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Original Research Expression of Depressive Symptoms in a Nonclinical Brazilian Adolescent Sample
Clarice Gorenstein, PhD, Laura Andrade, MD, PhD, Elaine Zanolo, Rinaldo Artes, PhD
(PDF)

Posttraumatic Stress Disorder and General Psychopathology in Children and Adolescents Following a Wildfire Disaster
Brett M McDermott, MBBS, Cert Child Psych, FRANZCP, Erica M Lee, BA, Dip Psych, Marianne Judd, BSc Psych, MEd, Peter Gibbon, PhD
(PDF)

Individual Change in Methylphenidate Use in a National Sample of Children Aged 2 to 11 Years
Elisa Romano, PhD, Raymond H Baillargeon, PhD, Isabel Fortier, PhD, Hong-Xing Wu, MSc4, Philippe Robaey, MD, Mark Zoccolillo, MD, Richard E Tremblay, PhD
(PDF)

An Introduction to Economic Evaluation: What’s in a Name?
Jeffrey S Hoch, MA, PhD, Carolyn S Dewa, MPH, PhD
(PDF)

Recherche Originale *Méthadone et Syndrome d’Apnées du Sommeil
Philippe Durst, MD, Jérôme Palazzolo, MD, PhD, Jean-Pierre Peyrelong, MD, Michel Berger, MD, Michel Chalabreysse, MD, Michel Billiard, PhD, André Vialle, MD
(PDF)

Review Paper
Using Metaanalysis to Evaluate Evidence: Practical Tips and Traps
Raymond W Lam, MD, FRCPC, Sidney H Kennedy, MD, FRCPC
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Brief Communication
Experimental Affective Symptoms in Panic Disorder Patients
Thea Overbeek, MD, PhD, Koen Schruers, MD, PhD, Ine Docters van Leeuwen, BSc, Tineke Klaassen, MD, PhD, Eric Griez, MA, MD, PhD
(PDF)

Book Reviews
(PDF)

The Treatment of Drinking
Problems: A Guide for the Helping Professions.
Review by
Nady el-Guebaly, MD, FRCPC

Bipolar Disorder: A Clinician’s Guide to Biological Treatments.
Review by
Review by: Rakesh Jain MD, MPH
Shailesh Jain, MD, MPH


Handbook of Female Psychopharmacology
Review by
Laura Calhoun, FRCPC

Sleep and Dreaming: Scientific Advances and Reconsiderations.
Review by
Alan Douglass, MD

Cognitive-Behavioral Treatment of Obesity. A Clinician’s Guide.
Review by
Hany Bissada, MD, FRCPC

Cognitive Therapy of Personality Disorders. Second Edition.
Review by
W John Livesley

Letters to the Editor
(PDF)

Hemorrhages During Escitalopram–Venlafaxine– Mirtazapine Combination Treatment of Depression

Re: Lorazepam-Induced Prolongation of the QT Interval in a Patient With Schizoaffective Disorder and Complete AV Block

Reply: Lorazepam-Induced Prolongation of the QT Interval in a Patient With Schizoaffective Disorder and Complete AV Block

Lithium-Associated Anencephaly

Aripiprazole-Induced Seizure

Prevalence of Bipolar Disorder and Major Depression Among Patients Seen in Primary and Secondary Care in Finland

The Need for More Community Nursing for Adults With Intellectual Disabilities and Mental Health Problems

Improvement in Tardive Dyskinesia With Aripiprazole Use

Brief Communication

Experimental Affective Symptoms in Panic Disorder Patients

Thea Overbeek, MD, PhD ¹, Koen Schruers, MD, PhD², Ine Docters van Leeuwen, BSc³, Tineke Klaassen, MD, PhD⁴, Eric Griez, MA, MD, PhD⁵

Controlled panic induction by means of experimental challenges is a well-known procedure. Hypersensitivity to the challenge is often accepted as indicative of panic disorder (PD). One available provocation method is the inhalation of a gas mixture of 35% carbon dioxide (CO₂) with 65% oxygen (O₂), originally described by Griez and others (1).

