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

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

Intensive behavioral therapy for agoraphobia.

BACKGROUND: We investigated the efficacy of an intensive 1-week behavioral therapy program focusing on agoraphobia for panic disorder patients with agoraphobia (PDA). DESIGN AND METHODS: The study design was a case-control study. Main outcome measure was the agoraphobia score of the Fear Questionnaire (FQ-AGO). The outcomes on the FQ-AGO of a 1-week intensive therapy (96 patients) and a twice-weekly therapy (98 patients) were compared. RESULTS: Agoraphobia improved significantly in both groups, 1 week and 3 months after therapy. Effect size for changes in the 1-week intensive therapy on the FQ-AGO was 0.75. LIMITATIONS: Limitations are use of antidepressants, no placebo group, and no long term follow-up. CONCLUSION: Behavioral therapy for agoraphobia can be shortened significantly if intensified without affecting therapy outcome, thus allowing patients a more rapid return to work and resumption of daily activities.

Therapygenetics: 5-HTTLPR genotype predicts the response to exposure therapy for agoraphobia.

This study was intended to assess the extent to which the low-expression allele of the serotonin transporter gene promoter predicts better response to exposure-based behavior therapy in patients with panic disorder with agoraphobia (PDA). Ninety-nine patients with PDA underwent a 1-week in vivo exposure-based behavior therapy program and provided saliva samples to extract genomic DNA and classify individuals according to four allelic forms (SA, SG, LA, LG) of the 5-HTT-linked polymorphic region (5-HTTLPR). We determined whether the 5-HTTLPR genotype predicted change in avoidance behavior in PDA following treatment. After controlling for pre-treatment avoidance behavior, the 5-HTTLPR low-expression genotypes showed a more favorable response to exposure therapy two weeks following treatment, compared to the other patients. This study suggests a genetic contribution to treatment outcome following behavior therapy and implicates the serotonergic system in response to exposure-based treatments in PDA.

Brainstem response to hypercapnia: a symptom provocation study into the pathophysiology of panic disorder.

BACKGROUND: The biological basis of uncued panic attacks is not yet understood. An important theory concerning the nature and cause of panic disorder is the 'suffocation false alarm theory'. This alarm is supposed to be over-sensitive in panic disorder patients and can be triggered by CO2. No neurobiological substrate has been identified for such an alarm. The present study investigates differences in brain activation in panic patients, healthy individuals and experienced divers in response to CO2, representing three groups with descending sensitivity to CO2. METHOD: Brain activation was measured with functional magnetic resonance imaging. Subjects breathed through a mouthpiece delivering a continuous flow of 100% oxygen for two minutes, followed by a hypercapnic gas mixture (7% CO2) for the next two minutes. Statistical analysis was performed using SPM8. RESULTS: There was a significant main effect of group in response to the CO2. Patients show increased brainstem activation in response to hypercapnia compared to controls and divers. Subjective feelings of breathing discomfort were positively correlated with brain activation in the anterior insula in all groups. CONCLUSION: This is the first study showing that the behavioural response to CO2 that characterises panic disorder patients is likely due to increased neural sensitivity to CO2 at brainstem level.

35% CO2 sensitivity in social anxiety disorder.

The 35% carbon dioxide (CO(2)) challenge is a well-established model of panic. This study aimed to investigate 35% CO(2) sensitivity in patients with social anxiety disorder (SAD) compared with patients with panic disorder (PD) and normal controls. First, a 35% CO(2) challenge was conducted including 16 patients with generalized SAD, 16 with PD and 16 normal subjects. Outcome was assessed by a Visual Analogue Scale for Fear (VAS-F) and the Panic Symptom List (PSL). Second, meta-analyses of fear and panic scores were performed, including data from the present experiment and from previous 35% CO(2) challenge studies in patients with SAD. The present 35% CO(2) challenge found equal increases in VAS-F and PSL in patients with SAD compared with normal controls, whereas the CO(2) response in patients with PD was significantly stronger than in controls. The meta-analyses confirmed the experimental data from this study, and in addition showed an intermediate panic rate in SAD patients, in between that of normal controls and patients with PD. In conclusion, neither our experiment nor the meta-analyses found evidence for a similarly exaggerated 35% CO(2) sensitivity in SAD and PD, suggesting that the pathogenesis of SAD is different from PD, although patients with SAD may be slightly more sensitive than non-anxious controls.

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.

Genetic moderation of CO2-induced fear by 5-HTTLPR genotype.

