Medically unexplained dyspnoea and panic.

Medically unexplained dyspnoea in the pulmonary setting is often accompanied by considerable levels of anxiety, suggestive of psychopathology, in particular panic disorder (PD). This pilot study investigates the value of the Multidimensional Dyspnea Profile as a tool to facilitate identification of a specific dyspnoea profile suggestive of comorbid PD. The verbal descriptors, feeling depressed, air hunger and concentrating on breathing, significantly differentiated between the two groups of patients with pulmonary disease with and without PD.

Effects of acute exercise on CO(2) -induced fear.

BACKGROUND: Acute exercise has shown to reduce the effects of experimental panic provocation in healthy volunteers and in patients with panic disorder. Recent evidence suggests that when larger amounts of CO(2) are inhaled, a large proportion of healthy subjects can also develop an affective response consistent with definitions of a panic attack. Our aim was to test whether exercise can show antipanic effects in healthy subjects when exposed to higher concentrations of CO(2). METHODS: Thirty-one healthy subjects, on four separate occasions in a randomized Latin square design, performed either moderate/hard or very-light exercise immediately followed by either a single or a double 35% CO(2)/65% O(2) inhalation. RESULTS: Compared to very-light exercise, when subjects performed moderate/hard exercise they reported a reduction in panic symptoms on the Panic Symptom List and the Visual Analogue Scale of Fear but no difference on the Visual Analogue Scale of Discomfort after a double CO(2) inhalation. After a single CO(2) inhalation, reductions were only seen on the Panic Symptom List. CONCLUSIONS: After intense exercise, subjects had less panic symptoms when exposed 35% CO(2), particularly after a double inhalation.

Sales of antidepressants, suicides and hospital admissions for depression in Veneto Region, Italy, from 2000 to 2005: an ecological study.

BACKGROUND: Increased prescription of antidepressants has been consistently associated with a decrease in suicide rates in several countries. The aim of this study is to explore antidepressant consumption, suicide rates and admission for depression in the Veneto Region, Italy, in order to see whether the same pattern could be detected. METHODS: Data from the Italian Ministry of Health (admissions for depression), the Pharmacy Service of a Local Health Unit (antidepressant prescribing) and from the Epidemiological System of the Veneto region (suicide rates) were collected from 2000 to 2005 for the Veneto region. RESULTS: Suicide rates did not show any marked increase but were stable in males and females. Antidepressant prescribing increased exponentially over the period examined, whilst admissions for depression markedly decreased. The trend for an exponential increase in antidepressant prescribing in the Veneto region is shared with other countries and locales. CONCLUSIONS: It is possible that the increase in antidepressant prescribing might be associated with earlier treatment of depression, thus decreasing the likelihood of aggravation of depression.

Nonhomogeneous results in place learning among panic disorder patients with agoraphobia.

Patients affected by panic disorder with agoraphobia (PDA) often suffer from visuo-spatial disturbances. In the present study, we tested the place-learning abilities in a sample of 31 PDA patients compared to 31 healthy controls (CTR) using the computer-generated arena (C-G Arena), a desktop-based computer program developed at the University of Arizona (Jacobs et al 1997, for further detail about the program, see http://web.arizona.edu/~arg/data.html). Subjects were asked to search the computer-generated space, over several trials, for the location of a hidden target. Results showed that control subjects rapidly learned to locate the invisible target and consistently returned to it, while PDA patients were divided in two subgroups: some of them (PDA-A) were as good as controls in place learning, while some others (PDA-B) were unable to learn the correct strategies to find the target. Further analyses revealed that PDA-A patients were significantly younger and affected by panic disorder from less time than PDA-B, indicating that age and duration of illness can be critical factors that influence the place-learning abilities. The existence of two different subgroups of PDA patients who differ in their spatial orientation abilities could provide new insight into the mechanisms of panic and open new perspectives in the cognitive-behavioral treatment of this diffuse and disabling disorder.

Assessment of the emotional responses produced by exposure to real food, virtual food and photographs of food in patients affected by eating disorders.

