Antipanic drugs and pulmonary function in panic disorder patients

Medicação antipânico e função pulmonar em pacientes com transtorno de pânico

ARTIGO ORIGINAL

Antipanic drugs and pulmonary function in panic disorder patients

Medicação antipânico e função pulmonar em pacientes com transtorno de pânico

Isabella Nascimento^I; Valfrido Leão de Melo-Neto^I; Alexandre Martins Valença^I; Fabiana Leão Lopes^I; Rafael Christophe da Rocha Freire^I; Laura Andréa Cassabian^II; Cristiane Sousa Nascimento Baez Garcia^III; Walter Araújo Zin^IV; Antonio Egidio Nardi^I

^ILaboratório de Pânico e Respiração, Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro (IPUB – UFRJ)

^IILaboratório de Função Pulmonar, Instituto de Doença do Tórax, Hospital Universitário Clementino Fraga Filho (HUCFF), UFRJ

^IIILaboratório de Investigação Pulmonar, Instituto de Biofísica Carlos Chagas Filho (IBCCF), UFRJ

^IVLaboratório de Fisiologia da Respiração, IBCCF, UFRJ

^{Endereço para correspondência}

ABSTRACT

BACKGROUND: Studies suggest an association between panic disorder (PD) and impairment of lung function.

OBJECTIVES: To evaluate lung function in 11 asymptomatic PD patients and to investigate antipanic drug effects on respiratory function.

METHOD: Lung function was evaluated on two different occasions (with antipanic drugs and after drug washout). It was comprised of a spirometric evaluation and a bronchodilation test (salbutamol inhalation). Subjective Units of Disturbance Scale (SUDS) was applied before and after each spirometric assessment.

RESULTS: One patient showed mild obstructive airway impairment. Before bronchodilation test forced expiratory volume in 1 sec (FEV₁) and forced expiratory flow between 25% and 75% of the forced vital capacity (FEF_25-75) were significantly higher in patients on antipanic drugs than in those in the washout period. After salbutamol inhalation, only FEV₁ was significantly higher in patients with antipanic drugs in comparison to the other group, whereas a significant increase in FEV₁ and FEF_25-75 after salbutamol inhalation was detected in patients without antipanic drugs. The subjective anxiety level was not different among PD patients in both test days.

DISCUSSION: These results suggest a possible beneficial effect of the antipanic drug on lung function in PD patients.

Keywords: Lung function, spirometry, respiration, salbutamol, anxiety disorder.

RESUMO

CONTEXTO: Estudos sugerem uma associação entre transtorno de pânico (TP) e prejuízos na função pulmonar.

OBJETIVOS: Avaliar a função pulmonar em 11 pacientes com TP assintomáticos e investigar efeitos da medicação antipânico na função respiratória.

MÉTODO: A função pulmonar foi avaliada em duas ocasiões diferentes (com medicação antipânico e após "washout"). Consistiu de uma avaliação espirométrica e do teste de broncodilatação (inalação de salbutamol). Subjective Units of Disturbance Scale (SUDS) foi aplicada antes e após cada teste espirométrico.

RESULTADOS: Um paciente apresentou obstrução leve de vias aéreas. Antes do teste de broncodilatação, o volume expiratório forçado no primeiro segundo (VEF₁) e o fluxo expiratório forçado entre 25% e 75% da capacidade vital forçada (FEF_25-75) foram significativamente maiores em pacientes com medicação antipânico do que no período de "washout". Após a inalação de salbutamol, apenas o VEF₁ foi significativamente maior em pacientes com medicação antipânico em comparação ao outro grupo, embora tenha sido detectado aumento significativo em VEF₁ e FEF_25-75 em pacientes sem medicação antipânico depois da inalação de salbutamol. O nível de ansiedade subjetiva não foi diferente entre os pacientes em ambos os dias de testes.

CONCLUSÃO: Os resultados sugerem uma possível ação benéfica da medicação antipânico na função pulmonar em pacientes com TP.

Palavras-chave: Função pulmonar, espirometria, respiração, salbutamol, transtorno de ansiedade.

