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The neuroendocrine response to fenfluramine in depressives and normal controls
BIOL PSYCHIATRY 1988;24:117-120
117
The Neuroendocrine Response to Fenfluramine in Depressives and Normal Controls Gregory M. Asnis, Jacques
Eisenberg
, Herman M. van Praag ,
Carmen 2. Lemus, Jill M. Harkavy Friedman, and Andrew H. Miller
Introduction Disturbances of central nervous system serotonin (5hydroxytryptamine, 5-HT) activity have been hypothesized to be associated with disturbances in mood, anxiety, and aggression regulation (Gardner 1985; van Praag 1985). Although the most direct assessment of central 5HT is via measurement of 5-hyroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) and in postmortem studies of 5-HT and 5-HIAA in the brain, difficulties in using these methods as a practical clinical evaluation of 5-HT are obvious. The development of an easily useable peripheral probe of central 5-HT activity to study 5-HT in psychiatry is essential. The most practical clinical method in studying monoamine (MA) neurotransmitters is the use of hormone challenge methods. Each peripheral hormone is regulated by hypothalmic peptides (inhibitory and/or stimulatory factors), which are in turn regulated by various MA neurotransmitters. As 5-HT is stimulatory to prolactin (PRL) and cortisol in humans (found in most, but not all,
From Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, and Jerusalem Mental Health Center (J.E.), Ekrath Nashim, Jerusalem, Israel. Supported in part by NIMH Grant MH ROI-33807, the Dorothy and Marty Silverman Chair in Psychiatry, and the Ruane Foundation. Address reprint requests to Dr. G. M. Ask, Department of Psychiahy; Montefiore Medical Center; I I1 East 210th Street, Bronx, NY 10467. Received March 31. 1987; revised October 5, 1987.
0 1988 Society of Biological
Psychiatry
studies) (Murphy et al. 1986; van Praag et al. 1986), one is able to administer a 5-HT agonist/antagonist, measure these easily accessible peripheral hormones, and learn about the functional state of central 5-HT systems. We were particularly interested in studying the neuroendocrine responses to fenfluramine, an anorexic agent releasing intraneuronal 5-I-IT and inhibiting 5-HT uptake (Rowland and Carlton 1986), as a possible 5-HT probe. The literature suggested that fenfluramine in low doses (< 120 mg/day) was highly selective for 5-HT (Shoulson and Chase 1975) and induced a dosedependent PRL and cortisol release (Murphy et al. 1986). Recently, Siever et al. (1984) reported that fenfluramine (60 mg orally) induced a significantly smaller PRL release in a group of depressives as compared to a group of normal controls, which is consistent with the 5-HT deficit hypothesis of depression.
Methods Fifteen depressed patients and 10 normal controls were studied as outpatients in an affective disorders clinic. The depressives (3 men and 12 women, mean age 49.5 + 15.2 years) did not differ significantly from the normal controls (4 men and 6 women, mean age 39.6 -+ 13.5 years) in regard to sex distribution (p = 0.38, Fisher’s Exact Test) or age (t = 1.66, p NS). All subjects were interviewed by a trained rater with 0006-3223t88tSO3.50
BIOL PSYCHlAl’R\ 14XX:?4~117-IX
IIX
Brief Reports
the Schedule for Affective Disorders and Schizophrenia (Endicott and Spitzer 1978); the patients received a diagnosis of major depressive disorder by Research Diagnostic Criteria (Spitzer et al. 1978), and the normals met criteria for “never mentally ill.” The depressives were mild to moderately ill, with a mean extracted Hamilton score of 20.4 i 5.8 (a range of 12-33) (Endicott et al. 198 1). All subjects had normal physical examinations and laboratory assessments, including thyroid indices. All subjects were drug free for a minimum of 3 weeks and had taken no steroids or birth control pills for at least 6 months. The subjects fasted from midnight. The following day, subjects awakened at 7:00 AM and came to the clinic for the procedure. A butterfly needle was inserted into a forearm vein at 9:00 AM and was kept patient with heparinized saline. Samples (4 ml) for plasma hormones (cortisol and PRL) were drawn at - 30 min and 0 time, just before the oral administration of 60 mg of fenfluramine, and every 30 min thereafter for 4 hr. A small group of depressives (n = 5), stud-
ied above, were studied again after being treated for 2 weeks with desipramine (lW150 mg/day). Plasma PRL and cortisol were assessed via a radioimmunoassay kit (Diagnostic Products. Los Angeles, CA). The interassay coefficient of variation for duplicate samples was 7.1% for a PRL pool of 21.5 ng/ml and 6.8% for a cortisol pool of 3.1 ng/ml.
