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Norepinephrine responses to postural and isometric stressors in acute and remitted depression
291
Psychiatry Research, 47:291-293 Elsevier
Letter
Norepinephrine Responses to Postural and Isometric Stressors in Acute and Remitted Depression To the Editors:
The pathophysiologic basis of mood disorders has been hypothesized to include altered stimulus-dependent regulation of the noradrenergic system (Siever and Davis, 1985). Responses to naturalistic challenges, such as orthostasis (Roy et al., 1985; Rudorfer et al., 1985) may reflect alterations in physiologic function (Gold et al., 1988) consistent with the paradigm of a dysregulated system that will not respond appropriately to specific stimuli (Siever and Davis, 1985). Plasma norepinephrine (NE), a product of the peripheral sympathetic nervous system, reflects acute behavioral challenge, may parallel central nervous system noradrenergic function, and is the primary response parameter used here. The present study tests the responsiveness of plasma NE, pulse, and blood pressure to (I) orthostasis, a primarily fixed demand challenge, and to (2) subsequent isometric exertion, a voluntary effortful task, in a group of acute and remitted endogenously depressed male patients and a group of ageand sex-matched healthy control subjects. The participants, all men, were 12 acutely depressed patients, 8 remitted depressed patients, and 13 normal control subjects. All acutely depressed patients met Research Diagnostic Criteria for current major depressive disorder at the time of assessment as determined by the Schedule for Affective Disorders and Schizophrenia-Lifetime version (SADS-L; Endicott and Spitzer, 1978); depressed patients in remission had a prior episode
0165-I 781/93/%06.00
Q 1993 Elsevier Scientific
of major depressive disorder as determined from the SADS-L, had not been hospitalized for at least 6 months, and had a score < 9 on the 23-item Hamilton Rating Scale for Depression (HRSD; Guy, 1976). Control subjects were recruited by advertisement, and had no personal or family history of major psychiatric disorder. All subjects were medication-free for a minimum of 2 weeks and followed a low monoamine diet before the protocol. Each protocol began at 8 a.m. after an overnight fast with the placement of an intravenous catheter. Supine subjects rose at 9 a.m., and after IO minutes of standing, squeezed a hand-held dynamometer with the dominant hand to one-third of their maximum effort for 5 minutes. Blood samples were drawn for baseline plasma NE determination and for response determination following 5 minutes of standing. Another sample was drawn after 5 minutes of isometric exertion while subjects were standing. The plasma NE was analyzed by the method of Hallman et al. (1978); intraassay and interassay coefficients of variation were both 8%. Pulse and blood pressure were determined at the same times by automated cuff (Dynamap Model 1846SX). Of the individuals who participated, one remitted depressed patient and three normal control subjects responded to the challenges with measured decreases of plasma NE. Given that plasma NE is expected to double in response to these challenges in both normal control subjects and in depressed patients (cf.
Publishers
Ireland
Ltd.
292 Roy et al., 1985; Rudorfer et al., 1985), it is presumed that other intervening variables, such as elevated baseline anxiety, may have contributed to these few abnormal individuals; it was therefore decided to eliminate them from further analysis. Consequently, the data from 12 acutely depressed patients, 7 remitted depressed patients, and 10 normal control subjects entered subsequent analyses. No significant differences were observed in any demographic or clinical variable assessed between the groups, other than the HRSD score (Table 1). Furthermore, basal plasma NE did not correlate significantly with age or weight in any of the three groups. No significant differences were found in supine basal plasma NE concentrations between the acute and remitted depressed patients (including or excluding the bipolar patients) and the normal control subjects. Repeated measures analysis of covariance revealed a significant plasma NE response difference between groups over the two tasks, whether covarying for baseline plasma NE alone (group X NE interaction: F = 5.58; df= 2, 26; p < 0.01) or also covarying for baseline pulse (group X NE interaction: F = 4.83; df = 2, 23; p < 0.02); no significant group differences were observed in pulse or blood pressure responses. In subsequent, more specific comparisons of plasma NE responses to the individual challenges, it was observed that (1) standing (an orthostatic challenge) did not differentiate groups, while (2) isometric exertion, covarying for plasma NE after standing ( F = 5. I I ; df = 2, 25; p < 0.02), or covarying for plasma NE at baseline and after standing (F = 4.78; df = 2,24; p < 0.02) did significantly differentiate between groups. Paired comparisons revealed statistically significant differences only between normal control subjects and acutely depressed patients, whether covarying for standing plasma NE levels alone (F = 7.53; df = 1, 19; p < 0.02) or for baseline and standing plasma NE levels (F = 7.3 1; df = I, 18; p < 0.02). The HRSD score did not correlate with plasma NE response in either the acute or remitted depressed patients. It appears that depressed patients, when shifting from a primarily fixed demand task (e.g., standing) to a voluntary task (e.g., isometric exertion), do not respond appropriately to the demand requirements of the voluntary task. This measure is thus sensitive to
Table 1. Subject characteristics and plasma norepinephrine responses (mean f SD) Acute Remitted Normal depressed depressed control (h=12) (i= 7) (n=lO) (range1
58.4zt7.6 40-73
Weight (kg)
71.3zt8.6
&X5.0&118.681.3 f12.3
43.7zt30.1
57.81t40.2
-
28.01t5.8
3.61-3.7
-
21 .O-38.5
0.0-8.0
25%
28%
Age WI
53.5k5.9 45-59
50.3zti 3.3 33-65
Days not receiving any medication Hamilton score’ (range) Bipolar depression
-
Plasma norepinephrine(pmoles/ml): Basal
1.4210.64
Standing
3.301b1.32 3.30f1.25
1.24kO.40
2.9111.12
After exertion
4.18k1.22
4.8711.64
4.381t1.28
1.4850.69
the NE response to both tasks. A combination of increased NE response to the fixed demand task (a finding consistent with some previous studies, e.g., Roy et al., 1985; Rudorfer et al., 1985) and decreased response to the effortful task may have contributed to the significantly reduced plasma NE response from the end of the orthostatic challenge to the end of the isometric exertion. Such a result might be expected if the acutely depressed patients simply were less motivated and therefore exerted less effort than did the normal control subjects. While one study that used a hand dynamometer found illness severity to correlate inversely with both maximal effort and the duration of half-maximal exertion in depression (Cohen et al., 1982) in this study illness severity did not relate to plasma NE response in either acutely depressed or remitted depressed patients. It is also of note that the findings do not fully replicate those of two previous studies that found significantly increased responses to orthostatic challenge in acute depression: one study. however, only examined women (Rudorfer et al., 1985) and the second included 75% women (Roy et al., 1985). while the present study included only men.
293 Our preliminary findings of state-dependent alterations in the noradrenergic system in response to a naturalistic challenge are consistent with an overt dysregulation of this system in acute depression that tends to normalize when patients are in remission (Siever and Davis, 1985; Trestman et al., 1992). The stateindependent growth hormone response to clonidine (a centrally mediated postsynaptic a,-agonist), in contrast, may reflect a persisting, centrally mediated vulnerability to depression in these patients (Siever et al., 1992). This work was supported in part by a grant from the National Institute of Mental Health(5ROl MH-41131) and by a grant from the National Institutes of Health (RR-00071) for the Mt. Sinai General Clinical Research Center. Acknowledgement.
References Cohen, R.M.; Weingartner, H.; Smallberg, S.A.; Pickar, D.; and Murphy, D.L. Effort and cognition in depression. Archives of General
Psychiatry,
39:593-597,
1982.
Endicott, J., and Spitzer, R.L. A diagnostic interview: Schedule for Affective Disorders and Schizophrenia. Archives of General Psychiatry,
35:837-844,
1978.
Gold, P.W.; Goodwin, F.K.; and Chrousos, G.P. Clinical and biochemical manifestations of depression: II. Relation to the neurobiology of stress. New England Journal of Medicine, 319:413-420, 1988. Guy, W., ed. ECDEU for Psychopharmacology,
Assessment Revised.
Manual
(DHEW Publication No. [ADM] 76-338) Washington, DC: Superintendent of Documents, U.S. Government Printing Office, 1976. Hallman, H.; Farnebo, L.; Hamberger, B.; and Jonsson, G. A sensitive method for the determination of plasma catecholamines using liquid chromatography with electrochemical detection. Life Sciences, 23:1049-1052, 1978. Roy, A.; Pickar, D.; Linnoila, M.; and Potter, W.Z. Plasma norepinephrine level in affective disorders: Relationship to melancholia. Archives of General Psychiatry, 42: 1181-l 185, 1985. Rudorfer, M.V.; Ross, R.J.; Linnoila, M.; Sherer, M.A.; and Potter, W.Z. Exaggerated orthostatic responsivity of plasma norepinephrine in depression. Archives of General
Psychiatry,
42:1186-l
192, 1985.