Introduction

The suffocation false alarm¹ and dyspnea-fear theories of panic disorder (PD)² emphasize the central role of dyspnea/suffocation symptom in panic attacks. Recently several studies have tested these hypotheses relating PD with respiratory system^3-6. The cingulate gyrus and limbic cortex are suprabulbar structures involved in the respiratory regulation⁷. The anterior cingulate gyrus produce an inhibitory effect on respiration, and serotonin may act as a synaptic transmitter in respiratory neurons, may change their sensitivity to external regulatory influences, and affect the respiratory response to limbic cortex stimulation⁷.

A growing number of clinical^8,9 and epidemiological¹⁰ studies suggests an association of anxiety disorder and asthma, although the specificity of this relationship remains unclear.

In order to explain the higher lifetime prevalence of PD in patients with respiratory disease, some studies investigated possible differences in lung function or in cognition between asthmatic patients with or without PD^11-13. Van Peski-Oosterbaan et al.¹⁴ observed that baseline levels of forced expiratory volume in 1 sec (FEV₁) and bronchial responsiveness to histamine were not significantly different in asthmatic patients with or without PD. They suggested that the presence of an airway disease or the degree of pulmonary function impairment is not related to panic symptoms. Perna et al.¹⁵ assessed lung function in 17 PD patients with or without agoraphobia and 20 healthy controls. They showed that PD patients had significantly lower values for some dynamic lung parameters, namely, peak expiratory flow rate (PEFR or FEF_max), forced expiratory flow at 75% of vital capacity (FEF₇₅) and maximal mid-expiratory flow rate (MMEF or FEF_25-75), suggesting subclinical impairment of lung airways. These findings, however, could not be replicated¹⁶. Carr et al.¹⁷ assessed airway impedance in response to a psychological stressor among 113 subjects divided in 4 groups: 61 with asthma alone, 10 with asthma and PD, 24 with PD alone, and 18 healthy controls. They demonstrated that PD patients (with or without asthma) present lower airway impedance (more dilated airways) than those without PD, suggesting a respiratory system more prepared to react to stress.

Since clinical data suggest that the susceptibility to spontaneous as well as CO₂-induced anxiety and hyperventilation is attenuated by selective serotonin reuptake inhibitor (SSRI) antidepressants, Olsson et al.¹⁸ explored the possible effect of paroxetine (SSRI) on baseline respiration and CO₂-induced hyperventilation in rats. They suggested that serotonin may influence brainstem regulation of baseline respiratory rate and ventilatory response to hypercapnia. Notably in their study tidal volume was not influenced by paroxetine treatment. Another animal study¹⁹ suggested that serotonin can induce the contraction of intrapulmonary arteriole smooth muscle cells via 5-HT2 receptors. Yeragani et al.²⁰ studied the influence of paroxetine on respiratory rate and tidal volume among humans with PD. They found that paroxetine decreases some linear measures of variability of lung volume after treatment²⁰.

The present work was designed to evaluate lung function in asymptomatic PD patients with or without agoraphobia, who had developed no panic attacks or agoraphobic symptoms in the last three months prior to the study. The aims were: 1) to investigate possible differences in lung function and in the subjective anxiety level on two occasions, with and without antipanic drugs; 2) to evaluate the influence of antipanic drugs on bronchial responsiveness to salbutamol inhalation in PD patients. We hypothesized that PD patients do not present any impairment in their lung function.

Methods

We consecutively enrolled 12 PD patients with or without agoraphobia who were under treatment at the Laboratory of Panic and Respiration of the Federal University of Rio de Janeiro, ranging from 18 and 65 years old, and agreed to participate in this protocol. The diagnosis was confirmed by the Structured Clinical Interview²¹ for DSM-IV²². Patients were clinically in good physical condition and were asymptomatic, i.e., did not report any panic attacks and agoraphobic symptoms in the last three consecutive months before the first lung function test. We considered three months a safe period to consider the patient remitted from his symptoms and consequently in a minimal level of risk for recurrency of the panic symptoms during discontinuation and washout periods of antipanic medication. Exclusion criteria were the existence of any other current mental disorder other than PD, a history of psychosis or bipolar disorder, epilepsy, substance abuse within the last 6 months, past or current diagnoses of respiratory disorders, significant concurrent medical problems, personal history of smoking, and pregnant or nursing women. The study design was explained to the patients and they signed a voluntary written informed consent for their participation in this study. They were informed that the objective was to assess the possible relationship between panic and lung function. The protocol, which complied with the principles laid down in the Declaration of Helsinki, was approved by our Hospital Ethics Committee.

