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The effect of oral dextroamphetamine on plasma cortisol in major depressive disorder
634
RIOL PSYCHIATRY 1989:20x534-636
BRIEF REPORTS
The Effect of Oral Dextroamphetamine Cortisol in Major Depressive Disorder
on Plasma
E.D. Myers
Introduction The hypersecretion of cortisol that occurs in some depressed patients (Sachar et al. 1973; Carroll et al. 1976) can be transiently corrected by dextroamphetamine administered intravenously (Sachar et al. 1980). In normal subjects, lo-20 mg oral dextroamphetamine causes an increase in plasma cortisol at a time when a decrease would be consistent with the normal diurnal variation (Brown et al. 1978). This study examines the effect of IO-20 mg oral dextroamphetamine on plasma cortisol level in depressed patients acting as their own controls.
Method The subjects were 12 consecutive inpatients suffering from major depressive disorder diagnosed according to DSM-III, medically healthy, and aged between 20 and 65 years. They received no antidepressive medication before testing but minor tranquilizers and benzodiazepine hypnotics were prescribed as required, A full physical examination, biochemical screen, and electrocardiogram were carried out, and informed consent to participate in the study was obtained from the subjects. Hamilton (1960) and Newcastle (Camey and Sheffield 1972) ratings were carried out within 2 days of admission.
Postgraduate Medicine, University of Keele, North Staffordshire. England. Address reprmt requests to Department of Postgraduate Medicine. University of Keele. Tbombumxv Drive. Hartshill, Stoke on Tent, ST4 7QB England. Received October 25. 1988: revised April 1I, 1989.
r;rirmthe Depattmentof
I(” 19X9 Society of Biological P\ychratry
With the subjects acting as their own controls, testing was carried out on 2 consecutive days as follows: 9:00 AM: Blood was taken for plasma cortisol, followed immediateIy by administration of 10-20 mg oral dextroamphetamine or identical placebo (Kindly supplied by Smith, Kline and French Laboratories Limited). lo:30 AW Blood was taken for plasma cortisol. The order of administration of dextroamphetamine and placebo (i.e., day 1 or 2) was randomized and the double-blind procedure was carried out, the key being held by the pharmacy. The interval of 90 min between the administration of the drug or placebo and the second blood sample was in accord with the work of Brown et al. ( 1978) who found that after oral dextroamphetamine, changes in plasma cortisol peaked at between 75 and 105 min. Total cortisol was estimated by radioimmunoassay using the Amerlex Cortisol RIA kit. Statistical analysis was by two-way analysis of variance (ANOVA), with drug and order of administration as main effects.
Results The details of the 12 subjects and the changes in plasma cortisol after dextroamphetamine and placebo are shown in Table 1. As 10 mg dextroamphetamine had caused no untoward effects, it was decided to increase the dose to 20 mg for subjects I 1 and 12 to increase the magnitude of any differential effect.
0006.3223!K9:$03.50
BIOL PSYCHIATRY 1989;26:634-636
Brief Reports
Table 1, Changes in Plasma Cortisol Levels Between 9:00 After Placebo and ~xtroamphetamine
CW2 no.
Gender
I 2 3 4 5 6 7 8 9 I0 II 12
F F M F F F M M F F M F
AM
and lo:30
DA Age
(mg)
Hr
NS
61 27 60 43 61 40 44 64 38 47 33 29
10 10 IO 10 IO 10 IO IO 10 10 20 20
I9 27 22 19 26 I3 14 18 19 20 I9 I4
3 3 5 2 7
Mean change in plasma cortisol
1 -I 8 4 6 3
635
AM
P (nmoi/liter)
D (nm~I/litcr)
+55 - 100 +213 + 224 -73 + 139 - 126 + 149 + 18 -38 -58 -39 1-30.3
- 192 - 240 - 17 + 148 - 290 +64 - 19 +214 - 193 + I7 - 66 - 150 ~ 60.7
DA, dose of dextroamphetamine: HI: Hamilton rating scale: NS: Newcastle scale; P: placebo: D: dextroamphetamine. ANOVA (effect of drug as independent variable): F = 6.618 p i 0.05.
