- Email: [email protected]
Sertraline Effects on Dyspnea in Patients With Obstructive Airways Disease
Sertraline Effects on Dyspnea in Patients With Obstructive Airways Disease JORDAN W. SMOLLER, M.D., MARK H. POLLACK, M.D. DAVID SYSTROM, M.D., RICHARD L. KRADIN, M.D.
Dyspnea can have a debilitating effect on psychosocial and physical functioning in patients with chronic obstructive airways disease. Previous research has suggested that treatment of concomitant mood or anxiety symptoms can improve dyspnea and exercise intolerance among patients with respiratory disease. The authors report here on a case series of 7 patients with obstructive airways disease who reported improvements in dyspnea after sertraline 25–100 mg/day was added to their medication regimens. Four of the seven patients did not appear to meet syndromal criteria for a mood or anxiety disorder. Subjective improvements in dyspnea may have been related to relief of mood or anxiety symptoms or to direct effects on central respiratory systems. Controlled studies are needed to clarify the potential antidyspneic effects of sertraline. (Psychosomatics 1998; 39:24–29)
P
atients with respiratory disease have been reported to have higher than expected rates of anxiety disorders, particularly panic disorder.1–3 For example, as many as one-fourth of patients with chronic obstructive pulmonary disease (COPD), including asthma, may meet criteria for panic disorder.2 Patients with COPD and breathlessness disproportionate to their degree of pulmonary disease may experience decreased dyspnea and improved exercise tolerance after successful treatment of depression or anxiety.4 One pathophysiological link between psychiatric and respiratory symptoms may be at the level of the serotonergic system. Animal studies have suggested that serotonin modulates central control of respiration,5 in part, by affecting sensitivity to carbon dioxide.6 In patients with COPD, greater degrees of CO2 sensitivity have been associated with more severe dyspnea.7 Dyspnea is also a central feature of panic attacks, and hypersensitivity to CO2 has been implicated in the pathogenesis of panic disorder.8 In light of these observations, Klein has 24
suggested that antipanic agents might have antidyspneic effects in some patients with COPD.9 Papp and colleagues10 recently reported on 6 patients with COPD, with and without mood or anxiety disorders, in whom sertraline 12.5–100 mg/day was well tolerated and associated with subjective improvement in well-being. Taken together, these observations suggest that selective serotonin reuptake inhibitors (SSRIs) may be particularly useful and welltolerated in anxious or depressed patients with COPD and might diminish dyspnea in some pulmonary patients, even in the absence of a diagnosable psychiatric disorder. We report on seven Received October 30, 1996; revised January 29, 1997; accepted March 4, 1997. From the Department of Psychiatry and Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts. Address reprint requests to Dr. Smoller, Anxiety Disorders Program, Massachusetts General Hospital, ACC–815, 15 Parkman Street, Boston, MA 02114. E-mail: [email protected]. harvard.edu. Copyright 䉷 1998 The Academy of Psychosomatic Medicine.
PSYCHOSOMATICS
Smoller et al.
patients with COPD who reported improvements in dyspnea after treatment with the SSRI sertraline by their pulmonologist. Six patients were retrospectively interviewed by a psychiatrist (JWS) who used modules for depression, dysthymia, panic disorder, agoraphobia, and generalized anxiety disorder from the Structured Clinical Interview for DSM-IV (SCID-IV). One patient was prospectively studied by using the Structured Clinical Interview for DSM-III-R (SCID-III-R).
Case Reports Case 1. Mr. A., a 45-year-old man with a 10-year history of idiopathic emphysema, developed intractable dyspnea that was poorly relieved by a regimen of multiple bronchodilators and home-oxygen therapy. He was unable to do any lifting or climb even four steps without developing intolerable breathlessness and was listed as a candidate for lung transplantation. Baseline pulmonary function tests (PFTs) showed a severe obstructive ventilatory defect with forced expiratory volume at 1 second (FEV1)⳱0.64 L (16% predicted). He reported marked anticipatory anxiety and avoidance of activity because of concerns about dyspnea. Retrospective SCID assessment indicated that he had panic attacks that would have qualified for panic disorder but occurred in the setting of apparent respiratory compromise. A trial of alprazolam (0.25 mg/bid) resulted in only mild symptomatic relief and sertraline (25–50 mg/day) was added to his regimen. Four weeks later, he reported marked improvement in exercise tolerance. After 2 months, he reported being “less conscious of the effort necessary to breathe” and was able to walk briskly and play with his young daughter without becoming dyspneic. He reported decreased anxiety associated with these activities. Repeat PFTs at 1 month showed no significant change. Case 2. Ms. B., a 64-year-old woman with a 50pack/year smoking history and a long history of severe asthma requiring steroids and intubation in the past, presented with complaints of dyspnea on mild exertion. She also had a history of obstructive sleep apnea requiring continuous positive airway pressure at night. She had remained dyspneic despite intensive therapeutic trials of bronchodilators and steVOLUME 39 • NUMBER 1
• JANUARY–FEBRUARY 1998