Lung function was assessed on two different days and comprised of spirometric evaluation and bronchodilation test (salbutamol inhalation). On the first test day all the patients were taking their regular antipanic drugs (antidepressant and/or benzodiazepine). It is worthy to note that this clinical sample followed the treatment protocol of the Laboratory of Panic and Respiration of the Federal University of Rio de Janeiro on that time, what indicated imipramine as the first choice antidepressant and clonazepam as the second medicine of choice to treat panic disorder patients. These drugs were reduced gradually to avoid discontinuation symptoms and recurrence of panic attacks. The patients were asked to washout the drugs for at least seven days before the second test day. The protocol was carried out in a single-blind fashion, so the experimenters performing the lung function test did not know whether the patients were taking antipanic drugs or not.

Procedure and Data Analysis

Lung function was assessed by spirometry (flow-volume and volume-time curves), according to recommendations of the American Thoracic Society²³, at the Laboratory of Lung Function, Clementino Fraga Filho University Hospital. All patients were tested in the morning, in the sitting position, by a pulmonary physician and a nurse trained to perform the test (Pulmonary Function System – Modular GS and DSIIA, Warren E. Collins Inc., Braintree, MA, USA). Patients were asked to perform three forced vital capacity maneuvers, and the highest values were used in the analysis. A maximum of eight attempts was allowed to obtain three acceptable curves, according to acceptability and reproducibility criteria²³. The following parameters were measured: forced vital capacity (FVC); forced expiratory volume in 1 sec (FEV₁); the ratio between FEV₁ and FVC (FEV₁/FVC); forced expiratory flow between the 25% and 75% of forced vital capacity (FEF_25-75); the highest instantaneous flow during the maneuver (FEF_max); and forced expiratory flow at 25% (FEF₂₅), 50% (FEF₅₀) and 75% (FEF₇₅) of forced vital capacity. All variables (except FEV₁/FVC) were expressed as absolute values as well as percentages of the predicted value according to Knudson et al.²⁴ After the first session of tests, patients inhaled 400 µg of a beta 2-agonist bronchodilator (salbutamol) divided in four doses every five minutes. After fifteen minutes, the second spirometric evaluation was performed. Patients were informed that they might experience some discomfort like headache, dizziness, trembling, palpitation or symptoms of anxiety with bronchodilator administration.

Subjective Units of Disturbance Scale (SUDS)²⁵, which reflects the degree of global subjective anxiety (ranging from 0 = none to 10 = extreme anxiety) was applied immediately before the first spirometric evaluation (SUDS 1), immediately after it (SUDS 2), immediately before the second spirometric evaluation (after inhaled bronchodilator) (SUDS 3) and at the end of the experiment (SUDS 4).

To compare the results, firstly, the normality of the data (Kolmogorov-Smirnov test with Lilliefors' correction) and the homogeneity of variances (Levene median test) were tested. If both conditions were satisfied, one-way repeated measures ANOVA was used; in the negative case, Friedman repeated measures ANOVA on ranks was selected instead. If multiple comparisons were then required, Student-Newman-Keuls' (parametric) or Dunn's (nonparametric) test was applied. The significance level was always set at 5%.

Results

One patient did not participate in the second test day ("without antipanic drugs" day) and was excluded. The remaining patients were 6 men (54.5%) and 5 women (45.5%). Their ages ranged from 26 to 47, with a mean (± SD) age of 35.6 (± 7.2) years. Ten patients (90.9%) also suffered from agoraphobia.

Tables 1 and 2 show the clinical variables in 11 PD patients before the first and the second test days, respectively.

Two patients reported limited symptoms of panic during washout (cases 6 and 8).

Only one patient (case 2) reported symptoms just after salbutamol inhalation on the second test day (without antipanic drugs). These symptoms were: dizziness, sweating, trembling and palpitation, but the subject did not report anxiety or panic symptoms.

One patient (case 4) presented a mild obstructive airway disturbance on both test days that was reversible with bronchodilator administration on second test day.

The SUDS level was not significantly different between the two test days, before and after inhaled bronchodilator (Figure 1).

Table 3 shows the mean values (± SD) of all lung function parameters.

Considering % predicted value, before bronchodilation test FEV₁ and FEF_25-75 were significantly higher in patients on antipanic drugs than in those in the washout period (Table 3). After salbutamol inhalation, only FEV₁ was significantly higher in patients on antipanic drugs than in those in the washout period (Table 3). We also observed a significant increase in FEV₁ and FEF_25-75 after salbutamol inhalation in patients without antipanic drugs (Table 3).

