Buspirone

The objective of this study was to determine if buspirone would alleviate anxiety and improve exercise tolerance of anxious patients with chronic airflow obstruction (CAO). Eleven male patients with mild to moderate anxiety and CAO completed this study comparing buspirone, 10 to 20 mg given three times a day, with placebo. Patients were evaluated with State Trait Anxiety Inventory, spirometry, 12-min walk, incremental exercise on a cycle ergometer to symptom limitation and measurement of dyspnea with a modified Borg scale at exercise levels and the end of each 2 min on 12-min walk. There were no significant differences in anxiety scores, work load, maximum oxygen consumption per minute, maximum expired volume per minute, [PETCO.sup.2], [PETO.sub.2], 12-min walking distance or dyspnea scores after 6 weeks of buspirone or placebo therapy. We conclude that administration of buspirone has no significant effect on anxiety levels, exercise capabilities or [PETO.sup.2] or [PETCO.sup.2] in patients with CAO and mild anxiety.

It has been estimated that over 15 million Americans have chronic airflow obstruction (CAO).[1] The exercise capacity of many patients with CAO is limited because of shortness of breath (dyspnea). Many different therapeutic modalities are available for the patient with CAO including bronchodilators, corticosteroids, rehabilitation, and oxygen therapy. Nevertheless, breathlessness during exercise still decreases the quality of life of many patients with CAO.

The exercise capacity of patients with CAO who are ventilatory-limited can be improved in one of three ways. (a) The ventilatory capabilities of the patient can be improved with therapeutic interventions such as bronchodilators or anti-inflammatory agents. (b) The ventilatory requirements of the patient at a given work load can be decreased. It appears that oxygen[2] and opiates[3,4] work at least in part via this mechanism. (c) The degree of discomfort associated with a given level of ventilation can be decreased. At least part of the benefit of pulmonary rehabilitation programs is due to this mechanism.[5] In addition, this is one of the mechanisms by which opiates improve exercise tolerance in the ventilatory-limited CAO patient.[3]

Previously we have shown[6] that changes in the 12-min walking distances were more closely associated with changes in the anxiety scores than with changes in the pulmonary function test results or changes in the arterial blood gases. We therefore hypothesized that if we could alleviate the anxiety of patients with CAO their exercise tolerance would improve.

The purpose of the present study was to determine if the new antianxiety agent, buspirone, would reduce anxiety levels in patients with CAO and increase their exercise tolerance. Buspirone is a new serotonergic anxiolytic drug[7] which appears to be useful for patients with generalized anxiety disorder, those with chronic anxiety, and the elderly who are anxious.[8] Buspirone was chosen as the study drug, because in addition to the aforementioned properties, it is a respiratory stimulant, at least in animals,[9,10] rather than a respiratory depressant as are other anti-anxiety agents, such as the benzodiazepines.[11,12]

MATERIALS AND METHODS

Patient Selection

The participants in the study were recruited from the Outpatient Pulmonary Clinic at the Veterans Administration Medical Center, Long Beach. Calif. The subjects agreed to participate in the study and signed informed consent forms approved by the Institutional Review Board at this institution.

Inclusion criteria for the study included an [FEV.sub.1] below 1.4 L, an [FEV.sub.1]/forced vital capacity (FVC) ratio less than 0.50, exercise limited by shortness of breath, and a stable disease state. The patients also were required to score above 50 on the Spielberger State-Trait Anxiety Inventory Scale (STAI).[13] In addition, patients had to be between 40 and 75 years of age. Patients continued their regular medication regimens throughout the study. Patients receiving alternate-day corticosteroids were given their usual dose on all study days.

Exclusion criteria included known left ventricular disease, active peptic ulcer disease, blindness, or any other contraindications to buspirone or known allergy to the drug. Patients were also excluded if they had neuromuscular or other medical problems which would preclude them from walking for 12 min or performing cycle ergometry. Also excluded were patients who had received tricyclic antidepressants or other major psychotropic drugs within the previous 2 months.