Results The PRL and cortisol response to 60 mg fenBuramine over 240 min is shown in Fig 1. A repeated measures ANOVA was performed on the group and time effects, covarying out age. There was a main effect for time on both PRL (F = 13.57, df = 9,249, p < 0.0001) and cortisol (F = 8,30, df = 9,249, p < 0.0001). but no group effect for PRL (F = 2.10, df = l,249,pNS)orcortisol(F = 2.38,df = 1,249, p NS) and no group x time interaction for PRL (F = 1.33, df = 9,249, p NS) or cortisol (F = 1.06, df = 9,249, p NS). Age was a highly significant covariate for PRL (F = 23.86, df = 2,249, p < 0.0001) and for cortisol (F =
22 IE
0 Normals 0 Deprersivrs
2
I
0
60
120
180
240
Time ( mind
2
i
1
.
0
60
120
180
240
Time (minr)
Figure I. The prolactin and cortisol response (mean k SD) to fenfluramine (60 mg) over 240 min in a group of depressives
(n = 151 and normal controls (n = IO).
119
BlOL PSYCHIATRY
Brief Reports
1988;24:117-120
58.82, df = 2,249, p < 0.0001). Age was negatively correlated with PRL in the normal controls at 180 min (r = 0.73, p < 0.02) and 210 min (r = -0.79, p < O.Ol), and was positively correlated with cortisol in the depressives at 30 min (r = 0.52, p < 0.05) at 60 min (r = 0.68, p < O.OOS),at 90 min (r = 0.74, p < 0.002), at 120 min (r = 0.72, p < 0.002), at 150 min (r = 0.58, p < 0.02), and at 180 min (r = 0.51, p < 0.05). Figure 2 demonstrates the PRL and cortisol response to 60 mg fenfluramine while drug free and again after 2 weeks of desipramine; t-tests for correlated means found no significant differences for either hormone at any time point.
Discussion Fenfluramine, the 5-HT probe used in this study, failed to differentiate depressives from normal controls in regard to PRL and cortisol release. These findings fail to replicate those of Siever et al. (1984) who found that depressives had a significantly smaller PRL response to fenfluramine than normal controls, which is consistent with the 5-HT hypothesis.
There are several possible explanations regarding these discrepant findings. First, we studied depressed outpatients, in contrast to Siever et al. (1984) who studied depressed inpatients. Studies of biological markers for depression have found that depressed inpatients demonstrate the most abnormal responses, with depressed outpatients frequently appearing no different than normal controls (eg. DST, TRH-TSH test) (Amsterdam et al. 1985; Arana et al. 1985; McGrath et al. 1985). Furthermore, most of our patients were unipolar depressives (3 of 15), in contrast to those of Siever et al. (1984) who were predominantly bipolar depressives (12 of 18 patients). Bipolarity may be a significant factor in serotonin dysfunction. This is supported by recent findings of Meltzer et al. ( 1984), who found that the cortisol response of oral 5-HTP, another serotonergic probe, was significantly greater in bipolar versus unipolar depression. Our negative findings may also be related to the 5-HT probe chosen. Fenfluramine is not as selective for 5-HT as originally described, and thus, may have obscured identification of a biochemically distinct subgroup; the racemic form of fenfluramine used in this study is not as se-
0 Drug Free 0 DMI 18. 3i ‘f ._ t 0”
14-
IO6.
4
0
60
I20
timo(mind
I80
240
I
4
0
60
120
I80
240
Timohinrl
Figure 2. The prolactin and cortisol response (mean ? SD) to fenfluramine (60 mg) over 240 min in a group of depressives (n = 5) while drug free and again after 2 weeks of desipramine treatment (lOO-150 mg).