For 9 of the 12 subjects, dextroamphetamine was followed by either a greater fall or lesser rise in plasma cortisol than the change in level following placebo. By ANOVA, the effect on the change in plasma cortisol after dextroamphetamine compared to the change after placebo was statistically signi~cant (F = 6.6 16, p < 0.05). The effect of order of administration was not significant nor was interaction between drug effect and order of administration. Inspection of the results indicated no relation between the changes in plasma cortisol and severity as rated by the Hamilton scale or allocation to endogenous or reactive category according to the Newcastle scale.
Discussion In this study, the administration of lo-20 mg dextroamphetamine was followed, in patients suffering from major depressive disorder, by a statistically significant decrement in plasma cortisol level between 9.00 AM and 10.30 AM compared to the change in level following the administration of identical placebo. This is consistent with the work of Sachar et al. (1980)
who found that intravenous dextroamphetamine reduced the cortisol level in depressed patients. It also contrasts approp~ately with the finding of Brown et al. ( 1978) that oral dextroamphetamine in normal subjects causes an increase in plasma cortisol compared to the normal diurnal variation. The findings are also consistent with those of Sachar et al. (1981) who found that dextroamphetamine administered intravenously in the morning and evening to 22 unmedicated patients with endogenous depression was followed by relative suppression of cortisol response compared with the effect in IX normal control. subjects. The small numbers preclude an analysis of the effects of age and gender; however, as the design of the study was a within-patient one, it is unlikely that effects of age and gender would alter the conciusions. As dextroamphetamine is considered to be principally noradrenergic in action, it might be that in the 3 subjects (nos. 7, 8. and 10) who did not show the relative decrement in plasma cortisol level, the depression was associated with disturbance in other than noradrenergic pathways. Van Kammen and Murphy ( 1978) and
636
Brief Reports
BIOL PSYCHIATRY 1989:26:634-636
Fawcett and Siomopoulos (1971) found a strong association between a positive behavioral response to dextroamphetamine and subsequent treatment response to imipramine and desipramine-both noradrenergic antidepressants. Ettigi et al. (1982)) on the other hand, in a 4-week trial with desipramine, found no such association. The disparity may be due to the difficulties inherent in rating behavioral responses. If the changes described in the present work can be confirmed in a larger sample, the technique may provide a more objective method for investigating, in patients suffering from depressive disorders, the associations between the effect of a single oral dose of dextroamphetamine and the subsequent response to a course of an antidepressant. I am obliged to Mr. N.S. Brown and Mr. H. Scott Drummond for helpful advice and for carrying out the cortisol assays, to Dr. S. Jones for the statistical analysis, and to Louise Ellis for secretarial assistance. I also thank Dr. Kumara Chandran for help in the initial stages of the work.
References Brown WA, Corriveau DP, Ebert MH (1978): Acute psychologic and neuroendocrine effects of dextroamphetamine and methylphenidate. Psychopharmaco&y 58: 189-J 95.
Camey MWP, Sheffield BF (1972): Depression and the Newcastle scales: Their relationship to Hamilton’s scale. Br J Psychiatry 12 1:35-40. Carroll BJ, Curtis CC, Mendels J (1976): Neuroendocrine regulation in depression. Arch Can Psychiatry 33: 1039-1044.
Ettigi PG. Hayes PE, Narasimachari N, Hamer RM, Goldberg S, Secord GJ (1982): d-Amphetamine response and dexamethasone suppression test as predictors of treatment outcome in unipolar depression. Biol Psych&T 18:499-504. Fawcett J, Siomopoulos V (1971): Dextroamphetamine response as a possible predictor of improvement with tricyclic therapy in depression. Arch Gen Psychiatr?, 251247-255.
Hamilton M (1960): A rating scale for depression. J Neural Neurosurg Psychiatry 23~56-62.
Sachar EJ, Asnis GM, Nathan RS, Halbreich U, Tabrizi MA, Halpem FS (1980): Dextroamphetamine and cortisol in depression. Arch Gen Psychiatry 37:755-757.
Sachar EJ, Hellman L. Roffwarg HP, Halpern FS, Fukushima DK, Gallagher TF (1973): Disrupted 24-hour patterns of cortisol secretion in depression. Arch Gen Psychiatry 28:19-24. Sachar EJ, Halbreich U, Asnis GM, Nathan RS, Halpem FS, Ostrow L (198 I ): Paradoxical cortisol responses to dextroamphetamine in endogenous depression. Arch Gen Psychiatry 38: I 113-I I 17. Van Kammen DP, Murphy DL (1978): Prediction in imipramine antidepressant response by a one day d-amphetamine trial. Am J Psych&q 135: 1 1791184.