Considering absolute values, before bronchodilation test FEV₁ and FEF_25-75 were significantly higher in patients on antipanic drugs than in those in the washout period (Table 3). We observed a significant increase in FEV₁ and FEF_25-75 after salbutamol inhalation in patients without antipanic drugs (Table 3).

Discussion

Our results suggest that lung function in PD patients is normal, as mentioned by Verburg et al.¹⁶ Only one patient presented a mild reversible airway obstruction in response to inhalation of 400 µg of salbutamol. This finding could result from either sampling error or asymptomatic asthma²⁶.

We observed higher values of FEV₁ and FEF_25-75 in patients on antipanic drugs than when they were in the washout period. This finding persisted in FEV₁ even after the inhalation of bronchodilator. Salbutamol acted to a larger extent in PD patients without antipanic drugs. They presented a significant increase in FEV₁ and FEF_25-75.

Olsson et al.¹⁸ found, in rats, a significant increase in baseline respiratory rate after 5 and 15 weeks of treatment with paroxetine. After 15 weeks of treatment the rats presented a reduction in the respiratory rate in response to CO₂ exposure and suggested that the regulation of respiration may be an important factor for the paroxetine antipanic effect. Olsson et al.¹⁸ did not report the change in response of CO₂-induced hyperventilation to an anxiety-reducing effect of paroxetine because they considered that the concentrations of CO₂ could not provoke anxiety in rats.

Some preliminary studies found sertraline (SSRI) useful in the management of dyspnea in chronic obstructive pulmonary disease and comorbid anxiety and mood disorders^27,28. It has been reported that the levels of free serotonin in plasma are increased in symptomatic patients with asthma^29,30. Lechin et al.²⁹ randomly assigned 69 children with asthma to receive tianeptine, an antidepressant drug, and/or placebo in a double-blind crossover trial that lasted 52 weeks. Tianeptine caused a sudden decrease in both clinical rating and free serotonin plasma levels and an improvement in pulmonary function. Nardi and Perna also discuss the serotonergic role of clonazepam³¹.

Perna et al.¹⁵ speculated that small airway subclinical obstruction in their study might be related to abnormalities in the mechanisms controlling bronchial tone, principally the tone of the smooth muscles in the small airways, finely regulated by autonomic nervous system (there are cholinergic, adrenergic and noncholinergic nonadrenergic influences). On the other hand, Carr et al.¹⁷ found that PD patients had wider airways in both stressful and non-stressful conditions.

Although vital capacity maneuvers might increase the anxiety level in PD patients owing to hyperventilation and catastrophic misinterpretation of respiratory symptoms³², mainly after inhalation of salbutamol, we observed that the median of SUDS ranged from 1 to 3 (Figure 1) without a significant difference. PD patients showed similar subjective anxiety levels with and without antipanic drugs. Perhaps the control of panic and agoraphobic symptoms is responsible for the low anxiety index in this sample.

To our knowledge the present study differs from other studies because it includes pulmonary asymptomatic PD patients, whose function tests were determined with and without antipanic drugs. Some studies found an association between panic attacks and anxiety sensitivity^11,13 that reflects an individual's concern about the consequences of experiencing anxiety-related symptoms. Carr et al.¹³ demonstrated that PD patients, asthmatic and nonasthmatic, displayed greater fear of bodily sensations on the Body Sensations Questionnaire³³ and more negative beliefs about the consequences of anxiety on the Anxiety Sensitivity Index³⁴ relative to those without PD. In addition, the presence of asthma alone had no effect on these measures of panic-related cognitions, since only asthmatic with PD had elevated scores. Finally, scores among asthmatics with PD tended to be lower than those among nonasthmatics with PD. Carr et al.¹³ found that anxiety sensitivity was unrelated to any of the pulmonary parameters measured (FCV, FEV₁, FEV₁/FCV or FEF₅₀), thus indicating that the relationship between anxiety sensitivity and PD was not mediated by extra impairment in lung function. Romano et al.³⁵ observed a significant reduction in anxiety sensitivity after 6 weeks of treatment with citalopram (SSRI), suggesting that fear of the consequences of body sensation could be normalized by pharmacological treatment and that a serotonergic mechanism might be involved in changing a cognitive distortion present in PD. These authors suggest that the decrease in anxiety sensitivity after drug treatment alone challenges the idea that the decrease of anxiety sensitivity is selectively mediated by cognitive/behavioral treatment³⁶.