BIOL PSYCHIATRY IY8X;XI 17 170
lective for S-HT as d-fenfluramine and releases dopamine and corepinephrine as well (Rowland and Carlton 1986). Further evidence in our study questioning whether or not fenfluramine is a selective 5-HT probe is the failure to demonstrate an augmented neuroendocrine response to fenfuramine in depressives treated with desipramine (100-150 mg) for 2 weeks. The sensitivity of S-HT postsynaptic area in the brain to iontophoretic S-HT is augmented with chronic tricyclic antidepressant treatment (including more norepinephrine-specific drugs, like desipramine) (Chamey et al. 1981). Consistent with this, and in contrast to our findings with fenfluramine, chronic desipramine treatment (>2 weeks) increased the PRL response to a 5-HT precursor, 1V tryptophan (Chamey et al. 1984; Corven et al. 1986). An interesting finding was that age was significantly related to the neuroendocrine responses to fen~uramine: age was positively correlated with the cortisol response in depressives and negatively correlated with the prolactin response in normal controls. The latter was recently reported by McBride et al. ( 1986). The full meaning of the age relationships within each group needs further study.
References
Brief Reports
Corven PJ, Geaney DP, Schachter M, Green R, Elliot M (1986): Desipramine treatment in normal subjects: Effects of neuroendocrine responses to tryptophan and on platelet serotonin (J-HT)-related receptors. Arch Gen Psychiatry 43:6 147. Endicott J, Spitzer RL f 1978): A diagnostic interview: The Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 35:837-844. Endicott J, Nee J, Cohen J, Fleiss J, Sarantakof F (1981): Hamilton Depression Rating Scale extracted from Schedule for Affective Disorder and Schizophrenia and SADS-C. Arch Gen Psyeh~ar~ 38:98-103. Gardner CR (1985): Ph~acoiogical studies of the role of serotonin in animal models of anxiety. In Green AR (ed), Neuropharmaccllogy of Serotonin. Oxford: University Press, pp 281-325. McBride PA, Kream J, Anderson G, Mann JJ (1986): Effect of age. upon measures of central and peripheral serotonergic function in human subjects. Presented at the Annual Meeting of the Society for Neuroscience. McCrath PJ, Quitkin FM, Stewart JW, Novacenko H, PuigAntich J, Asnis GM (1985): A comparative study of the pituitary TSH response to thyrotropin in outpatient depressives. Psychiarv Res 140:245-247. Meltzer HY, Pedine R, Tricou BJ, Lowy M, Robertson A ( 1984): Effect of 5-hyd~x~~toph~ on serum cortisol levels in major affective disorders. II. Relation to suicide, psychosis, and depressive symptoms. Arch Gen Ps_ychiatv 42:379-387. Murphy DL, Mueller EA, Garrick NA, Aulakh CS (1986): Use of serotonergic agents in the clinical assessment of central serotonin function. J Clin Psychiatry 47:9-l 3. Rowland NE, Carlton J (1986): Neurobiology of an anorectic drug: Fenfluramine. Prog ~~ara~ia~ 27: 13-62. Shoulson I, Chase TN (1975): Fenfluramine in man: Hypophagia associated with diminished serotonin turnover. Clin Pharmacol Ther 171616-62 1.
Amsterdam JD, Winokur A, Caroff SN, Conn J (1985): The Dexamethasone Suppression Test in outpatients with primary affective disorder and healthy control subjects. Am J Psyrhiatry 139:287-29 1.
Siever LJ, Murphy DL. Slater S, deLaVega E, Lipper S (1984): Plasma prolactin changes following fenfluramine in depressed patients compared to controls: .An evaluation of central serotonergic responsivity in deprtsaion. Life Sci 34:1029-1039.
Arana GW, Baldessarini RJ, Omsteen M (198.5): The Dexamethasone Suppression Test for diagnosis and prognosis in psychiatry. Commentary and review. Arch Gen Psychiatry 42:1193-1204.
Spitzer RL, Endicott J, Robins E (1978): Research Diagnostic Criteria: Rationale and reliability. Arch Gen Psychiatty 35~773-182.
Chamey DS, Menkes DB, Heninger GR (1981): Receptor sensitivity and the mechanism of action of antidepressant treatment. Arch Gen Psychiatry 38:1160-1180. Charney DS, Heninger GR, Stemberg DE (1984): Serotonin function and mechanism of action of antidepressant treatment: Effect of amitriptyline and desipramine. Arch Gen Psychiatry 41:359-365.
van Praag HM (1985): Brain serotonin, mood-regulation and aggression-re~uiation. Pichot P, Brenner P, Wolf R. Thii K (eds),?‘sychiatry, the State of the Art. vol. 2 Biological Psychiatry, Higher Nervous Activify. New York: Plenum Press, pp 327-339. van Praag HM, Lemus C, Kahn R (1986): Hormonal probes of central serotonergic activity. Do they really exist? Biol Psychiatr,y 22:R6-98.