roids, and PFTs showed an obstructive ventilatory defect with FEV1⳱0.75 L (34% predicted). Psychiatric interview suggested that she was probably experiencing a major depression at the time sertraline (50 mg) was prescribed. She tolerated the medication well, and after 8–16 weeks she reported improvements in mood, energy, ability to ambulate, and breathlessness. Repeat PFTs 8 months after sertraline was added showed some improvement in FEV1⳱1.09 (50% predicted). Case 3. Ms. C., a 51-year-old woman, has a 20year history of steroid-dependent asthma. She had been maintained on prednisone, theophylline, and inhalers, and attempts to taper prednisone in the past had been associated with intolerable increases in wheezing and dyspnea. Baseline PFTs showed evidence of some fixed obstruction. About 3 months before initiation of sertraline, a nedocromil sodium inhaler and a steroid inhaler were added to her regimen, but she continued to be unable to tolerate tapering of prednisone. Pulmonary function tests obtained before initiating sertraline showed a moderate obstructive defect, with FEV1⳱1.1 L (48%) and FVC⳱1.8 L (69%); her peak expiratory flow rate (PEFR) after bronchodilator was 3.2 L/sec (58%). To reduce fatigue and dysphoria associated with tapering of prednisone, sertraline was added (50 mg/ day) and increased to 100 mg per day after 2 weeks. At the time of the psychiatric interview, she had been on sertraline for about 7 months and had been able to taper her prednisone to 5 mg every other day, the lowest dose of steroids she had been on since the onset of her asthma. Her other medications had not changed, and the most recent pulmonary function testing showed little evidence of objective change, with FEV1⳱1.13 L (52%), FVC⳱1.8 L (70%), and PEFR 3.0 L/sec (55%). Nevertheless, she reported that she was markedly less dyspneic and no longer experienced dyspnea on exertion. She did not meet criteria for current or past mood or anxiety disorder. Case 4. Ms. D., a 59-year-old woman, has a long history of severe asthma for which she had been maintained on prednisone and multiple bronchodilator inhalers over the past 10 years. For much of the year before initiating sertraline, she had required prednisone (30–40 mg/day) in addition to betaagonist and steroid inhalers, and she had been hospitalized for a flare of her asthma 1 month before starting sertraline. She was troubled by depressed 25
Sertraline Effects on Dyspnea
mood and met criteria for dysthymia and generalized anxiety disorder on retrospective SCID interview at 11 weeks. Baseline PFTs showed a moderate obstructive defect (FEV1⳱1.3 L, 51% predicted). She was started on sertraline (50 mg/ day) and increased to 100 mg/day by 4 weeks. At the end of 4 weeks, the patient reported marked improvement in her breathing and her mood, was able to successfully taper her prednisone, and discontinued the use of nebulizers and one of her betaagonist inhalers. PFTs continued to demonstrate a moderate obstructive defect but no significant change in FEV1 (1.5 L, 58% predicted) or peak expiratory flow rate. At 11 weeks, she reported that her breathing “hasn’t been this good in 10 years.” She was able to taper prednisone to 5 mg every other day and planned to discontinue it in 1 week. She reported that she had gone from having difficulty climbing one flight of stairs to being able to walk around the mall for hours. She no longer met criteria for a mood or anxiety disorder. Case 5. Mr. E., a 52-year-old man, has a history of steroid-dependent COPD and dilated cardiomyopathy. He had been hospitalized for a respiratory decompensation 2 weeks before starting sertraline. He was started on a medical regimen that included digitalis, captopril, and furosemide for heart failure. Sertraline (25 mg) and a steroid inhaler were added to his regimen after discharge. After 4 weeks on this regimen, he reported a decrease in dyspnea. The sertraline dosage was increased to 50 mg, and alprazolam (0.25 mg bid) was added. At 9 weeks, Mr. E. reported improved exercise tolerance and decreased need for bronchodilator use. Ten months after starting sertraline, he reported continued marked improvement in dyspnea and exercise tolerance and decreased bronchodilator use, which he attributed to the sertraline and alprazolam. Psychiatric interview revealed no history of mood or anxiety disorder. Case 6. Ms. F., a 70-year-old woman, has a history of asthma and fear of suffocation. She had been treated with alprazolam (0.125 mg 3 times/day) for anxiety. Her PFTs before sertraline treatment showed a mild obstructive ventilatory defect. She complained of increased episodes of dyspnea and anxiety, and she was started on sertraline (50 mg). Alprazolam was increased to 0.25 mg four times daily. Because of initial jitteriness on sertraline, the dose was decreased to 25 mg/day. After 3 weeks, she reported fewer episodes of acute dyspnea and 26
panic. However, she discontinued sertraline because of jitteriness. On psychiatric interview 1 year later, there was no history of syndromal mood or anxiety disorders. Case 7. Ms. G., a 75-year-old woman, has a history of severe asthma and recurrent panic attacks associated with shortness of breath. On a structured assessment before sertraline treatment, she met criteria for panic disorder with agoraphobia. She had been maintained on chronic bronchodilators, and in the past she had required prednisone tapers for exacerbation of her wheezing. Baseline pulmonary assessment showed an obstructive defect: FEV1⳱0.86 L (61%). She was started on sertraline (25 mg/day), and after 4 weeks she reported a decrease in dyspnea and discontinuation of her bronchodilators. At 12 weeks, she reported sustained improvement in dyspnea and remission of panic and anticipatory anxiety. Coinciding with this were decreases on the Hamilton anxiety scale (from 14 to 8) and Hamilton depression scale (from 11 to 5). Repeat pulmonary assessment showed no clinically significant change in FEV1. Bicycle ergometry and carbon dioxide (7%) inhalation were performed at baseline and 12 weeks. Compared with baseline, CO2 sensitivity, as measured by change in minute ventilation per unit change in end-tidal CO2 (DVE/DPETCO2), decreased by 65% (from 1.56 L/min/mmHg to 0.56 L/min/ mmHg). She also reported less breathlessness during CO2 inhalation compared with baseline. No clinically significant changes were observed in either overall aerobic capacity (pretreatment VO2 max⳱599 ml/min, posttreatment⳱603 mL/min) or minute ventilation at peak exercise (pretreatment⳱15 L/min, posttreatment⳱16 L/min). Her exercise tolerance showed a modest improvement, with an increase in peak work from 15 Watts to 21 Watts and increased duration from 4 minutes 17 seconds to 5 minutes 34 seconds. She experienced a panic attack during exercise at baseline but not at 12 weeks.