The limitations of the study were: 1) the small sample. Our results should be interpreted cautiously, because the power of the performed test is bellow the desired one. The small sample also determined the non-stratification of the patients in groups according to their prescription scheme, for example one group with persons medicated only with SSRI and another one only on tricyclic antidepressants; 2) the PD patients were not submitted to a complete medical evaluation; 3) it was not possible to discriminate which drugs act in lung function (antidepressant, benzodiazepine or both) because of our small sample.

Further studies are required to evaluate if the improvement in lung function in asymptomatic PD patients is due to the antipanic effects in controlling bronchial tone or by decreasing anxiety sensitivity and panic-related cognitions. Follow-up studies with samples of asthmatic PD patients may also show the impact of PD treatment in the respiratory symptoms of asthma. Further prospective double-blind studies to evaluate pulmonary function on PD patients are required, since the acute phase until a remission stage, and stratified according to the medication under use (SSRI alone, tricyclic antidepressant alone, or these associated with benzodiazepines).

Acknowledgments

Supported by the Brazilian Council for Scientific and Technological Development (CNPq), Grant 304671/03-7.

Recebido: 14/9/2008

Aceito: 3/3/2009

Instituição onde o trabalho foi elaborado: Laboratório de Pânico e Respiração, Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro (UFRJ).