Protocol

On a screening day, the patient had spirometry and completed the Speilberger STAI to ascertain that screening criteria were met. The patient then underwent exercise testing with Borg scores as described in detail later to familiarize the patient with testing in our laboratory. The patient also performed three separate 12-min walk tests on this screening day for familiarization with the test and to decrease the variability in the test results.

The main protocol was a double-blind placebo-controlled randomized study where each patient received buspirone, 10 mg three times a day, or an identically appearing placebo, each for 6 weeks with a 2-week washout period between the two treatment periods. After six patients had completed the study, the protocol was altered so that the investigator had the option of doubling the dose of the medication after the first 3 weeks. The participants underwent spirometry, a maximal exercise test, a psychological assessment, and a 12-min walk baseline and after ingesting each study medication for 3 and 6 weeks.

Exercise Tests

Symptom-limited maximal exercise testing was performed in an incremental fashion to a symptom-limited maximum (Emax) on an electrically braked cycle ergometer (Gould Godart) in a manner similar to that previously described in our laboratory.[3,14,15] Initially, there was at least a 3-min equilibration period, with the patient seated on the cycle ergometer with mouthpiece and nose clips in place. When the patient appeared comfortable and relaxed, expired gases were collected for 3 min with the patient at rest. Then the work load on the bicycle ergometer was increased each minute so that the patient was expected to complete between five and eight levels of exercise. Expired gas was analyzed breath by breath for mixed expired fractions of oxygen and carbon dioxide and expired volume with a Sensormedics MMC Horizon System 4400 Metabolic Cart. During the last 30 s at each power output, measurements of cardiac and respiratory frequencies and a modified Borg scale score[16] (maximum value = 10) were obtained. Values obtained from the last completed half minute of cycling were considered to be maximal values.

The functional capability of the patient (submaximal exercise) was assessed with a 12-min walk.[17,18] The patient was told to walk at a pace that he could maintain for the entire 12 min and that the purpose of the walk was to determine the maximal distance that he could walk in 12 min. This test was performed in a carefully measured air-conditioned corridor. The technician did not walk with the patient; however, the patient was always visible to the technician. A modified Borg score for dyspnea was obtained at the end of each 2 min.

Psychological Tests

The presence of anxiety was assessed with the STAI developed by Spielberger and associates.[13] This examination consists of 40 multiple-choice questions. Twenty questions pertain to how the patient feels at that particular moment (state), while the remaining 20 questions deal with how the patient generally feels (trait). Each answer was scored on a scale of 1 to 4. The raw scores were then normalized. The mean normalized score for the general population has been 50.0, with a DS of 10.0.

The level of depression was assessed by the Beck Depression Inventory[19] which consists of 21 groups of statements, each with four possible responses. The patient was asked to select the one statement from each group that best described the way he had been feeling the past week. Each answer was scored on a scale of 0 to 3. A patient with a total score of 15 or more was considered to have significant depression.

Statistical Methods

The data are presented as the mean [+ or -] SD. Results at the end of the two different treatment periods were compared using the paired Student's t test. Values of p<0.05 were considered statistically significant.

RESULTS

Eleven male patients aged 66[+ or -]4 years completed the study. Four patients dropped out of the study. Two patients dropped out because they had gastrointestinal symptoms (nausea and diarrhea) and worsened dyspnea while they were taking buspirone. Another patient dropped out during the first week while he was taking buspirone due to dizziness, fatigue, and weakness. The fourth patient dropped out because of gastrointestinal side effects while he was receiving placebo. Four of the patients had the medications increased such that they were taking buspirone 20 mg three times a day for the last 3 weeks of the treatment period for buspirone.