RIOL PSYCHIATRY 1989:20x534-636
BRIEF REPORTS
The Effect of Oral Dextroamphetamine Cortisol in Major Depressive Disorder
on Plasma
E.D. Myers
Introduction The hypersecretion of cortisol that occurs in some depressed patients (Sachar et al. 1973; Carroll et al. 1976) can be transiently corrected by dextroamphetamine administered intravenously (Sachar et al. 1980). In normal subjects, lo-20 mg oral dextroamphetamine causes an increase in plasma cortisol at a time when a decrease would be consistent with the normal diurnal variation (Brown et al. 1978). This study examines the effect of IO-20 mg oral dextroamphetamine on plasma cortisol level in depressed patients acting as their own controls.
Method The subjects were 12 consecutive inpatients suffering from major depressive disorder diagnosed according to DSM-III, medically healthy, and aged between 20 and 65 years. They received no antidepressive medication before testing but minor tranquilizers and benzodiazepine hypnotics were prescribed as required, A full physical examination, biochemical screen, and electrocardiogram were carried out, and informed consent to participate in the study was obtained from the subjects. Hamilton (1960) and Newcastle (Camey and Sheffield 1972) ratings were carried out within 2 days of admission.
Postgraduate Medicine, University of Keele, North Staffordshire. England. Address reprmt requests to Department of Postgraduate Medicine. University of Keele. Tbombumxv Drive. Hartshill, Stoke on Tent, ST4 7QB England. Received October 25. 1988: revised April 1I, 1989.
r;rirmthe Depattmentof
I(” 19X9 Society of Biological P\ychratry
With the subjects acting as their own controls, testing was carried out on 2 consecutive days as follows: 9:00 AM: Blood was taken for plasma cortisol, followed immediateIy by administration of 10-20 mg oral dextroamphetamine or identical placebo (Kindly supplied by Smith, Kline and French Laboratories Limited). lo:30 AW Blood was taken for plasma cortisol. The order of administration of dextroamphetamine and placebo (i.e., day 1 or 2) was randomized and the double-blind procedure was carried out, the key being held by the pharmacy. The interval of 90 min between the administration of the drug or placebo and the second blood sample was in accord with the work of Brown et al. ( 1978) who found that after oral dextroamphetamine, changes in plasma cortisol peaked at between 75 and 105 min. Total cortisol was estimated by radioimmunoassay using the Amerlex Cortisol RIA kit. Statistical analysis was by two-way analysis of variance (ANOVA), with drug and order of administration as main effects.
Results The details of the 12 subjects and the changes in plasma cortisol after dextroamphetamine and placebo are shown in Table 1. As 10 mg dextroamphetamine had caused no untoward effects, it was decided to increase the dose to 20 mg for subjects I 1 and 12 to increase the magnitude of any differential effect.
0006.3223!K9:$03.50
BIOL PSYCHIATRY 1989;26:634-636
Brief Reports
Table 1, Changes in Plasma Cortisol Levels Between 9:00 After Placebo and ~xtroamphetamine
CW2 no.
Gender
I 2 3 4 5 6 7 8 9 I0 II 12
F F M F F F M M F F M F
AM
and lo:30
DA Age
(mg)
Hr
NS
61 27 60 43 61 40 44 64 38 47 33 29
10 10 IO 10 IO 10 IO IO 10 10 20 20
I9 27 22 19 26 I3 14 18 19 20 I9 I4
3 3 5 2 7
Mean change in plasma cortisol
1 -I 8 4 6 3
635
AM
P (nmoi/liter)
D (nm~I/litcr)
+55 - 100 +213 + 224 -73 + 139 - 126 + 149 + 18 -38 -58 -39 1-30.3
- 192 - 240 - 17 + 148 - 290 +64 - 19 +214 - 193 + I7 - 66 - 150 ~ 60.7
DA, dose of dextroamphetamine: HI: Hamilton rating scale: NS: Newcastle scale; P: placebo: D: dextroamphetamine. ANOVA (effect of drug as independent variable): F = 6.618 p i 0.05.
For 9 of the 12 subjects, dextroamphetamine was followed by either a greater fall or lesser rise in plasma cortisol than the change in level following placebo. By ANOVA, the effect on the change in plasma cortisol after dextroamphetamine compared to the change after placebo was statistically signi~cant (F = 6.6 16, p < 0.05). The effect of order of administration was not significant nor was interaction between drug effect and order of administration. Inspection of the results indicated no relation between the changes in plasma cortisol and severity as rated by the Hamilton scale or allocation to endogenous or reactive category according to the Newcastle scale.