• 1. Klein DF. False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis. Arch Gen Psychiatry. 1993; 50(4):306-17.
• 2. Ley R. Dyspneic-fear and catastrophic cognitions in hyperventilatory panic attacks. Behav Res Ther. 1989;27(2):549-54.
• 3. Papp LA, Klein DF, Gorman JM. Carbon dioxide hypersensitivity, hyperventilation, and panic disorder. Am J Psychiatry. 1993;150(8):1149-57.
• 4. Asmundson GJ, Stein MB. A preliminary analysis of pulmonary function in panic disorder: implications for the dyspnea-fear theory. J Anxiety Disord. 1994;8:63-9.
• 5. Stein MB, Millar TW, Larsen DK, Kryger MH. Irregular breathing during sleep in patients with panic disorder. Am J Psychiatry. 1995; 152(8):1168-73.
• 6. McNally RJ, Hornig CD, Donnell CD. Clinical versus nonclinical panic. A test of suffocation false alarm theory. Behav Res Ther. 1995; 33(2):127-31.
• 7. Vedyasova OA. Respiratory effects of stimulation of the limbic cortex in rats and their modulation with serotonin. Bull Exp Biol Med. 2005;140(3):265-7.
• 8. Perna G, Bertani A, Politi E, Colombo G, Bellodi L. Asthma and panic attacks. Biol Psychiatry. 1997;42(10):625-30.
• 9. Nascimento I, Nardi AE, Valença AM, Lopes FL, Mezzasalma MA, Nascentes R, et al. Psychiatric disorders in asthmatics outpatients. Psychiatry Res. 2002;110(1):73-80.
• 10. Goodwin RD, Jacobi F, Thefeld W. Mental disorders and asthma in the community. Arch Gen Psychiatry. 2003;60(11):1125-30.
• 11. Porzelius J, Vest M, Nochomovitz M. Respiratory function, cognitions, and panic in chronic obstructive pulmonary patients. Behav Res Ther. 1992;30(1):75-7.
• 12. Carr RE, Lehrer PM, Hochron SM. Panic symptoms in asthma and panic disorder: a preliminary test of dyspnea-fear theory. Behav Res Ther. 1992;30(3):251-61.
• 13. Carr RE, Lehrer PM, Rausch LL, Hochron SM. Anxiety sensitivity and panic attacks in an asthmatic population. Behav Res Ther. 1994; 32(4):411-8.
• 14. Van Peski-Oosterbaan AS, Spinhoven P, Van der Does AJ, Willems LN, Sterk PJ. Is there a specific relationship between asthma and panic disorder? Behav Res Ther. 1996;34(4):333-40.
• 15. Perna G, Marconi C, Battaglia M, Bertani A, Panzacchi A, Bellodi L. Subclinical impairment of lung airways in patients with panic disorder. Biol Psychiatry. 1994;36(9):601-5.
• 16. Verburg K, de Leeuw M, Pols H, Griez E. No dynamic lung function abnormalities in panic disorder patients. Biol Psychiatry. 1997;41(7):834-6.
• 17. Carr RE, Lehrer PM, Hochron SM, Jackson A. Effect of psychological stress on airway impedance in individuals with asthma and panic disorder. J Abnor Psychol. 1996;105(1):137-41.
• 18. Olsson M, Annerbrink K, Bengtsson F, Hedner J, Eriksson E. Paroxetine influences respiration in rats: implications for the treatment of panic disorder. Eur Neuropsychopharmacol. 2004;14(1):29-37.
• 19. Perez JF, Sanderson MJ. The contraction of smooth muscle cells of intrapulmonary arterioles is determined by the frequency of Ca2+ oscillations induced by 5-HT and KCl. J Gen Physiol. 2005;125(6):555-67.
• 20. Yeragani VK, Rao R, Tancer M, Uhde T. Paroxetine decreases respiratory irregularity of linear and nonlinear measures of respiration in patients with panic disorder. A preliminary report. Neuropsychobiology. 2004;49(2):53-7.
• 21. First MB, Spitzer RL, Gibbon M, Williams JBM. Structured Clinical Interview Diagnostic (SCID) for DSM IV axis I Disorders Clinician Version (SCID-CV). Washington: American Psychiatric Press; 1997.
• ²²
  American Psychiatric Association. Diagnostic and Statistic Manual of Mental Disorders – DSM-IV. 4^th ed. Washington: American Psychiatric Press; 1994.
• ²³
  American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis. 1991;144(5):1202-18.
• 24. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis. 1983;127(6):725-34.
• 25. Beck P, Kastrup M, Rafaelsen OJ. Mini-compendium of rating scales of anxiety, depression, mania, schizophrenia with corresponding DSM III syndromes. Acta Psychiatr Scand Suppl. 1986;326:1-37.
• 26. Boulet LP. Asymptomatic airway hyperresponsiveness. A curiosity or an opportunity to prevent asthma? Am J Respir Crit Care Med. 2003;167(3):371-8.
• 27. Papp LA, Weiss JR, Greenberg HE, Rifking A, Scharf SM, Gorman JM, et al. Sertraline for chronic obstructive pulmonary disease and comorbid anxiety and mood disorders. Am J Psychiatry. 1995;152(10):1531.
• 28. Smoller JW, Pollack MH, Systrom D, Kradin RL. Sertraline effects in dyspnea, in patients with obstructive airways disease. Psychosomatics.1998;39(1):24-9.
• 29. Lechin F, van der Dijs B, Orozco B, Jara H, Rada I, Lechin ME, et al. The serotonin uptake-enhancing drug tianeptine suppresses asthmatic symptoms in children: a double-blind, crossover, placebo-controlled study. J Clin Pharmacol. 1998;38(10):918-25.
• 30. Lechin F, van der Dijs B, Lechin AE. Severe asthma and plasma serotonin. Allergy. 2002;57(3):258-9.
• 31. Nardi AE, Perna G. Clonazepam in psychiatric disorders: an update. Int Clin Psychopharmacol. 2006;21(3):131-42.
• 32. Clark DM. A cognitive approach to panic. Behav Res Ther. 1986;24(4):461-70.
• 33. Chambless DL, Caputo GC, Bright P, Gallagher R. Assessment of fear of fear in agoraphobics: the body sensations questionnaire and the agoraphobic cognitions questionnaire. J Consult Clin Psychol. 1984;52(6):1090-7.
• 34. Peterson RA, Reiss S. The manual for the Anxiety Sensitivity Index. Worthington: International Diagnostic System; 1987.
• 35. Romano P, van Beek N, Cucchi M, Biff S, Perna G. Anxiety sensitivity and modulation of the serotonergic system in patients with PD. J Anxiety Disord. 2004;18(3):423-31.
• 36. Clark DM, Salkovski PM, Hackmann A, Middleton H, Anastasiades P, Gelder M. A comparison of cognitive therapy, applied relaxation and imipramine in the treatment of PD. Br J Psychiatry. 1994;164(6):759-69.

Publication Dates

• Publication in this collection
  14 Sept 2009
• Date of issue
  2009

History

• Accepted
  03 Mar 2009
• Received
  14 Sept 2008