DISCUSSION In the observed cases, patients with mild-tosevere obstructive lung disease and complaints of marked dyspnea reported a decrease in breathlessness and, in some cases, subjective improvement in exercise tolerance after treatment PSYCHOSOMATICS
Smoller et al.
with 25–100 mg/day of sertraline. These improvements occurred without any substantial concomitant change in the FEV1 in the four of five patients in whom testing was conducted before and after treatment. Four of the seven patients did not appear to meet syndromal criteria for a mood or anxiety disorder, although several experienced anxiety or even panic related to episodes of dyspnea. In addition, we did not assess somatization disorder, which may have contributed to the patients’ symptomatology. If, as preliminary evidence has suggested, SSRIs are helpful for such patients, the benefit observed with sertraline may have been related to its effects on somatization disorder. Given the uncontrolled and retrospective nature of patient and clinician reports and chart review, these results must be considered preliminary. In addition, the patients were on varying regimens of concomitant medications, which may have contributed to symptomatic changes. Nevertheless, our results support those of Papp and colleagues,10 who reported on six patients with COPD in whom sertraline treatment was associated with marked subjective improvement without objective changes in spirometry or blood gases. If SSRIs are able to improve dyspnea and exercise tolerance in COPD patients, they may do so by relieving mood and anxiety symptoms and/or by direct effects on serotonergic modulation of respiration. Patients with dyspnea disproportionate to their degree of pulmonary dysfunction have been reported to have high rates of depressive and anxious symptoms, and successful treatment of these symptoms has been associated with decreased dyspnea and increased exercise tolerance.4,11 It may be that sertraline improved the patients’ tolerance of breathlessness or alleviated an exaggerated fear and avoidance of dyspnea that is associated with functional impairment in some COPD patients.12 The possibility that sertraline decreased dyspnea by a neurobiological effect on respiratory control mechanisms is consistent with animal research showing that serotonin modulates respiratory function at the level of the brainstem.5,6,13–15 As noted earlier, serotonin may VOLUME 39 • NUMBER 1
• JANUARY–FEBRUARY 1998
function in part to decrease CO2 sensitivity, which is correlated with dyspnea in patients with COPD.7 The successful treatment of panic disorder with the serotonergic heterocyclic clomipramine was associated with decreased CO2 sensitivity in one series.16 We observed a similar phenomenon in the patient with panic in whom relief of dyspnea and panic was associated with a decrease in CO2 sensitivity. Dyspnea can be debilitating for patients with obstructive lung disease, and there are few pharmacologic options for treatment other than optimizing bronchodilator and steroid regimens. In unusual cases, opiates may be helpful but can depress ventilation, leading to CO2 retention.17 The use of psychotropic medications to relieve dyspnea in patients without psychiatric illness has received limited attention. An early case series18 suggested that diazepam might reduce breathlessness and improve exercise tolerance in nonanxious patients with COPD. However, subsequent reports, including controlled trials of alprazolam and diazepam, indicate that benzodiazepines do not improve dyspnea and can worsen exercise tolerance and blood gases in COPD patients.19–21 The anxiolytic buspirone is a partial agonist at 5-HT1A receptors and appears to have respiratory stimulant properties.22,23 However, controlled trials of buspirone in COPD patients have produced conflicting results with regard to its ability to lessen anxiety and dyspnea and improve exercise tolerance.24,25 Uncontrolled reports of tricyclic antidepressants suggest that they are effective for anxiety and mood disorders in patients with chronic airways obstruction.11 In a case report on a patient with COPD, nortriptyline treatment was associated with a decrease in both CO2 sensitivity and dyspnea. A placebo-controlled trial of nortriptyline26 found that it lessened depression, anxiety, and disability in depressed patients with COPD, although it had little effect on dyspnea. Relatively little is known about the safety of psychotropic medications in patients with pulmonary disease. Buspirone has also been well tolerated in patients with respiratory disease24,25,27,28 but has limited efficacy in depression and panic disorder, two common psychiat27
Sertraline Effects on Dyspnea
ric disorders in COPD patients. Some reports suggest that tricyclic antidepressants are poorly tolerated in patients with COPD29,30 and that benzodiazepines can worsen gas exchange. In the cases we have presented, the SSRI sertraline was well tolerated in six of seven patients and was not associated with an impairment of pulmonary function. Thus, SSRIs may be a useful option for treating depression and anxiety disorders in patients with COPD. Although we have not observed significant adverse effects associated with SSRI administration in these patients, it would seem prudent to initiate SSRI therapy at low doses with gradual upward titration in patients with severe lung disease, because blunting of CO2 sensitivity may have adverse effects in such patients. In addition, the potential for drug interactions with the SSRIs should be considered in patients on concomitant medications. For example, the SSRI fluvoxamine may
cause an elevation in theophylline levels due to inhibition of the cytochrome P450 1A2 isoenzyme. Drugs that strongly inhibit the 3A4 isoenzyme (e.g., fluvoxamine and nefazodone) may interfere with metabolism of corticosteroids.31 We have reported several cases of patients with obstructive lung disease with and without mood or anxiety disorders who reported improvements in dyspnea and exercise tolerance during treatment with sertraline. Sertraline was well tolerated and did not have a significant effect on pulmonary function testing. These cases suggest that sertraline may have antidyspneic effects that might be related to improvements in mood and anxiety symptoms as well as neurobiological effects on central respiratory centers. We are now conducting a clinical trial of SSRIs to further characterize their safety and efficacy in COPD patients with and without psychiatric illness.