Inhalation of an increased concentration of carbon dioxide (CO(2)) has been shown to induce a state of negative affect in healthy subjects that is closely related to the clinical phenomenon of panic. It has been suggested that the vulnerability to CO(2) is moderated by differences in serotonin (5-HT) activity, caused by a functional polymorphism in the promoter region of the 5-HT transporter (5-HTTLPR) gene. Our aim was to examine the relationship between bi- and tri-allelic 5-HTTLPR genotype and the affective response to different dosages of inhaled CO(2) in healthy volunteers. Ninety-six subjects performed a double inhalation of four mixtures containing, respectively, 0%, 9%, 17.5% and 35% CO(2), following a double-blind, cross-over, randomized design. Affective responses were measured with a visual analogue scale for fear and the Panic Symptom List. 5-HTTLPR genotype was expressed as LL, SL and SS. Subjects with the SL and SS genotype reported less fear than LL subjects. A significant interaction effect was found between genotype and CO(2) dosage: the SS genotype showed lower fear scores than the LL genotype, particularly in the 17.5% CO(2) dose condition. The present study suggests that the dose-dependent fear reaction to CO(2) is moderated by a polymorphism in the 5-HT transporter gene, particularly at intermediate CO(2) dosages. It also underscores the usefulness of the introduction of an intermediate phenotype related to panic to reveal an underlying genetic vulnerability otherwise staying elusive. These results are in line with current theories on the role of 5-HT in both panic and respiration.

Cigarette smoking and 35% CO(2) induced panic in panic disorder patients.

BACKGROUND: A disproportionately large number of persons with panic disorder (PD) smoke cigarettes compared to people in the general population and individuals with other anxiety disorders. Clinical and epidemiological data suggest that cigarette smoking increases the risk for the development and maintenance of PD. The carbon dioxide (CO(2)) challenge is well established as experimental model for panic. The present study seeks to examine whether cigarette smoking has an influence on laboratory elicited panic in PD patients. METHODS: In total 92 subjects (46 smokers and 46 non-smokers) with PD, according to the DSM-IV criteria, were compared. All subjects received a baseline clinical assessment and underwent a 35% CO(2) challenge. Response to the challenge was evaluated via the Panic Symptom List and the Visual Analogue Fear Scale. RESULTS: The two samples did not differ on baseline anxiety level. Smokers had a significantly higher increase in panic symptoms in response to the challenge compared to non-smokers (p=0.04). LIMITATIONS: This type of study does not provide information concerning the underlying mechanisms of the link between smoking and panic. Study limitations include lack of formal assessment of personality and of inter-rater reliability. CONCLUSIONS: The present findings are consistent with the idea that smoking facilitates panic in PD subjects. This may have clinical implications, as quitting smoking could become one of the relevant steps in the treatment of PD patients.

Cigarette smoking and panic: a critical review of the literature.

OBJECTIVE: Cigarette smoking increases the risk of panic disorder with or without agoraphobia's emerging. Although the cause of this comorbidity remains controversial, the main explanations are that (1) cigarette smoking promotes panic by inducing respiratory abnormalities/lung disease or by increasing potentially fear-producing bodily sensations, (2) nicotine produces physiologic effects characteristic of panic by releasing norepinephrine, (3) panic disorder promotes cigarette smoking as self-medication, and (4) a shared vulnerability promotes both conditions. The aim of this review was to survey the literature in order to determine the validity of these explanatory models. DATA SOURCES: Studies were identified by searching English language articles published from 1960 to November 27, 2008, in MEDLINE using the key words: nicotine AND panic, tobacco AND panic, and smoking AND panic. STUDY SELECTION: Twenty-four studies were reviewed and selected according to the following criteria: panic disorder with or without agoraphobia and nicotine dependence, when used, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, Fourth Edition, or Fourth Edition, Text Revision; no additional comorbidity or, if present, adjustment for it in the statistical analyses; use of adult or adolescent samples; comparison with a nonclinical control group or application of a crossover design. DATA EXTRACTION: Non-significant results or trends only were reported as no difference. Data on anxiety disorders or substance abuse in general were not included. DATA SYNTHESIS: Panic and cigarette smoking each appear to have the capacity to serve as a causal factor/facilitator in the development of the other. Although the temporal pattern and the pathogenetic explanations of such a co-occurrence are still being discussed, cigarette smoking tends to precede the onset of panic and to promote panic itself. CONCLUSIONS: Additional studies are strongly recommended.