117
The Neuroendocrine Response to Fenfluramine in Depressives and Normal Controls Gregory M. Asnis, Jacques
Eisenberg
, Herman M. van Praag ,
Carmen 2. Lemus, Jill M. Harkavy Friedman, and Andrew H. Miller
Introduction Disturbances of central nervous system serotonin (5hydroxytryptamine, 5-HT) activity have been hypothesized to be associated with disturbances in mood, anxiety, and aggression regulation (Gardner 1985; van Praag 1985). Although the most direct assessment of central 5HT is via measurement of 5-hyroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) and in postmortem studies of 5-HT and 5-HIAA in the brain, difficulties in using these methods as a practical clinical evaluation of 5-HT are obvious. The development of an easily useable peripheral probe of central 5-HT activity to study 5-HT in psychiatry is essential. The most practical clinical method in studying monoamine (MA) neurotransmitters is the use of hormone challenge methods. Each peripheral hormone is regulated by hypothalmic peptides (inhibitory and/or stimulatory factors), which are in turn regulated by various MA neurotransmitters. As 5-HT is stimulatory to prolactin (PRL) and cortisol in humans (found in most, but not all,
From Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, and Jerusalem Mental Health Center (J.E.), Ekrath Nashim, Jerusalem, Israel. Supported in part by NIMH Grant MH ROI-33807, the Dorothy and Marty Silverman Chair in Psychiatry, and the Ruane Foundation. Address reprint requests to Dr. G. M. Ask, Department of Psychiahy; Montefiore Medical Center; I I1 East 210th Street, Bronx, NY 10467. Received March 31. 1987; revised October 5, 1987.
0 1988 Society of Biological
Psychiatry
studies) (Murphy et al. 1986; van Praag et al. 1986), one is able to administer a 5-HT agonist/antagonist, measure these easily accessible peripheral hormones, and learn about the functional state of central 5-HT systems. We were particularly interested in studying the neuroendocrine responses to fenfluramine, an anorexic agent releasing intraneuronal 5-I-IT and inhibiting 5-HT uptake (Rowland and Carlton 1986), as a possible 5-HT probe. The literature suggested that fenfluramine in low doses (< 120 mg/day) was highly selective for 5-HT (Shoulson and Chase 1975) and induced a dosedependent PRL and cortisol release (Murphy et al. 1986). Recently, Siever et al. (1984) reported that fenfluramine (60 mg orally) induced a significantly smaller PRL release in a group of depressives as compared to a group of normal controls, which is consistent with the 5-HT deficit hypothesis of depression.
Methods Fifteen depressed patients and 10 normal controls were studied as outpatients in an affective disorders clinic. The depressives (3 men and 12 women, mean age 49.5 + 15.2 years) did not differ significantly from the normal controls (4 men and 6 women, mean age 39.6 -+ 13.5 years) in regard to sex distribution (p = 0.38, Fisher’s Exact Test) or age (t = 1.66, p NS). All subjects were interviewed by a trained rater with 0006-3223t88tSO3.50
BIOL PSYCHlAl’R\ 14XX:?4~117-IX
IIX
Brief Reports
the Schedule for Affective Disorders and Schizophrenia (Endicott and Spitzer 1978); the patients received a diagnosis of major depressive disorder by Research Diagnostic Criteria (Spitzer et al. 1978), and the normals met criteria for “never mentally ill.” The depressives were mild to moderately ill, with a mean extracted Hamilton score of 20.4 i 5.8 (a range of 12-33) (Endicott et al. 198 1). All subjects had normal physical examinations and laboratory assessments, including thyroid indices. All subjects were drug free for a minimum of 3 weeks and had taken no steroids or birth control pills for at least 6 months. The subjects fasted from midnight. The following day, subjects awakened at 7:00 AM and came to the clinic for the procedure. A butterfly needle was inserted into a forearm vein at 9:00 AM and was kept patient with heparinized saline. Samples (4 ml) for plasma hormones (cortisol and PRL) were drawn at - 30 min and 0 time, just before the oral administration of 60 mg of fenfluramine, and every 30 min thereafter for 4 hr. A small group of depressives (n = 5), stud-
ied above, were studied again after being treated for 2 weeks with desipramine (lW150 mg/day). Plasma PRL and cortisol were assessed via a radioimmunoassay kit (Diagnostic Products. Los Angeles, CA). The interassay coefficient of variation for duplicate samples was 7.1% for a PRL pool of 21.5 ng/ml and 6.8% for a cortisol pool of 3.1 ng/ml.