References
1. Karajgi B, Rifkin A, Doddi S, et al: The prevalence of anxiety disorders in patients with chronic obstructive pulmonary disease. Am J Psychiatry 1990; 147:200– 201 2. Yellowlees PM, Alpers JH, Bowden JJ, et al: Psychiatric morbidity in patients with chronic airflow obstruction. Med J Austral 1987; 146:305–307 3. Zandbergen J, Bright M, Pols H, et al: Higher lifetime prevalence of respiratory diseases in panic disorder? Am J Psychiatry 1991; 148: 1583–1585 4. Burns BH, Howell JBL: Disproportionately severe breathlessness in chronic bronchitis. QJM 1969; 38:277–284 5. Mueller R, Lundberg D, Breese G, et al: The neuropharmacology of respiratory control. Pharmacol Rev 1982; 34:255–285 6. Lundberg D, Mueller R, Breese G: An evaluation of the mechanism by which serotonergic activation depresses respiration. J Pharmacol Exp Ther 1980; 212:397–404 7. Matthews AW: The relationship between central carbon dioxide sensitivity and clinical features in patients with chronic airways obstruction. QJM 1977; 46:179– 195 8. Papp LA, Klein DF, Gorman JM: Carbon dioxide hypersensitivity, hyperventilation and panic disorder. Am J Psychiatry 1993; 150:1149–1157 9. Klein DF: False suffocation alarms, spontaneous panics, and related conditions: an integrative hypothesis. Arch Gen Psychiatry 1993; 50:306–317 28
10. Papp LA, Weiss JR, Greenberg HE, et al: Sertraline for chronic obstructive pulmonary disease and comorbid anxiety and mood disorders (letter). Am J Psychiatry 1995; 52:1531 11. Yellowlees PM: The treatment of psychiatric disorders in patients with chronic airways obstruction. Med J Aust 1987; 147:349–352 12. Agle DP, Baum GL: Psychological aspects of chronic obstructive pulmonary disease. Med Clin North Am 1977; 61:749–758 13. Mueller R, Lundberg D, Breese G: Evidence that respiratory depression by serotonin agonists may be exerted in the central nervous system. Pharmacol Biochem Behav 1980; 13:247–255 14. Rampin O, Pierrefiche O, Denavit-Saubie M: Effects of serotonin and substance P on bulbar respiratory neurons in vivo. Brain Res 1993; 622:185–193 15. Morin D, Hennequin S, Monteau R, et al: Serotonergic influences on central respiratory activity: an in vitro study in the newborn rat. Brain Res 1990; 535:281–287 16. Pols H, Lousberg H, Zandbergen J, et al: Panic disorder patients show decrease in ventilatory response to CO2 after clomipramine treatment (letter). Psychiatry Res 1993; 47:295–296 17. Sweer L, Zwillich CW: Dyspnea in the patient with chronic obstructive pulmonary disease: etiology and management. Clin Chest Med 1990; 11:417–445 18. Mitchell-Heggs P, Murphy K, Minty K, et al: DiazePSYCHOSOMATICS
Smoller et al.
pam in the treatment of dyspnea in the “pink puffer” syndrome. QJM 1980; 49:9–20 19. Woodcock AA, Gross ER, Geddes DM: Drug treatment of breathlessness: contrasting effects of diazepam and promethazine in pink puffers. BMJ 1981; 283:343–346 20. Eimer M, Cable T, Gal P, et al: Effects of clorazepate on breathlessness and exercise tolerance in patients with chronic airflow obstruction. J Fam Pract 1985; 21:359–362 21. Man GCW, Hsu K, Sproule BJ: Effect of alprazolam on exercise and dyspnea in patients with chronic obstructive pulmonary disease. Chest 1986; 90:832– 836 22. Garner SJ, Eldridge FL, Wagner PG, et al: Buspirone: an anxiolytic drug that stimulates respiration. American Review of Respiratory Disease 1989; 139:946– 950 23. Mendelson WB, Martin JV, Rapoport DM: Effects of buspirone on sleep and respiration. American Review of Respiratory Disease 1990; 141:1527–1530 24. Singh NP, Despars JA, Stansbury DW, et al: Effects of buspirone on anxiety levels and exercise tolerance in patients with chronic airflow obstruction and mild anxiety. Chest 1993; 103:800–804 25. Argyropoulou P, Patakas D, Koukou A, et al: Buspi-
VOLUME 39 • NUMBER 1
• JANUARY–FEBRUARY 1998
rone effect on breathlessness and exercise performance in patients with chronic obstructive pulmonary disease. Respiration 1993; 60:216–220 26. Borson S, McDonald GJ, Gayle T, et al: Improvement in mood, physical symptoms, and function with nortriptyline for depression in patients with chronic obstructive pulmonary disease. Psychosomatics 1992; 33:190–201 27. Craven J, Sutherland A: Buspirone for anxiety disorders in patients with severe lung disease. Lancet 1991; 338:249 28. Alderman C, Frith P, Ben-Tovim D: Buspirone for the treatment of anxiety in patients with chronic obstructive airways disease. J Clin Psychopharmacol 1996; 16:410–411 29. Gordon GH, Michiels TM, Mahutts K, et al: Effect of desipramine on control of ventilation and depression scores in patients with severe chronic obstructive pulmonary disease. Psychiatry Res 1985; 15:25–32 30. Light RW, Merrill EJ, Despars J, et al: Doxepin treatment of depressed patients with chronic obstructive pulmonary disease. Arch Intern Med 1986; 146:1377– 1380 31. Nemeroff C, DeVane C, Pollock B: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996; 153:311–320
29
Dyspnea can have a debilitating effect on psychosocial and physical functioning in patients with chronic obstructive airways disease. Previous research has suggested that treatment of concomitant mood or anxiety symptoms can improve dyspnea and exercise intolerance among patients with respiratory disease. The authors report here on a case series of 7 patients with obstructive airways disease who reported improvements in dyspnea after sertraline 25–100 mg/day was added to their medication regimens. Four of the seven patients did not appear to meet syndromal criteria for a mood or anxiety disorder. Subjective improvements in dyspnea may have been related to relief of mood or anxiety symptoms or to direct effects on central respiratory systems. Controlled studies are needed to clarify the potential antidyspneic effects of sertraline. (Psychosomatics 1998; 39:24–29)