Siever, L.J., and Davis, K.L. Overview: Toward a dysregulation hypothesis of depression. American Journal of Psychiatry, 142:1017-1031,
1985.
Siever, L.J.; Trestman, R.L.; Coccaro, E.F.; Bernstein, D.P.; Gabriel, S.M.; Owen, K.; Moran, M.; Lawrence, T.L.; Rosenthal, J.; and Horvath, T.B. The growth hormone response to clonidine in acute and remitted depressed male patients. Neuropsychopharmacology,
6:165-177,
1992.
Trestman, R.L.; Lawrence, T.L.; Coccaro, E.F.; Harvey, P.; Bernstein, D.; Lawrence, E.K.; Condello, V.; Mahon, T.; Yang, R.-K.; Knott, P.; Horvath, T.B.; and Siever, L.J. Noradrenergic responses to clonidine in acute and remitted depressed male patients. Psychiatry Research,
43:199-213,
1992.
Robert L. Trestman, Ph.D., M.D.1 Department of Psychiatry Bronx Denartment of Veterans Affairs Medical Center and Mt. Sinai School of Medicine New York NY Emil F. Coccaro.
M.D. Department of Psychiatry Medical College of Pennsylvania Philadelphia, PA
Mina Apovian, B.A. Mt. Sinai School of Medicine New York, NY David Bernstein, Ph.D. Timothy Lawrence, M.D. Peter Knott, Ph.D.
Bronx Department Medical Center Bronx, NY Thomas
B. Horvarh,
Brooklyn Department Medical Center Brooklyn, NY
of Veterans
Affairs
M.D. of Veterans
Affairs
Larry J. Sever, M.D. Department of Psychiatry Bronx Department of Veterans Affairs Medical Center and Mt. Sinai School of Medicine New York, NY December
12, 1992
1. Reprint requests to Dr. R.L. Trestman, Psychiatry Service, 116A, Bronx DVA Medical Center, 130 W. Kingsbridge Rd., Bronx, NY 10468, USA.
Psychiatry Research, 47:291-293 Elsevier
Letter
Norepinephrine Responses to Postural and Isometric Stressors in Acute and Remitted Depression To the Editors:
The pathophysiologic basis of mood disorders has been hypothesized to include altered stimulus-dependent regulation of the noradrenergic system (Siever and Davis, 1985). Responses to naturalistic challenges, such as orthostasis (Roy et al., 1985; Rudorfer et al., 1985) may reflect alterations in physiologic function (Gold et al., 1988) consistent with the paradigm of a dysregulated system that will not respond appropriately to specific stimuli (Siever and Davis, 1985). Plasma norepinephrine (NE), a product of the peripheral sympathetic nervous system, reflects acute behavioral challenge, may parallel central nervous system noradrenergic function, and is the primary response parameter used here. The present study tests the responsiveness of plasma NE, pulse, and blood pressure to (I) orthostasis, a primarily fixed demand challenge, and to (2) subsequent isometric exertion, a voluntary effortful task, in a group of acute and remitted endogenously depressed male patients and a group of ageand sex-matched healthy control subjects. The participants, all men, were 12 acutely depressed patients, 8 remitted depressed patients, and 13 normal control subjects. All acutely depressed patients met Research Diagnostic Criteria for current major depressive disorder at the time of assessment as determined by the Schedule for Affective Disorders and Schizophrenia-Lifetime version (SADS-L; Endicott and Spitzer, 1978); depressed patients in remission had a prior episode
0165-I 781/93/%06.00
Q 1993 Elsevier Scientific
of major depressive disorder as determined from the SADS-L, had not been hospitalized for at least 6 months, and had a score < 9 on the 23-item Hamilton Rating Scale for Depression (HRSD; Guy, 1976). Control subjects were recruited by advertisement, and had no personal or family history of major psychiatric disorder. All subjects were medication-free for a minimum of 2 weeks and followed a low monoamine diet before the protocol. Each protocol began at 8 a.m. after an overnight fast with the placement of an intravenous catheter. Supine subjects rose at 9 a.m., and after IO minutes of standing, squeezed a hand-held dynamometer with the dominant hand to one-third of their maximum effort for 5 minutes. Blood samples were drawn for baseline plasma NE determination and for response determination following 5 minutes of standing. Another sample was drawn after 5 minutes of isometric exertion while subjects were standing. The plasma NE was analyzed by the method of Hallman et al. (1978); intraassay and interassay coefficients of variation were both 8%. Pulse and blood pressure were determined at the same times by automated cuff (Dynamap Model 1846SX). Of the individuals who participated, one remitted depressed patient and three normal control subjects responded to the challenges with measured decreases of plasma NE. Given that plasma NE is expected to double in response to these challenges in both normal control subjects and in depressed patients (cf.