The baseline data from the first day of the first treatment period are shown in Table 1. The patients had moderate to severe CAO ([FEV.sub.1]=1.28 [+ or -] 0.29 L). The mean state anxiety score was 48.7 [+ or -] 12.9 which was slightly lower than the score which qualified the subjects for the study on the screening day. This suggested that once the patients had undergone their initial screening tests, the anxiety component associated with participating in a research study diminished and hence their subsequent anxiety score decreased. The exercise capacity of the patients was reduced at the time of the baseline evaluation. The predicted work load for men who were greater than 55 years of age is 179 W with a maximum oxygen consumption per minute of 2,430 ml/min,[20] while the mean values for our patients were 78 W and 1,008 ml/min, respectively.

The results of the anxiety scores, the walking distance, and the maximal exercise tests were not significantly different after the patients had been treated with placebo or with buspirone for 6 weeks (Table 1). The anxiety scores were actually lower after the patients had received placebo for 6 weeks after they had received buspirone for 6 weeks. The FVC was significantly (p<0.05) higher after the treatment with buspirone than after the treatment with placebo. However, the clinical significance of this is questionable since the FVC after buspirone treatment (3.29 L) was virtually identical to the baseline FVC (3.30 L [Table 1]).

The distance walked in 12 min was quite similar after the two different treatment periods (Table 1). The mean Borg score at the end of the 12-min walk tended to be lower after the treatment with buspirone, but the difference did not achieve statistical significance and was due to one patient having a much higher Borg score while receiving placebo. Although the mean maximum work load, expired volume per minute, oxygen consumption per minute, and carbon dioxide production per minute tended to be higher after treatment with buspirone, none of the differences achieved statistical significance.

There was no evidence from this study that the administration of buspirone decreased ventilatory drive. At rest, the [PETCO.sub.2] was slightly lower after buspirone than it was after placebo administration while at Emax, it was slightly higher (Table 1). In a similar manner the [PETO.sub.2] was slightly higher at rest after buspirone and slightly lower at Emax after buspirone treatment. None of the differences achieved statistical significance.

Since there is some inherent fluctuation in the level of pulmonary function and the exercise capabilities of patients with CAO with time, we analyzed the changes in the various parameters over the two different treatment periods (Table 2). When the data were analyzed in this manner, the patients taking buspirone had larger decreases in their mean anxiety score and depression scores while the patients taking placebo tended to have more improvement in the 12-min walk and the cycle ergometry tests. However, in no case did the results with the two different treatments achieve statistical significance.

A separate analysis was done of the four patients who had the buspirone dose doubled at the end of the third week. This was done to evaluate the possibility that the initial dose was inadequate. In analyzing the data on this subgroup, no statistically significant differences between buspirone and placebo treatments were found.

At the end of the study, the patients were given the option of continuing buspirone therapy if they wished. Four patients showed interest. One patient continued to receive 60 mg/d. Another patient continued taking 60 mg/d, however, he stopped because of gastrointestinal side effects while receiving the higher dose. The third patient, due to exacerbation of CAO, wished to start after he improved, but subsequently lost interest. The last patient stopped due to drowsiness and lack of subjective beneficial effects.

DISCUSSION

In the present study, the administration of buspirone, 30 to 60 mg/d, did not lead to a significant improvement in the anxiety scores or the exercise tolerance of anxious patients with CAO. There are several possible explanations for the lack of beneficial response in the present study.

First, the dose of buspirone may have been too low or the drug may not have been given long enough. We believe these explanations are unlikely. All the patients in the present study were given at least 30 mg/d and in other studies, mean doses of 18[21] and 23 mg[22] have been effective in alleviating anxiety. Moreover, there was no evidence that the administration of 60 mg was effective in the four patients who received this higher dose in the present study. Also it is unlikely that the patients did not receive the drug long enough. In previous studies, there has been a definite alleviation of anxiety after patients have received the drug for 3 weeks,[21-23] and all the patients received the drug for 6 weeks in the present study.

[TABULAR DATA OMITTED]

Second, the patients in the present study had only mild anxiety which may not have been severe enough to respond to buspirone therapy. On the screening day, we only required a normalized STAI score of 50 to enter the study, and at the time of the first main evaluation, the normalized mean STAI score was only 48.7

(Table 1). Since the mean anxiety score for men in the general population is 50 with a standard deviation of 10 for this instrument, our patients had at most, mild anxiety. Previously, we have shown that the mean anxiety score of patients with CAO in our clinic using this instrument is relatively low.[24] Only one patient had a STAI score of more than 60 at the time he initially started to take the buspirone. The anxiety score in this patient initially was 76 and it did not change after 3 and 6 weeks of therapy.

