.

Stress-system dysregulation is thought to increase the risk for anxiety disorders. Here we describe both hypothalamic pituitary adrenal (HPA) axis and autonomic nervous system (ANS) activity in basal non-challenging conditions and after 0.5mg dexamethasone in generalized social anxiety disorder (gSAD) patients. To ensure stress-free sampling we collected saliva and determined cortisol and alpha-amylase (sAA), the latter a relative new marker of autonomic activity. Forty-three untreated gSAD patients without comorbidity were compared with 43 age and gender matched controls in non-stressed conditions on sAA and cortisol after awakening, during the day (including late evening), and after a low dose (0.5mg) of dexamethasone. Cortisol and sAA were analyzed with mixed models. Additional analyses were done with paired t-tests. Apart from the assessments in the morning, gSAD patients had significantly higher diurnal and post-dexamethasone 1600h sAA levels. No differences between gSAD and controls in any cortisol measurements were found. In conclusion, in gSAD in basal, non-stimulated conditions and after dexamethasone, we found hyperactivity of the ANS, as measured with sAA, but not of the HPA-axis. This suggests a relative increased activity of the ANS as compared to the HPA-axis, in line with the observed hyperarousal in gSAD.

Association between anxiety and factors of coagulation and fibrinolysis.

BACKGROUND: Psychological stress and anxiety have been shown to produce an activation of coagulation and fibrinolysis. Resulting hypercoagulability is a risk factor for cardiovascular diseases, and could therefore contribute to an increased prevalence of coronary artery disease in anxiety patients. However, hemostasis function has not yet been studied in patients with clinically relevant anxiety disorders. METHODS: A group of anxiety patients (panic disorder with agoraphobia or social phobia) and a healthy control group (each n = 29) completed some questionnaires [SCL-K9 (a short form of the SCL-90-R), State Trait Anxiety Inventory, ADS (general depression scale)], and had blood drawn after a 15-min rest period. To assess the reaction of the hemostatic system by global entities, sum scores were computed from parameters of coagulation and fibrinolysis (fibrinogen, FVII, FVIII, vWF, F1 + 2, TAT, D-dimer, alpha(2)-AP, PAP, tPA, PAI-1). Interfering variables, such as age, gender, alcohol consumption and smoking status, were controlled. RESULTS: Anxiety patients scored higher in a composite hemostatic score and a sum score of fibrinolysis in comparison to the control group, with a predominant activation of inhibitors in fibrinolysis. However, the psychological variable with the closest association to hemostasis was not trait anxiety, but self-perceived worry about blood drawing before blood sampling was performed. CONCLUSIONS: The coagulation and fibrinolysis system is activated in the direction of a hypercoagulable state in patients with severe phobic anxiety, triggered by fear of blood drawing. This could be one mediating factor for the increased risk of cardiovascular diseases in this population. Acute situational phobic anxiety should be monitored closely when studying the association between anxiety and hemostasis.

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.

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.

Nerve growth factor serum concentrations rise after successful cognitive-behavioural therapy of generalized anxiety disorder.

Generalized anxiety disorder (GAD) is a chronic stress disease with permanent physical tension and cognitive strain. Raised nerve growth factor (NGF) serum levels were reported as an acute stress reaction in soldiers before their first parachute jump even before the rise in cortisol. Taking GAD as a clinical model of chronic stress, we measured NGF in the serum of 22 patients with GAD before and after cognitive-behavioural therapy (CBT) and compared them to those of healthy normal controls. Treatment response was tested by the values of the State and Trait of Anxiety Inventory (STAI) and the Hamilton Anxiety Scale (HAM-A) as treatment outcome variables. The NGF values of patients and controls were similar at baseline (p=0.8941); however, with successful treatment, corresponding to a mean reduction in the HAM-A by more than 50% and a reduction in the clinical global impression scale (CGI) median from 4 to 1, the patients' NGF serum concentrations rose significantly (p=0.0006) which might correspond to an altered stress reaction, possibly contributing to good therapeutic response with CBT. There were 3 patients with a HAM-A decrease of less than 15%. In those patients NGF rose only marginally. Hence, the increase in serum NGF seems to indicate good treatment response.

Hyponatremia-induced seizure during carbamazepine treatment.