BACKGROUND: Many researchers and clinicians have proposed using virtual reality (VR) in adjunct to in vivo exposure therapy to provide an innovative form of exposure to patients suffering from different psychological disorders. The rationale behind the 'virtual approach' is that real and virtual exposures elicit a comparable emotional reaction in subjects, even if, to date, there are no experimental data that directly compare these two conditions. To test whether virtual stimuli are as effective as real stimuli, and more effective than photographs in the anxiety induction process, we tested the emotional reactions to real food (RF), virtual reality (VR) food and photographs (PH) of food in two samples of patients affected, respectively, by anorexia (AN) and bulimia nervosa (BN) compared to a group of healthy subjects. The two main hypotheses were the following: (a) the virtual exposure elicits emotional responses comparable to those produced by the real exposure; (b) the sense of presence induced by the VR immersion makes the virtual experience more ecological, and consequently more effective than static pictures in producing emotional responses in humans. METHODS: In total, 10 AN, 10 BN and 10 healthy control subjects (CTR) were randomly exposed to three experimental conditions: RF, PH, and VR while their psychological (Stait Anxiety Inventory (STAI-S) and visual analogue scale for anxiety (VAS-A)) and physiological (heart rate, respiration rate, and skin conductance) responses were recorded. RESULTS: RF and VR induced a comparable emotional reaction in patients higher than the one elicited by the PH condition. We also found a significant effect in the subjects' degree of presence experienced in the VR condition about their level of perceived anxiety (STAI-S and VAS-A): the higher the sense of presence, the stronger the level of anxiety. CONCLUSIONS: Even though preliminary, the present data show that VR is more effective than PH in eliciting emotional responses similar to those expected in real life situations. More generally, the present study suggests the potential of VR in a variety of experimental, training and clinical contexts, being its range of possibilities extremely wide and customizable. In particular, in a psychological perspective based on a cognitive behavioral approach, the use of VR enables the provision of specific contexts to help patients to cope with their diseases thanks to an easily controlled stimulation.

Selective processing of social stimuli in the superficial amygdala.

The human amygdala plays a pivotal role in the processing of socially significant information. Anatomical studies show that the human amygdala is not a single homogeneous structure but is composed of segregable subregions. These have recently been functionally delineated by using a combination of functional magnetic resonance imaging (fMRI) and cytoarchitectonically defined probabilistic maps. However, the response characteristics and individual contribution of these subregions to the processing of social-emotional stimuli are little understood. Here, we used this novel technique to segregate intra-amygdalar responses to facial expressions and nonsocial control stimuli. We localized facial expression-evoked signal changes bilaterally in the superficial amygdala, which suggests that this subregion selectively extracts the social value of incoming sensory information.

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.

High-frequency stimulation of the dorsolateral periaqueductal gray and ventromedial hypothalamus fails to inhibit panic-like behaviour.

Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) and one of its target structures, the ventromedial hypothalamus (VMH), produces a typical behaviour in rats consisting of vigorous running and jumping which is known as "escape behaviour". Escape behaviour in rodents closely mimics panic attacks in humans. Since electrical stimulation at higher frequencies generally inhibits the stimulated region, we tested in this study the hypothesis that deep brain stimulation (DBS) of the dlPAG and VMH at higher frequencies (> 100 Hz) would not induce escape behaviour. More specifically, we evaluated whether experimental DBS could be used to inhibit panic-like behaviour. Rats underwent implantation of DBS-electrodes at the level of the dlPAG and VMH and the effects of various stimulation parameters were assessed. In addition, we studied the neural activation pattern resulting from DBS of the dlPAG and VMH using c-Fos immunohistochemistry. We found that stimulation amplitude is the most important stimulation parameter in the induction of escape behaviour. Remarkably, stimulation frequency (1-300 Hz) had no effect on stimulation-induced escape behaviour and therefore it was not possible to prevent the induction of escape behaviour with higher frequencies. The neuronal activation pattern resulting from dlPAG and VMH DBS was similar. These findings suggest that DBS of the dlPAG and VMH induces panic-related behaviours even at higher frequencies.

Validation of the electronic Visual Analogue Scale of Anxiety.

Currently, the use of electronic scales is increasing rapidly, which is not surprising considering its accuracy, the ease of use and the increased compliance. The value of Visual Analogue Scales as a mean to objectify subjective variables has long been recognised. The current study aimed to validate the electronic Visual Analogue Scale of Anxiety (eVAAS). Seventy-one subjects, control subjects (n=46) and Panic Disorder patients (n=25), filled out the paper VAAS and the eVAAS in a randomised order. Panic was provoked using 35% CO(2) inhalation allowing us to include maximal scores in our analyses. The correlation between eVAAS and pVAAS was very strong and highly significant (r=0.98, p<0.001). pVAAS scores were slightly higher than eVAAS scores (p<0.001), but this difference is clinically unimportant. The VAAS established on a tablet PC is a useful and valid measure of anxiety and holds intrinsic benefits for anxiety assessment.