P
atients with respiratory disease have been reported to have higher than expected rates of anxiety disorders, particularly panic disorder.1–3 For example, as many as one-fourth of patients with chronic obstructive pulmonary disease (COPD), including asthma, may meet criteria for panic disorder.2 Patients with COPD and breathlessness disproportionate to their degree of pulmonary disease may experience decreased dyspnea and improved exercise tolerance after successful treatment of depression or anxiety.4 One pathophysiological link between psychiatric and respiratory symptoms may be at the level of the serotonergic system. Animal studies have suggested that serotonin modulates central control of respiration,5 in part, by affecting sensitivity to carbon dioxide.6 In patients with COPD, greater degrees of CO2 sensitivity have been associated with more severe dyspnea.7 Dyspnea is also a central feature of panic attacks, and hypersensitivity to CO2 has been implicated in the pathogenesis of panic disorder.8 In light of these observations, Klein has 24
suggested that antipanic agents might have antidyspneic effects in some patients with COPD.9 Papp and colleagues10 recently reported on 6 patients with COPD, with and without mood or anxiety disorders, in whom sertraline 12.5–100 mg/day was well tolerated and associated with subjective improvement in well-being. Taken together, these observations suggest that selective serotonin reuptake inhibitors (SSRIs) may be particularly useful and welltolerated in anxious or depressed patients with COPD and might diminish dyspnea in some pulmonary patients, even in the absence of a diagnosable psychiatric disorder. We report on seven Received October 30, 1996; revised January 29, 1997; accepted March 4, 1997. From the Department of Psychiatry and Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts. Address reprint requests to Dr. Smoller, Anxiety Disorders Program, Massachusetts General Hospital, ACC–815, 15 Parkman Street, Boston, MA 02114. E-mail: [email protected]. harvard.edu. Copyright 䉷 1998 The Academy of Psychosomatic Medicine.
PSYCHOSOMATICS
Smoller et al.
patients with COPD who reported improvements in dyspnea after treatment with the SSRI sertraline by their pulmonologist. Six patients were retrospectively interviewed by a psychiatrist (JWS) who used modules for depression, dysthymia, panic disorder, agoraphobia, and generalized anxiety disorder from the Structured Clinical Interview for DSM-IV (SCID-IV). One patient was prospectively studied by using the Structured Clinical Interview for DSM-III-R (SCID-III-R).
Case Reports Case 1. Mr. A., a 45-year-old man with a 10-year history of idiopathic emphysema, developed intractable dyspnea that was poorly relieved by a regimen of multiple bronchodilators and home-oxygen therapy. He was unable to do any lifting or climb even four steps without developing intolerable breathlessness and was listed as a candidate for lung transplantation. Baseline pulmonary function tests (PFTs) showed a severe obstructive ventilatory defect with forced expiratory volume at 1 second (FEV1)⳱0.64 L (16% predicted). He reported marked anticipatory anxiety and avoidance of activity because of concerns about dyspnea. Retrospective SCID assessment indicated that he had panic attacks that would have qualified for panic disorder but occurred in the setting of apparent respiratory compromise. A trial of alprazolam (0.25 mg/bid) resulted in only mild symptomatic relief and sertraline (25–50 mg/day) was added to his regimen. Four weeks later, he reported marked improvement in exercise tolerance. After 2 months, he reported being “less conscious of the effort necessary to breathe” and was able to walk briskly and play with his young daughter without becoming dyspneic. He reported decreased anxiety associated with these activities. Repeat PFTs at 1 month showed no significant change. Case 2. Ms. B., a 64-year-old woman with a 50pack/year smoking history and a long history of severe asthma requiring steroids and intubation in the past, presented with complaints of dyspnea on mild exertion. She also had a history of obstructive sleep apnea requiring continuous positive airway pressure at night. She had remained dyspneic despite intensive therapeutic trials of bronchodilators and steVOLUME 39 • NUMBER 1
• JANUARY–FEBRUARY 1998
roids, and PFTs showed an obstructive ventilatory defect with FEV1⳱0.75 L (34% predicted). Psychiatric interview suggested that she was probably experiencing a major depression at the time sertraline (50 mg) was prescribed. She tolerated the medication well, and after 8–16 weeks she reported improvements in mood, energy, ability to ambulate, and breathlessness. Repeat PFTs 8 months after sertraline was added showed some improvement in FEV1⳱1.09 (50% predicted). Case 3. Ms. C., a 51-year-old woman, has a 20year history of steroid-dependent asthma. She had been maintained on prednisone, theophylline, and inhalers, and attempts to taper prednisone in the past had been associated with intolerable increases in wheezing and dyspnea. Baseline PFTs showed evidence of some fixed obstruction. About 3 months before initiation of sertraline, a nedocromil sodium inhaler and a steroid inhaler were added to her regimen, but she continued to be unable to tolerate tapering of prednisone. Pulmonary function tests obtained before initiating sertraline showed a moderate obstructive defect, with FEV1⳱1.1 L (48%) and FVC⳱1.8 L (69%); her peak expiratory flow rate (PEFR) after