We report the case of a 54-year-old woman who was admitted for benzodiazepine withdrawal. After 6 weeks of carbamazepine treatment (600, then 200 mg) the patient suddenly suffered from a grand mal seizure. Laboratory findings revealed a clinical significant hyponatremia of Na 125 mmol/l (baseline: 143 mmol/l). CCT and ECG were normal. To our knowledge, this is the first description of a seizure related to hyponatremia in an adult carbamazepine-treated patient.

Plasma alprazolam concentrations. Relation to efficacy and side effects in the treatment of panic disorder.

A series of 237 patients with DSM-III-diagnosed panic disorder, or agoraphobia with panic attacks, received alprazolam as part of the placebo-controlled Cross-National Collaborative Panic Study. After a 1-week drug-free period, alprazolam dosage was titrated upward with the objective of reaching 6.0 mg/d in all patients. At week 3 of treatment, alprazolam plasma levels were significantly correlated with daily dosage (regression slope: 11.7 ng/mL per milligram per day) but with considerable individual variation. Among patients with spontaneous panic attacks, 70% of those with plasma alprazolam levels greater than 20 ng/mL achieved complete remission vs 31% of those with levels less than 20 ng/mL. Situational panic attack remission increased in frequency with increasing plasma levels, but the relationship was not significant. Patient- and physician-rated global improvement and Hamilton Anxiety and Depression Scale score reductions were maximal at 20 to 39 ng/mL, with no further benefit at higher levels. Central nervous system-depressant side effects increased in frequency with higher plasma levels. Between weeks 3 and 8 of treatment, physicians were permitted to adjust dosage (maximum: 10 mg/d) to optimize response. At week 8, the dose-concentration relationship was essentially identical (regression slope: 10.8 ng/mL per milligram per day), but plasma levels were no longer related to efficacy or side effects. Thus, monitoring of plasma alprazolam concentrations may have a clinically useful role during short-term treatment of panic disorder.

Situational panic attacks. Behavioral, physiologic, and biochemical characterization.

To investigate the pathophysiology of nonpharmacologically induced panic attacks, 18 drug-free agoraphobic patients and 13 matched healthy subjects underwent structured exposure to phobic situations. Heart rate, blood pressure, and plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG), cortisol, growth hormone, and prolactin levels were measured before, during, and after exposure. Fifteen patients experienced situational panic attacks during exposure. Panicking patients displayed significantly greater increases in heart rate but not blood pressure or plasma free MHPG or cortisol in comparison with the healthy subjects. Growth hormone and prolactin responses tended to be smaller in the patients. If brain noradrenergic hyperactivity occurs during situational panic attacks, it may be too brief or too restricted in regional localization to affect MHPG levels in plasma. Chronically recurrent attacks may cause an adaptation of neuroendocrine mechanisms activated by anxiety or stress.

Cortisol and sodium lactate-induced panic.

Sodium lactate infusions induce panic attacks in patients with panic disorder, but not in normal controls, by an unknown mechanism. We studied the plasma cortisol response to infusion of 0.5 mol/L of sodium lactate in 103 patients with panic disorder or agoraphobia with panic attacks, and 32 normal controls. Baseline cortisol levels did not distinguish early panickers from non-panickers and controls, but late panickers had significantly elevated baseline cortisol levels. In addition, a higher percentage of late panickers manifested an increase in cortisol during the baseline period compared with the other groups. Despite the fact that late panickers manifested elevated baseline cortisol levels, early panickers had significantly greater somatic distress as measured by the Acute Panic inventory. There was no increase in cortisol with lactate-induced panic, and cortisol levels fell significantly during the lactate infusion in all groups. Cortisol elevation occurred with moderate anxiety but not with severe panic anxiety. These results suggest different pathophysiologic mechanisms of early and late panic, and differences between anticipatory anxiety and panic anxiety.

Lactate provocation of panic attacks. II. Biochemical and physiological findings.

Thirty-one of 43 patients with panic disorder or agoraphobia with panic attacks and none of 20 normal controls panicked in response to infusions of sodium lactate. Before receiving lactate, patients showed higher heart rates than controls and also signs of hyperventilation. During lactate infusion, patients who did not panic, nevertheless, developed higher lactate and pyruvate levels and greater ionized calcium and pH changes than controls. Lactate-induced panic attacks were regularly accompanied by biological changes consistent with hyperventilation and central noradrenergic activation and irregularly by elevation of plasma norepinephrine and cortisol levels. Panic attacks were not associated with changes in epinephrine or calcium levels or pH. Baseline arousal increased the likelihood of panic during lactate infusion. It is hypothesized that lactate-induced panic primarily involves central noradrenergic discharge with inconsistent peripheral manifestations.