Results The PRL and cortisol response to 60 mg fenBuramine over 240 min is shown in Fig 1. A repeated measures ANOVA was performed on the group and time effects, covarying out age. There was a main effect for time on both PRL (F = 13.57, df = 9,249, p < 0.0001) and cortisol (F = 8,30, df = 9,249, p < 0.0001). but no group effect for PRL (F = 2.10, df = l,249,pNS)orcortisol(F = 2.38,df = 1,249, p NS) and no group x time interaction for PRL (F = 1.33, df = 9,249, p NS) or cortisol (F = 1.06, df = 9,249, p NS). Age was a highly significant covariate for PRL (F = 23.86, df = 2,249, p < 0.0001) and for cortisol (F =
22 IE
0 Normals 0 Deprersivrs
2
I
0
60
120
180
240
Time ( mind
2
i
1
.
0
60
120
180
240
Time (minr)
Figure I. The prolactin and cortisol response (mean k SD) to fenfluramine (60 mg) over 240 min in a group of depressives
(n = 151 and normal controls (n = IO).
119
BlOL PSYCHIATRY
Brief Reports
1988;24:117-120
58.82, df = 2,249, p < 0.0001). Age was negatively correlated with PRL in the normal controls at 180 min (r = 0.73, p < 0.02) and 210 min (r = -0.79, p < O.Ol), and was positively correlated with cortisol in the depressives at 30 min (r = 0.52, p < 0.05) at 60 min (r = 0.68, p < O.OOS),at 90 min (r = 0.74, p < 0.002), at 120 min (r = 0.72, p < 0.002), at 150 min (r = 0.58, p < 0.02), and at 180 min (r = 0.51, p < 0.05). Figure 2 demonstrates the PRL and cortisol response to 60 mg fenfluramine while drug free and again after 2 weeks of desipramine; t-tests for correlated means found no significant differences for either hormone at any time point.
Discussion Fenfluramine, the 5-HT probe used in this study, failed to differentiate depressives from normal controls in regard to PRL and cortisol release. These findings fail to replicate those of Siever et al. (1984) who found that depressives had a significantly smaller PRL response to fenfluramine than normal controls, which is consistent with the 5-HT hypothesis.
There are several possible explanations regarding these discrepant findings. First, we studied depressed outpatients, in contrast to Siever et al. (1984) who studied depressed inpatients. Studies of biological markers for depression have found that depressed inpatients demonstrate the most abnormal responses, with depressed outpatients frequently appearing no different than normal controls (eg. DST, TRH-TSH test) (Amsterdam et al. 1985; Arana et al. 1985; McGrath et al. 1985). Furthermore, most of our patients were unipolar depressives (3 of 15), in contrast to those of Siever et al. (1984) who were predominantly bipolar depressives (12 of 18 patients). Bipolarity may be a significant factor in serotonin dysfunction. This is supported by recent findings of Meltzer et al. ( 1984), who found that the cortisol response of oral 5-HTP, another serotonergic probe, was significantly greater in bipolar versus unipolar depression. Our negative findings may also be related to the 5-HT probe chosen. Fenfluramine is not as selective for 5-HT as originally described, and thus, may have obscured identification of a biochemically distinct subgroup; the racemic form of fenfluramine used in this study is not as se-
0 Drug Free 0 DMI 18. 3i ‘f ._ t 0”
14-
IO6.
4
0
60
I20
timo(mind
I80
240
I
4
0
60
120
I80
240
Timohinrl
Figure 2. The prolactin and cortisol response (mean ? SD) to fenfluramine (60 mg) over 240 min in a group of depressives (n = 5) while drug free and again after 2 weeks of desipramine treatment (lOO-150 mg).