In PD patients, this intervention yields symptoms of anxiety, as well as somatic symptoms that closely resemble a real-life panic attack. This method has frequently been used to investigate the underlying pathophysiological mechanisms of PD in a laboratory setting (2–4). It is implicitly assumed that CO₂ only induces panic anxiety. To date, other affective symptoms have not been assessed in a systematic way. However, it is widely known that the symptoms of anxiety and mood disorders overlap considerably (5). Symptoms of depression, anxiety, and aggression have been hypothesized to form a cluster related to serotonergic functions and (or) dysfunctions (6,7). According to this hypothesis, these serotonergic dysfunctions persist in times of remission. Moreover, feelings of aggression are frequently described in PD patients, and anger attacks have been proposed as a specific variant of panic attacks (8,9). Therefore, it would be interesting to assess whether the supposedly panic-specific challenge test with 35% CO₂ might induce other affective symptoms, such as aggression and depression.

In this pilot study, we compared PD patients without a history of depression and PD patients with comorbid (concurrent or lifetime) depressive disorder. Previously, PD plus major depressive disorder (MDD) patients were shown to react to the CO₂ provocation with increased anxiety symptoms, when compared with PD patients with no MDD (10). We hypothesize that the CO₂ challenge will induce aggressive and depressive symptoms in only those PD patients with current or lifetime MDD.

Methods

Subjects were recruited at the Academic Anxiety Center, Maastricht, the Netherlands, an outpatient clinic specialized in anxiety disorders. All patients were evaluated by means of a clinical psychiatric interview, with an emphasis on anxiety and affective spectrum symptoms, and the structured Mini International Neuropsychiatric Interview (MINI, 11). Two experienced psychiatrists confirmed the diagnoses. Additionally, patients underwent a physical examination and routine blood tests. Patients who met DSM-IV (12) criteria for panic disorder (with or without agoraphobia) were informed about the experimental intervention and were invited to participate in the study. All participating patients gave written informed consent. The study was approved by the Investigation Review Board of the University of Maastricht and was conducted according to the Declaration of Helsinki. We excluded patients with other Axis 1 diagnoses, current or lifetime, except for those with comorbid MDD. We also excluded patients who were currently using benzodiazepines or antidepressant medication (washout period of 2 weeks, except for fluoxetine, with a washout period of 6 weeks) and patients with physical conditions that could be compromised by the challenge (for example, cardiovascular or pulmonary disease, epilepsy, pregnancy, or a known cerebral aneurysm).

Intervention

The experimental intervention was the CO₂ inhalation method, which is described in detail elsewhere (1,13). This procedure requires the inhalation of a single breath of a CO₂ (35%) and O₂ (65%) gas mixture.

Assessments

At baseline, just before the CO₂ inhalation, patients were asked to complete the Panic Symptom List (PSL), comprised of 13 items reflecting panic symptoms that are scored from 0 to 4. This scale has previously been used to assess experimental panic anxiety (14,15). Patients were also requested to complete the adapted short Profile of Mood States on Aggression (POMS-Ag) and on Depression (POMS-D) (16), which comprises 7 mood states relating to depression (unhappy, miserable, depressed, downhearted, sad, gloomy, and lonely) and 7 relating to aggression (angry, bitter, annoyed, bad-tempered, furious, spiteful, and ready to fight), respectively, each scored from 0 to 4.

The other scales to be scored were a visual analogue scale (0 to 100) on anxiety (VAS-A), aggression (VAS-Ag), and depression (VAS-D). All these assessments were repeated immediately after the CO₂ challenge. The occurrence of a panic attack was defined as an increase of at least 25% on the VAS-A (that is, an increase of 25 points) and any increase on at least 4 PSL symptoms (17).

Statistical Analysis

We analyzed the data with SPSS for Windows, version 11.0 (18). We used Student’s t test to test mean age differences and the chi-square test to test sex distribution. We tested between-group differences, using the nonparametric Mann– Whitney U test for unrelated samples, owing to nonnormal data distribution. Significance levels were set at P < 0.05.