Discussion In this study, the administration of lo-20 mg dextroamphetamine was followed, in patients suffering from major depressive disorder, by a statistically significant decrement in plasma cortisol level between 9.00 AM and 10.30 AM compared to the change in level following the administration of identical placebo. This is consistent with the work of Sachar et al. (1980)
who found that intravenous dextroamphetamine reduced the cortisol level in depressed patients. It also contrasts approp~ately with the finding of Brown et al. ( 1978) that oral dextroamphetamine in normal subjects causes an increase in plasma cortisol compared to the normal diurnal variation. The findings are also consistent with those of Sachar et al. (1981) who found that dextroamphetamine administered intravenously in the morning and evening to 22 unmedicated patients with endogenous depression was followed by relative suppression of cortisol response compared with the effect in IX normal control. subjects. The small numbers preclude an analysis of the effects of age and gender; however, as the design of the study was a within-patient one, it is unlikely that effects of age and gender would alter the conciusions. As dextroamphetamine is considered to be principally noradrenergic in action, it might be that in the 3 subjects (nos. 7, 8. and 10) who did not show the relative decrement in plasma cortisol level, the depression was associated with disturbance in other than noradrenergic pathways. Van Kammen and Murphy ( 1978) and
636
Brief Reports
BIOL PSYCHIATRY 1989:26:634-636
Fawcett and Siomopoulos (1971) found a strong association between a positive behavioral response to dextroamphetamine and subsequent treatment response to imipramine and desipramine-both noradrenergic antidepressants. Ettigi et al. (1982)) on the other hand, in a 4-week trial with desipramine, found no such association. The disparity may be due to the difficulties inherent in rating behavioral responses. If the changes described in the present work can be confirmed in a larger sample, the technique may provide a more objective method for investigating, in patients suffering from depressive disorders, the associations between the effect of a single oral dose of dextroamphetamine and the subsequent response to a course of an antidepressant. I am obliged to Mr. N.S. Brown and Mr. H. Scott Drummond for helpful advice and for carrying out the cortisol assays, to Dr. S. Jones for the statistical analysis, and to Louise Ellis for secretarial assistance. I also thank Dr. Kumara Chandran for help in the initial stages of the work.
References Brown WA, Corriveau DP, Ebert MH (1978): Acute psychologic and neuroendocrine effects of dextroamphetamine and methylphenidate. Psychopharmaco&y 58: 189-J 95.
Camey MWP, Sheffield BF (1972): Depression and the Newcastle scales: Their relationship to Hamilton’s scale. Br J Psychiatry 12 1:35-40. Carroll BJ, Curtis CC, Mendels J (1976): Neuroendocrine regulation in depression. Arch Can Psychiatry 33: 1039-1044.
Ettigi PG. Hayes PE, Narasimachari N, Hamer RM, Goldberg S, Secord GJ (1982): d-Amphetamine response and dexamethasone suppression test as predictors of treatment outcome in unipolar depression. Biol Psych&T 18:499-504. Fawcett J, Siomopoulos V (1971): Dextroamphetamine response as a possible predictor of improvement with tricyclic therapy in depression. Arch Gen Psychiatr?, 251247-255.
Hamilton M (1960): A rating scale for depression. J Neural Neurosurg Psychiatry 23~56-62.
Sachar EJ, Asnis GM, Nathan RS, Halbreich U, Tabrizi MA, Halpem FS (1980): Dextroamphetamine and cortisol in depression. Arch Gen Psychiatry 37:755-757.
Sachar EJ, Hellman L. Roffwarg HP, Halpern FS, Fukushima DK, Gallagher TF (1973): Disrupted 24-hour patterns of cortisol secretion in depression. Arch Gen Psychiatry 28:19-24. Sachar EJ, Halbreich U, Asnis GM, Nathan RS, Halpem FS, Ostrow L (198 I ): Paradoxical cortisol responses to dextroamphetamine in endogenous depression. Arch Gen Psychiatry 38: I 113-I I 17. Van Kammen DP, Murphy DL (1978): Prediction in imipramine antidepressant response by a one day d-amphetamine trial. Am J Psych&q 135: 1 1791184.