Increased anxiogenic effects of caffeine in panic disorders.

The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages.

Relationship between anxiety and thyroid function in patients with panic disorder.

The aim of this study was to investigate correlations between thyroid function and severity of anxiety or panic attacks in patients with panic disorder. The authors examined 66 out-patients with panic disorder (medicated, n=41; non-medicated, n=25), and measured their free thriiodothyronine (T3), free thyroxine (T4) and thyroid-stimulating hormone (TSH) levels. Significant correlations between the thyroid hormone levels and clinical features were observed in the non-medicated patients. The more severe current panic attacks were, the higher the TSH levels were. In addition, severity of anxiety correlated negatively with free T4 levels. In this study, we discuss relationship between thyroid function and the clinical severity or features of panic disorder.

Platelet [3H]imipramine binding in generalized anxiety disorder, panic disorder, and agoraphobia with panic attacks.

The density of platelet [3H]imipramine binding sites is reported to be decreased in unipolar depression and, hence, is a putative biological marker. There is considerable evidence for a phenomenological and biological relationship of panic disorder with affective disorder. We studied platelet [3H]imipramine binding site density in unmedicated subjects with generalized anxiety disorder (GAD; n = 55), panic disorder (PD) with and without agoraphobia (n = 52), and normal controls (n = 26) in order to determine whether or not patients with panic disorder differed from controls in this biological assay. We found no differences in binding site density (Bmax) or affinity (Kd) among the PD, PD with agoraphobia, GAD, and control groups. Nor did we find a relationship between Bmax or Kd and the severity of depressive symptoms or the presence of a family history of affective disorder. In view of two conflicting prior studies, the use of [3H]imipramine binding in panic disorder remains problematic.

Paradoxical growth-hormone responses to thyrotropin-releasing hormone in panic disorder.

Thyrotropin-releasing hormone (TRH) has been reported to stimulate growth hormone (GH) release in a variety of pathological conditions, including some studies of major depression. Because of the considerable phenomenological and neuroendocrine overlap between major depression and panic disorder, we investigated the rate of positive GH responses to TRH in 38 patients with panic disorder and 23 normal controls. There were no between-group differences in mean GH response to TRH or in the proportion of subjects with positive responses. These findings are discussed in the context of neuroendocrine regulation of GH secretion and the relationship between anxiety and affective disorders.

Platelet monoamine oxidase activity in patients with panic disorder.

Preliminary reports have indicated that platelet monoamine oxidase (MAO) activity is elevated in patients with anxiety disorder. We compared MAO activity in 20 drug-free patients with panic disorder with 20 age- and sex-matched normal controls. MAO activity in patients was significantly higher than in normals. MAO activity was not correlated with age or plasma catecholamine levels. The authors speculate about the possible significance of elevated MAO activity in patients with panic disorder.

Higher postdexamethasone serum cortisol levels in agoraphobic than in nonagoraphobic panic disorder patients.

The dexamethasone suppression test (DST) was performed in panic disorder (PD) patients with (n = 32) or without (n = 31) agoraphobia and in normal controls (n = 49). Postdexamethasone serum cortisol levels were significantly higher in agoraphobic PD patients (105.3 +/- 19.3 nmol/L) both when compared to PD patients without agoraphobia (47.3 +/- 7.7 nmol/L; p less than 0.01) and when compared to healthy controls (51.7 +/- 8.3 nmol/L; p less than 0.01). The rate of nonsuppressors (i.e., subjects displaying postdexamethasone cortisol levels greater than 138 nmol/L) was 28% and 3% in agoraphobic and nonagoraphobic PD patients, respectively, and 12% in controls. In patients, the postdexamethasone cortisol levels did not correlate with the number of panic attacks per week, baseline anxiety as measured using the Hamilton Anxiety Scale, depressive symptoms as measured using the Montgomery-Asberg Depression scale, or duration of illness. Data from eight patients in whom a second DST was performed after treatment with imipramine or clomipramine for three months indicate that a marked reduction of the number of anxiety attacks is not necessarily accompanied by a normalization of a pathological DST. In conclusion, it is suggested that the elevated postdexamethasone cortisol levels sometimes observed in agoraphobic PD patients are more closely related to the agoraphobic behavior than to the panic attacks per se.