Results

Patient characteristics are summarized in Table 1. We included 25 PD patients in this study. Nine of these 25 patients (36%) had a comorbid lifetime depressive disorder (that is, PD plus MDD). Five of these 9 subjects met the criteria for a current depression. Baseline ratings did not differ between the 2 subgroups, and postchallenge ratings were significantly higher for the PD plus MDD group on all affective ratings, except for specific panic symptoms (Table 1).

Discussion

This study demonstrates that a panic challenge may give rise to depressive and aggressive symptoms as well. This effect was most pronounced in the PD plus MDD group. Some studies previously used the challenge paradigm to assess PD patients with and without comorbid MDD. However, they were all restricted to anxiety symptoms for outcome measures.

The present study confirmed the higher increase in anxiety measures for the PD plus MDD group, as reported earlier by Verburg and colleagues (10). In addition, we found a difference in the other affective dimensions of depression and aggression.

The role of MDD in this respect is not clear. It has been reported that ventilation of MDD patients decreases after a CO₂ challenge (19,20), whereas in PD patients, there is an increased ventilatory response (21). This physiological reaction is paralleled by a lower increase in heart rate following a hyperventilation challenge in MDD patients, compared with PD and compared with MDD with sporadic panic attacks (22). This mild physiological reaction is also reflected in the lack of psychological distress to this hyperventilation challenge, since it did not result in an increase in subjective units of discomfort sensations, which is comparable to our VAS assessment in MDD patients. Perna and others have shown that, when their panic and anxiety symptoms are measured, patients with an MDD (without panic attacks or PD) do not respond to this provocation method; rather, they react in the same way as healthy control subjects do (23). Unfortunately, we have no data on other affective dimensions of aggression and depression in MDD patients. Neither Perna and colleagues (23) nor Verburg and colleagues (10) assessed these affects.
From these data, we infer that MDD and PD patients react to a panicogenic challenge in different ways. However, when both disorders are present, MDD is no longer protective against the challenge, and PD seems to determine the response.

Some limitations of the present study must be mentioned. Because we did not include a control group of depression patients without PD, we cannot say with any certainty whether the CO₂ challenge can increase aggressive or depressive feelings, even though this seems unlikely. Also, a control group of healthy subjects could have been included to control for the broader affective symptoms that might be raised by a CO₂ challenge. Another limitation of this study is the small sample of comorbid patients with depression and PD. A larger group would have made it possible to analyze possible differential effects of the CO₂ challenge in the subgroups. It would have been interesting to look at the effect of a lifetime depressive episode (in PD patients) as a trait marker that gives rise to a vulnerability to the experimental provocation of depressive and aggressive symptoms.

Future studies using the CO₂ challenge paradigm should take into account the assessment of affective spectrum symptoms for outcome measures. They should be targeted at assessing the effect of a CO₂ challenge on pure MDD patients (with present and lifetime MDD patients in separate groups) on the dimensions of aggression and depression. Also, future research needs to focus on assessing affective symptoms after a panic challenge in pure PD patients, compared with comorbid PD patients.

References

1. Griez EJ, Lousberg H, van den Hout MA, van der Molen GM. CO₂ vulnerability in panic disorder. Psychiatry Res 1987;20:87–95.

2. Griez E, Schruers K. Experimental pathophysiology of panic. J Psychosom Res 1998;45:493–503.

3. Gorman JM, Papp LA, Martinez J, Goetz RR, Hollander E, Liebowitz MR, and others. High-dose carbon dioxide challenge test in anxiety disorder patients. Biol Psychiatry 1990;28:743–7.

4. Perna G, Gabriele A, Caldirola D, Bellodi L. Hypersensitivity to inhalation of carbon dioxide and panic attacks. Psychiatry Res 1995;57:267–73.

5. Di Nardo PA, Barlow DH. Syndrome and symptom co-occurrence in the anxiety disorders. In: Maser JD, Cloninger CR, editors. Comorbidity of mood and anxiety disorders. Washington (DC): American Psychiatric Press;1990. p 205–30.