Publishers
Ireland
Ltd.
292 Roy et al., 1985; Rudorfer et al., 1985), it is presumed that other intervening variables, such as elevated baseline anxiety, may have contributed to these few abnormal individuals; it was therefore decided to eliminate them from further analysis. Consequently, the data from 12 acutely depressed patients, 7 remitted depressed patients, and 10 normal control subjects entered subsequent analyses. No significant differences were observed in any demographic or clinical variable assessed between the groups, other than the HRSD score (Table 1). Furthermore, basal plasma NE did not correlate significantly with age or weight in any of the three groups. No significant differences were found in supine basal plasma NE concentrations between the acute and remitted depressed patients (including or excluding the bipolar patients) and the normal control subjects. Repeated measures analysis of covariance revealed a significant plasma NE response difference between groups over the two tasks, whether covarying for baseline plasma NE alone (group X NE interaction: F = 5.58; df= 2, 26; p < 0.01) or also covarying for baseline pulse (group X NE interaction: F = 4.83; df = 2, 23; p < 0.02); no significant group differences were observed in pulse or blood pressure responses. In subsequent, more specific comparisons of plasma NE responses to the individual challenges, it was observed that (1) standing (an orthostatic challenge) did not differentiate groups, while (2) isometric exertion, covarying for plasma NE after standing ( F = 5. I I ; df = 2, 25; p < 0.02), or covarying for plasma NE at baseline and after standing (F = 4.78; df = 2,24; p < 0.02) did significantly differentiate between groups. Paired comparisons revealed statistically significant differences only between normal control subjects and acutely depressed patients, whether covarying for standing plasma NE levels alone (F = 7.53; df = 1, 19; p < 0.02) or for baseline and standing plasma NE levels (F = 7.3 1; df = I, 18; p < 0.02). The HRSD score did not correlate with plasma NE response in either the acute or remitted depressed patients. It appears that depressed patients, when shifting from a primarily fixed demand task (e.g., standing) to a voluntary task (e.g., isometric exertion), do not respond appropriately to the demand requirements of the voluntary task. This measure is thus sensitive to
Table 1. Subject characteristics and plasma norepinephrine responses (mean f SD) Acute Remitted Normal depressed depressed control (h=12) (i= 7) (n=lO) (range1
58.4zt7.6 40-73
Weight (kg)
71.3zt8.6
&X5.0&118.681.3 f12.3
43.7zt30.1
57.81t40.2
-
28.01t5.8
3.61-3.7
-
21 .O-38.5
0.0-8.0
25%
28%
Age WI
53.5k5.9 45-59
50.3zti 3.3 33-65
Days not receiving any medication Hamilton score’ (range) Bipolar depression
-
Plasma norepinephrine(pmoles/ml): Basal
1.4210.64
Standing
3.301b1.32 3.30f1.25
1.24kO.40
2.9111.12
After exertion
4.18k1.22
4.8711.64
4.381t1.28
1.4850.69
the NE response to both tasks. A combination of increased NE response to the fixed demand task (a finding consistent with some previous studies, e.g., Roy et al., 1985; Rudorfer et al., 1985) and decreased response to the effortful task may have contributed to the significantly reduced plasma NE response from the end of the orthostatic challenge to the end of the isometric exertion. Such a result might be expected if the acutely depressed patients simply were less motivated and therefore exerted less effort than did the normal control subjects. While one study that used a hand dynamometer found illness severity to correlate inversely with both maximal effort and the duration of half-maximal exertion in depression (Cohen et al., 1982) in this study illness severity did not relate to plasma NE response in either acutely depressed or remitted depressed patients. It is also of note that the findings do not fully replicate those of two previous studies that found significantly increased responses to orthostatic challenge in acute depression: one study. however, only examined women (Rudorfer et al., 1985) and the second included 75% women (Roy et al., 1985). while the present study included only men.