bronchodilator was 3.2 L/sec (58%). To reduce fatigue and dysphoria associated with tapering of prednisone, sertraline was added (50 mg/ day) and increased to 100 mg per day after 2 weeks. At the time of the psychiatric interview, she had been on sertraline for about 7 months and had been able to taper her prednisone to 5 mg every other day, the lowest dose of steroids she had been on since the onset of her asthma. Her other medications had not changed, and the most recent pulmonary function testing showed little evidence of objective change, with FEV1⳱1.13 L (52%), FVC⳱1.8 L (70%), and PEFR 3.0 L/sec (55%). Nevertheless, she reported that she was markedly less dyspneic and no longer experienced dyspnea on exertion. She did not meet criteria for current or past mood or anxiety disorder. Case 4. Ms. D., a 59-year-old woman, has a long history of severe asthma for which she had been maintained on prednisone and multiple bronchodilator inhalers over the past 10 years. For much of the year before initiating sertraline, she had required prednisone (30–40 mg/day) in addition to betaagonist and steroid inhalers, and she had been hospitalized for a flare of her asthma 1 month before starting sertraline. She was troubled by depressed 25
Sertraline Effects on Dyspnea
mood and met criteria for dysthymia and generalized anxiety disorder on retrospective SCID interview at 11 weeks. Baseline PFTs showed a moderate obstructive defect (FEV1⳱1.3 L, 51% predicted). She was started on sertraline (50 mg/ day) and increased to 100 mg/day by 4 weeks. At the end of 4 weeks, the patient reported marked improvement in her breathing and her mood, was able to successfully taper her prednisone, and discontinued the use of nebulizers and one of her betaagonist inhalers. PFTs continued to demonstrate a moderate obstructive defect but no significant change in FEV1 (1.5 L, 58% predicted) or peak expiratory flow rate. At 11 weeks, she reported that her breathing “hasn’t been this good in 10 years.” She was able to taper prednisone to 5 mg every other day and planned to discontinue it in 1 week. She reported that she had gone from having difficulty climbing one flight of stairs to being able to walk around the mall for hours. She no longer met criteria for a mood or anxiety disorder. Case 5. Mr. E., a 52-year-old man, has a history of steroid-dependent COPD and dilated cardiomyopathy. He had been hospitalized for a respiratory decompensation 2 weeks before starting sertraline. He was started on a medical regimen that included digitalis, captopril, and furosemide for heart failure. Sertraline (25 mg) and a steroid inhaler were added to his regimen after discharge. After 4 weeks on this regimen, he reported a decrease in dyspnea. The sertraline dosage was increased to 50 mg, and alprazolam (0.25 mg bid) was added. At 9 weeks, Mr. E. reported improved exercise tolerance and decreased need for bronchodilator use. Ten months after starting sertraline, he reported continued marked improvement in dyspnea and exercise tolerance and decreased bronchodilator use, which he attributed to the sertraline and alprazolam. Psychiatric interview revealed no history of mood or anxiety disorder. Case 6. Ms. F., a 70-year-old woman, has a history of asthma and fear of suffocation. She had been treated with alprazolam (0.125 mg 3 times/day) for anxiety. Her PFTs before sertraline treatment showed a mild obstructive ventilatory defect. She complained of increased episodes of dyspnea and anxiety, and she was started on sertraline (50 mg). Alprazolam was increased to 0.25 mg four times daily. Because of initial jitteriness on sertraline, the dose was decreased to 25 mg/day. After 3 weeks, she reported fewer episodes of acute dyspnea and 26
panic. However, she discontinued sertraline because of jitteriness. On psychiatric interview 1 year later, there was no history of syndromal mood or anxiety disorders. Case 7. Ms. G., a 75-year-old woman, has a history of severe asthma and recurrent panic attacks associated with shortness of breath. On a structured assessment before sertraline treatment, she met criteria for panic disorder with agoraphobia. She had been maintained on chronic bronchodilators, and in the past she had required prednisone tapers for exacerbation of her wheezing. Baseline pulmonary assessment showed an obstructive defect: FEV1⳱0.86 L (61%). She was started on sertraline (25 mg/day), and after 4 weeks she reported a decrease in dyspnea and discontinuation of her bronchodilators. At 12 weeks, she reported sustained improvement in dyspnea and remission of panic and anticipatory anxiety. Coinciding with this were decreases on the Hamilton anxiety scale (from 14 to 8) and Hamilton depression scale (from 11 to 5). Repeat pulmonary assessment showed no clinically significant change in FEV1. Bicycle ergometry and carbon dioxide (7%) inhalation were performed at baseline and 12 weeks. Compared with baseline, CO2 sensitivity, as measured by change in minute ventilation per unit change in end-tidal CO2 (DVE/DPETCO2), decreased by 65% (from 1.56 L/min/mmHg to 0.56 L/min/ mmHg). She also reported less breathlessness during CO2 inhalation compared with baseline. No clinically significant changes were observed in either overall aerobic capacity (pretreatment VO2 max⳱599 ml/min, posttreatment⳱603 mL/min) or minute ventilation at peak exercise (pretreatment⳱15 L/min, posttreatment⳱16 L/min). Her exercise tolerance showed a modest improvement, with an increase in peak work from 15 Watts to 21 Watts and increased duration from 4 minutes 17 seconds to 5 minutes 34 seconds. She experienced a panic attack during exercise at baseline but not at 12 weeks.