Even though buspirone did not decrease the mean anxiety score or increase the exercise tolerance of our patients, there was no evidence that its administration was associated with a blunting of the ventilatory drive as is the case with other anxiolytic agents. The [PETO.sub.2] and the [PETCO.sub.2] were nearly identical after the patients took either buspirone or placebo for 6 weeks. Even though the end-tidal measurements do not accurately reflect the arterial values in these patients, significant trends in either the [PaO.sub.2] or the [PaCO.sub.2] should be reflected by similar changes in the end tidal values.[25] In addition, the ventilatory response to exercise was very similar after the two different treatments. These results are consistent with the observations of Rapoport et al[26] who demonstrated that buspirone in contrast to diazepam did not change the ventilation level or the response to carbon dioxide. It should be noted that buspirone appears to be a respiratory stimulant in the anesthetized cat[9] and in the nonanesthetized rat.[10]

Previous researchers have demonstrated that alleviation of depression or anxiety in patients with CAO is associated with an increased functional capacity. Burns and Howell[27] studied 31 patients with chronic bronchitis who appeared to have disproportionate breathlessness in relation to the severity of their pulmonary disease. They found that 16 of these patients were depressed, and treatment of these 16 patients with a tricyclic antidepressant drug resulted in a complete resolution of their depressive illness and a marked improvement in the exercise tolerance of 12 of the 16 patients. Their patients had only mild CAO with a mean [FEV.sub.1] of about 2 L. Agle et al[5] studied 24 patients with CAO who participated in a rehabilitation program. They found that those who had the greatest increase in their physical activity tended to be less depressed and less anxious originally and to have improvement of their anxiety and depression scores during the rehabilitation, while the poor responders tended to be more anxious originally and to respond less well to treatment. Previously, we have reported that changes in the 12-min walking test are more closely correlated with changes in depression scores or anxiety scores than they are with changes in the pulmonary function test results or the arterial blood gases.[6]

In conclusion, the administration of buspirone, 30 to 60 mg/d, to CAO patients with mild anxiety did not significantly affect their anxiety levels or their exercise tolerance. Additionally, buspirone did not affect the [PETCO.sub.2], [PETO.sub.2], or the ventilatory response to exercise. Since buspirone is effective in other medical patients with severe anxiety,[21] and since it does not adversely affect the ventilatory drive, its effectiveness should be assessed in patients with CAO and moderate to severe anxiety.

REFERENCES

[1] Higgins M. Epidemiology of COPD. Chest 1984; 85:3S-8S

[2] Light RW, Mahutte CK, Stansbury DW, Fischer CE, Brown SE. Relationship between improvement in exercise performance with supplemental oxygen and hypoxic ventilatory drive in patients with chronic airflow obstruction. Chest 1989; 95:751-56

[3] Light RW, Muro JR, Sato RI, Stansbury DW, Fischer CE, Brown SE. Effects of oral morphine on breathlessness and exercise tolerance in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 139:126-33

[4] Woodcock AA, Gross ER, Gellert A, Shah S, Johnson M, Geddes DM. Effects of dihydrocodeine, alcohol, and caffeine on breathlessness and exercise tolerance in patients with chronic obstructive lung disease and normal blood gases. N Engl J Med 1981; 305:1611-16

[5] Agle DP, Baum GL, Chester EH, Wendt M. Multidisciplinary treatment of chronic pulmonary insufficiency: psychological aspects of rehabilitation. Psychosom Med 1973; 35:41-49

[6] Light RW, Merrill EJ, Despars J, Gordon GH, Mutalipassi LR. Comparison of doxepin and placebo in treating depressed patients with chronic obstructive pulmonary disease. Arch Intern Med 1986; 146:1377-80