293 Our preliminary findings of state-dependent alterations in the noradrenergic system in response to a naturalistic challenge are consistent with an overt dysregulation of this system in acute depression that tends to normalize when patients are in remission (Siever and Davis, 1985; Trestman et al., 1992). The stateindependent growth hormone response to clonidine (a centrally mediated postsynaptic a,-agonist), in contrast, may reflect a persisting, centrally mediated vulnerability to depression in these patients (Siever et al., 1992). This work was supported in part by a grant from the National Institute of Mental Health(5ROl MH-41131) and by a grant from the National Institutes of Health (RR-00071) for the Mt. Sinai General Clinical Research Center. Acknowledgement.
References Cohen, R.M.; Weingartner, H.; Smallberg, S.A.; Pickar, D.; and Murphy, D.L. Effort and cognition in depression. Archives of General
Psychiatry,
39:593-597,
1982.
Endicott, J., and Spitzer, R.L. A diagnostic interview: Schedule for Affective Disorders and Schizophrenia. Archives of General Psychiatry,
35:837-844,
1978.
Gold, P.W.; Goodwin, F.K.; and Chrousos, G.P. Clinical and biochemical manifestations of depression: II. Relation to the neurobiology of stress. New England Journal of Medicine, 319:413-420, 1988. Guy, W., ed. ECDEU for Psychopharmacology,
Assessment Revised.
Manual
(DHEW Publication No. [ADM] 76-338) Washington, DC: Superintendent of Documents, U.S. Government Printing Office, 1976. Hallman, H.; Farnebo, L.; Hamberger, B.; and Jonsson, G. A sensitive method for the determination of plasma catecholamines using liquid chromatography with electrochemical detection. Life Sciences, 23:1049-1052, 1978. Roy, A.; Pickar, D.; Linnoila, M.; and Potter, W.Z. Plasma norepinephrine level in affective disorders: Relationship to melancholia. Archives of General Psychiatry, 42: 1181-l 185, 1985. Rudorfer, M.V.; Ross, R.J.; Linnoila, M.; Sherer, M.A.; and Potter, W.Z. Exaggerated orthostatic responsivity of plasma norepinephrine in depression. Archives of General
Psychiatry,
42:1186-l
192, 1985.
Siever, L.J., and Davis, K.L. Overview: Toward a dysregulation hypothesis of depression. American Journal of Psychiatry, 142:1017-1031,
1985.
Siever, L.J.; Trestman, R.L.; Coccaro, E.F.; Bernstein, D.P.; Gabriel, S.M.; Owen, K.; Moran, M.; Lawrence, T.L.; Rosenthal, J.; and Horvath, T.B. The growth hormone response to clonidine in acute and remitted depressed male patients. Neuropsychopharmacology,
6:165-177,
1992.
Trestman, R.L.; Lawrence, T.L.; Coccaro, E.F.; Harvey, P.; Bernstein, D.; Lawrence, E.K.; Condello, V.; Mahon, T.; Yang, R.-K.; Knott, P.; Horvath, T.B.; and Siever, L.J. Noradrenergic responses to clonidine in acute and remitted depressed male patients. Psychiatry Research,
43:199-213,
1992.
Robert L. Trestman, Ph.D., M.D.1 Department of Psychiatry Bronx Denartment of Veterans Affairs Medical Center and Mt. Sinai School of Medicine New York NY Emil F. Coccaro.
M.D. Department of Psychiatry Medical College of Pennsylvania Philadelphia, PA
Mina Apovian, B.A. Mt. Sinai School of Medicine New York, NY David Bernstein, Ph.D. Timothy Lawrence, M.D. Peter Knott, Ph.D.
Bronx Department Medical Center Bronx, NY Thomas
B. Horvarh,
Brooklyn Department Medical Center Brooklyn, NY
of Veterans
Affairs
M.D. of Veterans
Affairs
Larry J. Sever, M.D. Department of Psychiatry Bronx Department of Veterans Affairs Medical Center and Mt. Sinai School of Medicine New York, NY December
12, 1992
1. Reprint requests to Dr. R.L. Trestman, Psychiatry Service, 116A, Bronx DVA Medical Center, 130 W. Kingsbridge Rd., Bronx, NY 10468, USA.