A specific attentional bias in panic disorder?

According to cognitive theories, panic patients are assumed to have an attentional bias toward bodily sensations. To date, there is only some indirect evidence of such a bias measured by an emotional Stroop task. Moreover, the content and disorder specificity of this bias is rather unclear. The aim of this study was to investigate the specificity of attentional bias in patients with panic disorder (PD). Patients with PD (n=32), patients with mixed anxiety disorders (n=25), and a healthy control group (n=26) performed an emotional Stroop task with three word types: panic threat, general threat, and neutral. There were no differences on reaction times between the different groups, or on the different word types. Despite the generally accepted existence of attentional biases in anxiety disorders, we found no evidence of a specific attentional bias in patients with PD.

Acute exercise reduces the effects of a 35% CO2 challenge in patients with panic disorder.

BACKGROUND: Chronic exercise has been shown to have therapeutic effects in panic disorder (PD). The mechanism of these effects is unknown. Acute exercise reduces the effect of a panic challenge in healthy volunteers. Such an effect has not yet been demonstrated in PD patients. The present study aimed at exploring the antipanic effects of acute exercise on a 35% CO2 panic provocation in treatment-naïve PD patients to further elucidate the mechanisms of the beneficial effects of exercise on panic. METHODS: Eighteen PD patients performed either moderate/hard exercise or very-light exercise before a 35% CO2 challenge in a randomized, between-group design. The reactivity to CO2 was assessed with the Visual Analogue Anxiety Scale and the DSM-IV Panic Symptom List. RESULTS: Panic reactions to CO2 were smaller in patients that performed moderate/hard exercise in contrast to those that performed very-light exercise. Increments in both measurements and panic rates were consistently reduced by intense exercise. LIMITATIONS: Since this study focuses on the acute effects of exercise on CO2 sensitivity in patients with PD, the results of repetitive exercise sessions on the rate of spontaneous panic attacks and overall symptoms are warranted. The small sample size and other limitations are addressed. CONCLUSIONS: Exercise reduced the panicogenic effects of a CO2 challenge. In addition to its therapeutic potential, exercise may also be useful as a laboratory maneuver with heuristic value in experimental research into the mechanisms of antipanic treatment.

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.

Visual presentation of phobic stimuli: amygdala activation via an extrageniculostriate pathway?

In the present study, event-related functional magnetic resonance imaging (fMRI) was used to examine the neural correlates of phobic fear by exposing spider phobic subjects to a visual presentation of spiders. In contrast to control subjects, spider phobics showed significantly increased activation in the amygdala and the pulvinar nucleus of the thalamus on the basis of region of interest (ROI) analysis. Furthermore, voxelwise analysis revealed increased activation related to phobia-specific pictures bilaterally in the anterior cingulate cortex, the left insular cortex and bilaterally in the supplementary motor area. These findings confirm the involvement of the amygdala in the processing of phobia-relevant stimuli as found earlier in a recent study. Moreover, the thalamus findings support the involvement of an extrageniculostriate pathway in the process of phobic fear.

Relative lack of depressive cognitions in post-myocardial infarction depression.

BACKGROUND: Depression has been associated with adverse clinical events in myocardial infarction (MI) patients, but many questions about the nature of post-MI depression remain unanswered. We examined whether depressive cognitions characteristic of depression in psychiatric patients are also present in post-MI patients with major depression (MD). METHODS: Non-depressed (n=40) and depressed (n=40) post-MI patients, and psychiatric outpatients (n=40) treated for clinical depression, matched on age and sex, were interviewed using a structured clinical interview to diagnose DSM-IV MD. All patients also completed the Beck Depression Inventory (BDI) and the Beck Cognition Checklist-Depression subscale (CCL-D). RESULTS: Mean levels of depressive cognitions were considerably higher in depressed psychiatric patients compared with depressed post-MI patients (34.9 versus 28.0; p=.013), and higher in depressed post-MI patients compared with non-depressed post-MI patients (28.0 versus 17.8; p<.0001), adjusted for age, sex, educational level, and marital status. Younger age (p=.024), absence of a partner (p=.016) and depressed psychiatric status (p=.016) were independently associated with depressive cognitions. Psychiatric patients also had higher mean levels of depressive symptoms as compared to depressed post-MI patients (25.1 versus 17.8; p=.001). LIMITATIONS: This study is based on a cross-sectional design. CONCLUSIONS: The symptom presentation of MD in post-MI patients is both quantitatively and qualitatively different from that seen in psychiatric patients, suggesting that depressive symptoms in post-MI patients differ in content from those in psychiatric patients. These findings could have important consequences for the design and contents of therapeutic programs for treating depression in post-MI patients.