6. Apter A, van Praag HM, Plutchik R, Sevy S, Korn M, Brown SL. Interrelationships among anxiety, aggression, impulsivity, and mood: a serotonergically linked cluster? Psychiatry Res 1990;32:191–9.

7. van Praag HM. Anxiety and increased aggression as pacemakers of depression. Acta Psychiatr Scand 1998;Suppl;393:81–8.

8. Fava M, Anderson K, Rosenbaum JF. “Anger attacks”: possible variants of panic and major depressive disorders. Am J Psychiatry 1990;147:867–70.

9. George DT, Anderson P, Nutt DJ, Linnoila M. Aggressive thoughts and behavior: another symptom of panic disorder? Acta Psychiatr Scand 1989;79:500–2.

10. Verburg K, Klaassen T, Pols H, Griez E. Comorbid depressive disorder increases vulnerability to the 35% carbon dioxide (CO₂) challenge in panic disorder patients. J Affect Disord 1998;49:195–201.

11. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, and others. The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59;Suppl 20:22–33.

12. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington (DC): American Psychiatric Press; 1994.

13. Verburg K, Pols H, de Leeuw M, Griez E. Reliability of the 35% carbon dioxide panic provocation challenge. Psychiatry Res 1998;78:207–14.

14. Verburg K, Griez E, Meijer J, Pols H. Discrimination between panic disorder and generalized anxiety disorder by 35% carbon dioxide challenge. Am J Psychiatry 1995;152:1081–3.

15. Schruers K, Klaassen T, Pols H, Overbeek T, Deutz N, Griez E. Effects of tryptophan-depletion on carbon dioxide provoked panic in panic disorder patients. Psychiatry Res 2000;93:179–87.

16. Terry PC, Lane AM, Keohane L. Development and validation of a mood measure for adolescents. J Sports Sci 1999;17:861–72.

17. Klaassen T, Klumperbeek J, Deutz NE, van Praag HM, Griez E. Effects of tryptophan depletion on anxiety and on panic provoked by carbon dioxide challenge. Psychiatry Res 1998;77:167–74.

18. Statistical Software Package for the Social Sciences. Version 11.0. Chicago (IL): SPSS Inc; 2002.

19. Shershow JC, Kanarek DJ, Kazemi H. Ventilatory response to carbon dioxide inhalation in depression. Psychosom Med 1976;38:282–7.

20. Damas-Mora J, Jenner FA, Sneddon J, Addis WD. Ventilatory responses to carbon dioxide in syndromes of depression. J Psychosom Res 1978;22:473–6.

21. Gorman JM, Kent J, Martinez J, Browne S, Coplan J, Papp LA. Physiological changes during carbon dioxide inhalation in patients with panic disorder, major depression, and premenstrual dysphoric disorder: evidence for a central fear mechanism. Arch Gen Psychiatry 2001;58:125–31.

22. Nardi AE, Valenca AM, Nascimento I, Zin WA. Hyperventilation challenge test in panic disorder and depression with panic attacks. Psychiatry Res 2001;105:57–65.

23. Perna G, Barbini B, Cocchi S, Bertani A, Gasperini M. 35% CO₂ challenge in panic and mood disorders. J Affect Disord 1995;33:189–94.

Manuscript recieved November 2003, revised, and accepted April 2004.

1. Research Physician, Academic Anxiety Center, Psychiatric Hospital Vijverdal, Maastricht, the Netherlands.

2. Assistant Professor of Psychiatry, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands.

3. Physician, University of Maastricht, Maastricht, the Nethetherlands. Psychiatrist, Vincent van Gogh Institute for Psychiatry, Venray, the Netherlands.

4. Professor of Experimental Psychiatry, Department of Psychiatry. and Neuropsychology, Maastricht University, Maastricht, the Netherlands

Address for correspondence: Dr T Overbeek, Academic Anxiety Center, PO BOX 88 6200 AB Maastricht, the Netherlands

e-mail: thea.overbeek@pn.unimaas.nl

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