DISCUSSION In the observed cases, patients with mild-tosevere obstructive lung disease and complaints of marked dyspnea reported a decrease in breathlessness and, in some cases, subjective improvement in exercise tolerance after treatment PSYCHOSOMATICS
Smoller et al.
with 25–100 mg/day of sertraline. These improvements occurred without any substantial concomitant change in the FEV1 in the four of five patients in whom testing was conducted before and after treatment. Four of the seven patients did not appear to meet syndromal criteria for a mood or anxiety disorder, although several experienced anxiety or even panic related to episodes of dyspnea. In addition, we did not assess somatization disorder, which may have contributed to the patients’ symptomatology. If, as preliminary evidence has suggested, SSRIs are helpful for such patients, the benefit observed with sertraline may have been related to its effects on somatization disorder. Given the uncontrolled and retrospective nature of patient and clinician reports and chart review, these results must be considered preliminary. In addition, the patients were on varying regimens of concomitant medications, which may have contributed to symptomatic changes. Nevertheless, our results support those of Papp and colleagues,10 who reported on six patients with COPD in whom sertraline treatment was associated with marked subjective improvement without objective changes in spirometry or blood gases. If SSRIs are able to improve dyspnea and exercise tolerance in COPD patients, they may do so by relieving mood and anxiety symptoms and/or by direct effects on serotonergic modulation of respiration. Patients with dyspnea disproportionate to their degree of pulmonary dysfunction have been reported to have high rates of depressive and anxious symptoms, and successful treatment of these symptoms has been associated with decreased dyspnea and increased exercise tolerance.4,11 It may be that sertraline improved the patients’ tolerance of breathlessness or alleviated an exaggerated fear and avoidance of dyspnea that is associated with functional impairment in some COPD patients.12 The possibility that sertraline decreased dyspnea by a neurobiological effect on respiratory control mechanisms is consistent with animal research showing that serotonin modulates respiratory function at the level of the brainstem.5,6,13–15 As noted earlier, serotonin may VOLUME 39 • NUMBER 1
• JANUARY–FEBRUARY 1998
function in part to decrease CO2 sensitivity, which is correlated with dyspnea in patients with COPD.7 The successful treatment of panic disorder with the serotonergic heterocyclic clomipramine was associated with decreased CO2 sensitivity in one series.16 We observed a similar phenomenon in the patient with panic in whom relief of dyspnea and panic was associated with a decrease in CO2 sensitivity. Dyspnea can be debilitating for patients with obstructive lung disease, and there are few pharmacologic options for treatment other than optimizing bronchodilator and steroid regimens. In unusual cases, opiates may be helpful but can depress ventilation, leading to CO2 retention.17 The use of psychotropic medications to relieve dyspnea in patients without psychiatric illness has received limited attention. An early case series18 suggested that diazepam might reduce breathlessness and improve exercise tolerance in nonanxious patients with COPD. However, subsequent reports, including controlled trials of alprazolam and diazepam, indicate that benzodiazepines do not improve dyspnea and can worsen exercise tolerance and blood gases in COPD patients.19–21 The anxiolytic buspirone is a partial agonist at 5-HT1A receptors and appears to have respiratory stimulant properties.22,23 However, controlled trials of buspirone in COPD patients have produced conflicting results with regard to its ability to lessen anxiety and dyspnea and improve exercise tolerance.24,25 Uncontrolled reports of tricyclic antidepressants suggest that they are effective for anxiety and mood disorders in patients with chronic airways obstruction.11 In a case report on a patient with COPD, nortriptyline treatment was associated with a decrease in both CO2 sensitivity and dyspnea. A placebo-controlled trial of nortriptyline26 found that it lessened depression, anxiety, and disability in depressed patients with COPD, although it had little effect on dyspnea. Relatively little is known about the safety of psychotropic medications in patients with pulmonary disease. Buspirone has also been well tolerated in patients with respiratory disease24,25,27,28 but has limited efficacy in depression and panic disorder, two common psychiat27
Sertraline Effects on Dyspnea
ric disorders in COPD patients. Some reports suggest that tricyclic antidepressants are poorly tolerated in patients with COPD29,30 and that benzodiazepines can worsen gas exchange. In the cases we have presented, the SSRI sertraline was well tolerated in six of seven patients and was not associated with an impairment of pulmonary function. Thus, SSRIs may be a useful option for treating depression and anxiety disorders in patients with COPD. Although we have not observed significant adverse effects associated with SSRI administration in these patients, it would seem prudent to initiate SSRI therapy at low doses with gradual upward titration in patients with severe lung disease, because blunting of CO2 sensitivity may have adverse effects in such patients. In addition, the potential for drug interactions with the SSRIs should be considered in patients on concomitant medications. For example, the SSRI fluvoxamine may
cause an elevation in theophylline levels due to inhibition of the cytochrome P450 1A2 isoenzyme. Drugs that strongly inhibit the 3A4 isoenzyme (e.g., fluvoxamine and nefazodone) may interfere with metabolism of corticosteroids.31 We have reported several cases of patients with obstructive lung disease with and without mood or anxiety disorders who reported improvements in dyspnea and exercise tolerance during treatment with sertraline. Sertraline was well tolerated and did not have a significant effect on pulmonary function testing. These cases suggest that sertraline may have antidyspneic effects that might be related to improvements in mood and anxiety symptoms as well as neurobiological effects on central respiratory centers. We are now conducting a clinical trial of SSRIs to further characterize their safety and efficacy in COPD patients with and without psychiatric illness.