BIOL PSYCHIATRY IY8X;XI 17 170
lective for S-HT as d-fenfluramine and releases dopamine and corepinephrine as well (Rowland and Carlton 1986). Further evidence in our study questioning whether or not fenfluramine is a selective 5-HT probe is the failure to demonstrate an augmented neuroendocrine response to fenfuramine in depressives treated with desipramine (100-150 mg) for 2 weeks. The sensitivity of S-HT postsynaptic area in the brain to iontophoretic S-HT is augmented with chronic tricyclic antidepressant treatment (including more norepinephrine-specific drugs, like desipramine) (Chamey et al. 1981). Consistent with this, and in contrast to our findings with fenfluramine, chronic desipramine treatment (>2 weeks) increased the PRL response to a 5-HT precursor, 1V tryptophan (Chamey et al. 1984; Corven et al. 1986). An interesting finding was that age was significantly related to the neuroendocrine responses to fen~uramine: age was positively correlated with the cortisol response in depressives and negatively correlated with the prolactin response in normal controls. The latter was recently reported by McBride et al. ( 1986). The full meaning of the age relationships within each group needs further study.
References
Brief Reports
Corven PJ, Geaney DP, Schachter M, Green R, Elliot M (1986): Desipramine treatment in normal subjects: Effects of neuroendocrine responses to tryptophan and on platelet serotonin (J-HT)-related receptors. Arch Gen Psychiatry 43:6 147. Endicott J, Spitzer RL f 1978): A diagnostic interview: The Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 35:837-844. Endicott J, Nee J, Cohen J, Fleiss J, Sarantakof F (1981): Hamilton Depression Rating Scale extracted from Schedule for Affective Disorder and Schizophrenia and SADS-C. Arch Gen Psyeh~ar~ 38:98-103. Gardner CR (1985): Ph~acoiogical studies of the role of serotonin in animal models of anxiety. In Green AR (ed), Neuropharmaccllogy of Serotonin. Oxford: University Press, pp 281-325. McBride PA, Kream J, Anderson G, Mann JJ (1986): Effect of age. upon measures of central and peripheral serotonergic function in human subjects. Presented at the Annual Meeting of the Society for Neuroscience. McCrath PJ, Quitkin FM, Stewart JW, Novacenko H, PuigAntich J, Asnis GM (1985): A comparative study of the pituitary TSH response to thyrotropin in outpatient depressives. Psychiarv Res 140:245-247. Meltzer HY, Pedine R, Tricou BJ, Lowy M, Robertson A ( 1984): Effect of 5-hyd~x~~toph~ on serum cortisol levels in major affective disorders. II. Relation to suicide, psychosis, and depressive symptoms. Arch Gen Ps_ychiatv 42:379-387. Murphy DL, Mueller EA, Garrick NA, Aulakh CS (1986): Use of serotonergic agents in the clinical assessment of central serotonin function. J Clin Psychiatry 47:9-l 3. Rowland NE, Carlton J (1986): Neurobiology of an anorectic drug: Fenfluramine. Prog ~~ara~ia~ 27: 13-62. Shoulson I, Chase TN (1975): Fenfluramine in man: Hypophagia associated with diminished serotonin turnover. Clin Pharmacol Ther 171616-62 1.
Amsterdam JD, Winokur A, Caroff SN, Conn J (1985): The Dexamethasone Suppression Test in outpatients with primary affective disorder and healthy control subjects. Am J Psyrhiatry 139:287-29 1.
Siever LJ, Murphy DL. Slater S, deLaVega E, Lipper S (1984): Plasma prolactin changes following fenfluramine in depressed patients compared to controls: .An evaluation of central serotonergic responsivity in deprtsaion. Life Sci 34:1029-1039.
Arana GW, Baldessarini RJ, Omsteen M (198.5): The Dexamethasone Suppression Test for diagnosis and prognosis in psychiatry. Commentary and review. Arch Gen Psychiatry 42:1193-1204.
Spitzer RL, Endicott J, Robins E (1978): Research Diagnostic Criteria: Rationale and reliability. Arch Gen Psychiatty 35~773-182.
Chamey DS, Menkes DB, Heninger GR (1981): Receptor sensitivity and the mechanism of action of antidepressant treatment. Arch Gen Psychiatry 38:1160-1180. Charney DS, Heninger GR, Stemberg DE (1984): Serotonin function and mechanism of action of antidepressant treatment: Effect of amitriptyline and desipramine. Arch Gen Psychiatry 41:359-365.
van Praag HM (1985): Brain serotonin, mood-regulation and aggression-re~uiation. Pichot P, Brenner P, Wolf R. Thii K (eds),?‘sychiatry, the State of the Art. vol. 2 Biological Psychiatry, Higher Nervous Activify. New York: Plenum Press, pp 327-339. van Praag HM, Lemus C, Kahn R (1986): Hormonal probes of central serotonergic activity. Do they really exist? Biol Psychiatr,y 22:R6-98.