[7] Taylor DP, Moon SL. Buspirone and related compounds as alternative anxiolytics. Neuropep 1991; 19(suppl):15-19

[8] Rickels K. Buspirone in clincal practice. J Clin Psych 1990; 51(suppl):51-54

[9] Garner SJ, Eldridge FL, Wagner PG, Dowell RT. Buspirone, an anxiolytic drug that stimulates respiration. Am Rev Respir Dis 1989; 139:946-50

[10] Mendelson WB, Martin JV, Rapoport DM. Effects of buspirone on sleep and respiration. Am Rev Respir Dis 1990; 141:1527-30

[11] Woodcock AA, Gross ER, Geddes DM. Drug treatment of breathlessness: contrasting effects of diazepam and promethazine in pink puffers. Br Med J 1981; 283:343-45

[12] Geddes DM, Rudolf M, Saunders KB. Effect of nitrazepam and flurazepam on the ventilatory response to carbon dioxide. Thorax 1976; 31:548-51

[13] Spielberger CD, Gorsuch RL, Lushene RE. STAI manual. Palo Alto, Calif: Consulting Psychologists Press Inc, 1970

[14] Kirsch JL, Muro JR, Stansbury DW, Fischer CE, Monfore R, Light RW. Effect of naloxone on maximal exercise performance and control of ventilation in COPD. Chest 1989; 96:761-66

[15] Giron AE, Stansbury DW, Fischer CE, Light RW. Lack of effect of dextromethorphan on breathlessness and exercise performance in patients with chronic obstructive pulmonary disease (COPD). Eur Respir Dis J 1991; 4:532-35

[16] Borg GAV. Psychophysical basis of perceived exertion. Med Sci Sports Exer 1982; 14:377-81

[17] McGavin CR, Gupta SP, McHardy GJR. Twelve-minute walking test for assessing disability in chronic bronchitis. Br Med J 1976; 1:822-23

[18] McGavin CR, Artvinli M, Naoe H, McHardy GJ. Dyspnoea, disability, and distance walked: comparison of estimates of exercise performance in respiratory disease. Br Med J 1978; 2:241-43

[19] Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961; 4:561-71

[20] Blackie SP, Fairbarn MF, McElvaney GN, Morrison NJ, Wilcox PG, Pardy RL. Prediction of maximal oxygen uptake and power during cycle ergometry in subjects older than 55 years of age. Am Rev Respir Dis 1989; 139:1424-29

[21] Bohm C, Robinson DS, Gammans RE, Shrotriya RC, Alms DR, Leroy A, et al. Buspirone therapy in anxious elderly patients: a controlled clinical trial. J Clin Psychopharmacol 1990; 10:47S-51S

[22] Bohm C, Placchi M, Stallone F, Gammans RE, Alms DR, Shrotriya RC, et al. A double-blind comparison of buspirone, clobazam and placebo in patients with anxiety treated in a general practice setting. J Clin Psychopharmacol 1990; 10:38S-42S

[23] Petracca A, Nisita C, McNair D, Melis G, Guerani G, Cassano GB. Treatment of generalized anxiety disorder: preliminary clinical experience with buspirone. J Clin Psychiatry 1990; 51(suppl 9):31-39

[24] Light RW, Merrill EJ, Despars J, Gordon GH, Multalipassi LA. Prevalence of depression and anxiety in patients with chronic obstructive pulmonary disease: relationship to functional capacity. Chest 1985; 87:35-38

[25] Hansen JE, Sue DY, Wasserman K. Predicted values for clinical exercise testing. Am Rev Respir Dis 1984; 129(suppl):S49-S55

[26] Rapoport DM, Greenberg HE, Goldring RM. Differing effects of the anxiolytic agents buspirone and diazepam on control of breathing. Clin Pharmacol Ther 1991; 49:394-401

[27] Burns BH, Howell JBL. Disproportionately severe breathlessness in chronic bronchitis. Quart J Med 1969; 38:277-94

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