References
1. Karajgi B, Rifkin A, Doddi S, et al: The prevalence of anxiety disorders in patients with chronic obstructive pulmonary disease. Am J Psychiatry 1990; 147:200– 201 2. Yellowlees PM, Alpers JH, Bowden JJ, et al: Psychiatric morbidity in patients with chronic airflow obstruction. Med J Austral 1987; 146:305–307 3. Zandbergen J, Bright M, Pols H, et al: Higher lifetime prevalence of respiratory diseases in panic disorder? Am J Psychiatry 1991; 148: 1583–1585 4. Burns BH, Howell JBL: Disproportionately severe breathlessness in chronic bronchitis. QJM 1969; 38:277–284 5. Mueller R, Lundberg D, Breese G, et al: The neuropharmacology of respiratory control. Pharmacol Rev 1982; 34:255–285 6. Lundberg D, Mueller R, Breese G: An evaluation of the mechanism by which serotonergic activation depresses respiration. J Pharmacol Exp Ther 1980; 212:397–404 7. Matthews AW: The relationship between central carbon dioxide sensitivity and clinical features in patients with chronic airways obstruction. QJM 1977; 46:179– 195 8. Papp LA, Klein DF, Gorman JM: Carbon dioxide hypersensitivity, hyperventilation and panic disorder. Am J Psychiatry 1993; 150:1149–1157 9. Klein DF: False suffocation alarms, spontaneous panics, and related conditions: an integrative hypothesis. Arch Gen Psychiatry 1993; 50:306–317 28
10. Papp LA, Weiss JR, Greenberg HE, et al: Sertraline for chronic obstructive pulmonary disease and comorbid anxiety and mood disorders (letter). Am J Psychiatry 1995; 52:1531 11. Yellowlees PM: The treatment of psychiatric disorders in patients with chronic airways obstruction. Med J Aust 1987; 147:349–352 12. Agle DP, Baum GL: Psychological aspects of chronic obstructive pulmonary disease. Med Clin North Am 1977; 61:749–758 13. Mueller R, Lundberg D, Breese G: Evidence that respiratory depression by serotonin agonists may be exerted in the central nervous system. Pharmacol Biochem Behav 1980; 13:247–255 14. Rampin O, Pierrefiche O, Denavit-Saubie M: Effects of serotonin and substance P on bulbar respiratory neurons in vivo. Brain Res 1993; 622:185–193 15. Morin D, Hennequin S, Monteau R, et al: Serotonergic influences on central respiratory activity: an in vitro study in the newborn rat. Brain Res 1990; 535:281–287 16. Pols H, Lousberg H, Zandbergen J, et al: Panic disorder patients show decrease in ventilatory response to CO2 after clomipramine treatment (letter). Psychiatry Res 1993; 47:295–296 17. Sweer L, Zwillich CW: Dyspnea in the patient with chronic obstructive pulmonary disease: etiology and management. Clin Chest Med 1990; 11:417–445 18. Mitchell-Heggs P, Murphy K, Minty K, et al: DiazePSYCHOSOMATICS
Smoller et al.
pam in the treatment of dyspnea in the “pink puffer” syndrome. QJM 1980; 49:9–20 19. Woodcock AA, Gross ER, Geddes DM: Drug treatment of breathlessness: contrasting effects of diazepam and promethazine in pink puffers. BMJ 1981; 283:343–346 20. Eimer M, Cable T, Gal P, et al: Effects of clorazepate on breathlessness and exercise tolerance in patients with chronic airflow obstruction. J Fam Pract 1985; 21:359–362 21. Man GCW, Hsu K, Sproule BJ: Effect of alprazolam on exercise and dyspnea in patients with chronic obstructive pulmonary disease. Chest 1986; 90:832– 836 22. Garner SJ, Eldridge FL, Wagner PG, et al: Buspirone: an anxiolytic drug that stimulates respiration. American Review of Respiratory Disease 1989; 139:946– 950 23. Mendelson WB, Martin JV, Rapoport DM: Effects of buspirone on sleep and respiration. American Review of Respiratory Disease 1990; 141:1527–1530 24. Singh NP, Despars JA, Stansbury DW, et al: Effects of buspirone on anxiety levels and exercise tolerance in patients with chronic airflow obstruction and mild anxiety. Chest 1993; 103:800–804 25. Argyropoulou P, Patakas D, Koukou A, et al: Buspi-
VOLUME 39 • NUMBER 1
• JANUARY–FEBRUARY 1998
rone effect on breathlessness and exercise performance in patients with chronic obstructive pulmonary disease. Respiration 1993; 60:216–220 26. Borson S, McDonald GJ, Gayle T, et al: Improvement in mood, physical symptoms, and function with nortriptyline for depression in patients with chronic obstructive pulmonary disease. Psychosomatics 1992; 33:190–201 27. Craven J, Sutherland A: Buspirone for anxiety disorders in patients with severe lung disease. Lancet 1991; 338:249 28. Alderman C, Frith P, Ben-Tovim D: Buspirone for the treatment of anxiety in patients with chronic obstructive airways disease. J Clin Psychopharmacol 1996; 16:410–411 29. Gordon GH, Michiels TM, Mahutts K, et al: Effect of desipramine on control of ventilation and depression scores in patients with severe chronic obstructive pulmonary disease. Psychiatry Res 1985; 15:25–32 30. Light RW, Merrill EJ, Despars J, et al: Doxepin treatment of depressed patients with chronic obstructive pulmonary disease. Arch Intern Med 1986; 146:1377– 1380 31. Nemeroff C, DeVane C, Pollock B: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996; 153:311–320
29