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.

Comorbidity of obsessive-compulsive disorder and depression: prevalence, symptom severity, and treatment effect.

BACKGROUND: The goal of this study was to investigate the co-occurrence of depressive disorders in obsessive-compulsive disorder (OCD) and the effect of these disorders on combined pharmacologic and behavioral treatment for OCD. METHOD: A retrospective chart analysis was performed on baseline ratings of 120 OCD patients and posttreatment ratings of 72 of these patients. For depressive symptoms, the Montgomery-Asberg Depression Rating Scale and the Self-Rating Depression Scale were applied; for obsessive-compulsive symptoms, the Yale-Brown Obsessive Compulsive Scale and the Maudsley Obsessive Compulsive Inventory were used; and for general anxiety symptoms, the Self-Rating Anxiety Scale, the Clinical Anxiety Scale, and the State-Trait Anxiety Inventory were given. RESULTS: One third of the OCD patients in our sample were found to be depressed. Symptom severity on OCD symptoms at baseline did not differ between depressed and nondepressed OCD patients; on general anxiety symptoms, the comorbid group was more severely affected. Both depressed and nondepressed OCD patients responded well to treatment, as reflected in assessments for depressive, obsessive-compulsive, and general anxiety symptoms. However, comorbid depression had a negative effect on treatment: depressed OCD patients showed less improvement than nondepressed OCD patients on most scales. CONCLUSION: Depression frequently accompanies OCD and appears to affect treatment outcome negatively. While both groups of patients improved with combination treatment, the OCD-alone group had more improvement than the group that had comorbid depression.

L-5-hydroxytryptophan induced increase in salivary cortisol in panic disorder patients and healthy volunteers.

BACKGROUND: Hypersensitivity of brain serotonin receptors has been proposed as a causal mechanism in the pathophysiology of panic disorder. This theory can be tested, using serotonergic stimulation of the HPA axis. Up to now, plasma cortisol has generally been used as the outcome measure in such studies. Assessment of salivary cortisol is a non-invasive alternative to measure HPA axis activity. METHOD: Salivary cortisol levels were measured in 24 panic disorder patients and 24 healthy volunteers, following ingestion of 200 mg L-5-hydroxytryptophan or placebo. RESULTS: A significant rise in cortisol was observed in both patients and controls following ingestion of L-5-hydroxytryptophan. No such effects were seen in the placebo condition. CONCLUSION: The results show that L-5-hydroxytryptophan stimulated salivary cortisol is a useful probe of serotonin function in healthy volunteers as well as panic disorder patients, and provide some evidence against a serotonin receptor hypersensitivity in panic disorder.

Hypothalamic-pituitary-adrenal axis function following a 35% CO2 inhalation in healthy volunteers.

RATIONALE: The hypothalamic-pituitary-adrenal axis (HPA axis) is a central component of the brain's neuroendocrine response to stress. The extent of increase in cortisol secretion, provides an index of the HPA axis activity, and in this way, objectively reflects perceived stress. In healthy subjects, the 35% CO(2) inhalation does hardly induce stress, as expressed in anxiety. However, inconsistent results have been found in studies investigating the cortisol response following CO(2) inhalation. Clarity has to be reached about the normal reaction to this challenge, especially because this model is still a very valuable method to study central aspects of panic. OBJECTIVES: The present study aimed to test the hypothesis that a single breath of 35% CO(2) would not induce cortisol release in healthy volunteers. METHODS: In the current study, 20 healthy subjects underwent both a 35% CO(2) and a placebo inhalation in a randomised, single blind fashion. Cortisol levels were determined in saliva samples, taken at regular intervals. RESULTS: No differences were found between the CO(2) and the placebo condition. In both conditions a significant time effect was found, which can be subscribed to normal variation in the circadian rhythm. Furthermore, only modest subjective anxiety scores were found in the CO(2) condition. CONCLUSIONS: These results provide biological evidence for the hypothesis that healthy subjects are not affected by the 35% CO(2) challenge in a clinically significant way. Characteristic, PD patients react much stronger to the inhalation. Thus, in addition to psychological parameters, healthy subjects also constitute an ideal comparison group with regard to endocrinological parameters.