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The unipolar-bipolar depressive dichotomy and the relationship between afternoon prolactin and cortisol levels
189
Journal of Affective Disorders, 14 (1988) 189-193 Elsevier
JAD 00528
The unipolar-bipolar depressive dichotomy and the relationship between afternoon prolactin and cortisol levels P.R. Joyce ‘, J.D. Sellman I, R.A. Donald
2, J.H. Livesey
2 and P.A. Elder 3
I Affective Disorders Unit, Sunnyside Hospital, Christchurch, New Zealand, ’ Department of Endocrinology, The Princess Margaret Hospital, Christchurch, New Zealand
and 3 Department
of Biochemistry,
Christchurch Hospital, Christchurch, New Zealand
(Received 15 June 1987) (Revision received 13 October 1987) (Accepted 22 October 1987)
Summary Afternoon prolactin and cortisol levels were measured in 29 patients suffering from a current major depressive episode. Among the 15 unipolar depressed patients the afternoon prolactin and cortisol levels were positively correlated, but 14 bipolar depressed patients did not show a similar relationship, and had prolactin levels lower than the unipolar patients. This finding adds to the growing list of ways in which the neurobiology of bipolar and unipolar depression may differ.
Key words: Unipolar
depression;
Bipolar
depression;
Introduction Multiple neuroendocrine abnormalities have been reported in many patients with major depressive disorders (Risch et al., 1981; Johnson, 1982; Joyce 1985), with cortisol hypersecretion the best documented abnormality (Sachar et al., 1973; Carroll et al., 1976; Halbreich et al., 1985; Linkowski et al., 1985; Pfohl et al., 1985). There are conflicting reports as to whether basal levels of prolactin in depression are higher, lower or similar to those in control subjects, but it does appear that the
Address for correspondence: Professor Peter Joyce, Department of Psychological Medicine, Christchurch School of Medicine, Christchurch Hospital, Christchurch, New Zealand. 0165-0327/88/$03.50
0 1988 Elsevier Science Publishers
Neurobiological
difference
24-h rhythm of prolactin is altered (Halbreich et al., 1979) with unipolar and bipolar depressed patients having differing prolactin rhythms (Mendlewicz et al., 1980). In addition to these abnormalities of prolactin rhythm, blunted prolactin responses to opiates (Judd et al., 1982; Robertson et al., 1984), tryptophan (Heninger et al., 1984) and fenfluramine (Siever et al., 1984) have been reported in major depression. As part of an earlier study of patients with unipolar depression we noted that afternoon prolactin levels correlated with post-dexamethasone cortisol levels (Joyce et al., 1985) and with the simultaneous afternoon cortisol levels (Joyce et al., 1986). Furthermore, other studies have suggested that there is a relationship in depressed patients between post-dexamethasone cortisol and post-
B.V. (Biomedical
Division)
190
dexamethasone prolactin levels (Meltzer et al., 1982; Klein et al., 1984; Atkinson et al., 1986), with the latter two studies also finding a correlation between post-dexamethasone prolactin and severity of depression which was more significant than with post-dexamethasone cortisol. In this study we wanted to establish whether we could replicate our earlier finding of a relationship between basal afternoon prolactin and cortisol levels, and to see whether a similar relationship occurs in both bipolar and non-bipolar depressed patients.
which has an inter-assay coefficient of variation of less than 11%. Prolactin was measured by radioimmunoassay (Livesey and Donald, 1982) which has a current inter-assay coefficient of variation of 13%. The hormone levels from the three separate samples were averaged to give simultaneous mean afternoon cortisol and prolactin levels. Results are expressed as mean k standard deviation. Relationships between cortisol and prolactin levels were calculated using a Kendall rank correlation. Results
Patients and methods Twenty-nine consenting patients meeting the DSM-III criteria for a current major depressive episode participated in this study. Twenty-one of the patients were hospitalized and had been inpatients for at least 5 days prior to testing. The other eight patients were outpatients attending the affective disorders unit. Fourteen of the patients met DSM-III criteria for bipolar affective disorder, and the other 15 had no history of mania and were designated as unipolar. The bipolar patients had a mean age of 41 years (+14) (range 22-64) and the unipolar patients had a mean age of 44 years (&20) (range 21-78). Nine of the bipolar and nine of the unipolar patients were males, and of the 11 females six were postmenopausal. Patients were physically healthy and without evidence of any known factors which would alter cortisol or prolactin levels. All patients were on stable dosage of tricyclic antidepressants and/or lithium, but had been off neuroleptics for at least 1 month. Patients followed their normal diets and routines and reported for neuroendocrine evaluation in the afternoon. The patient then either sat in a comfortable chair or reclined on a bed; an indwelling intravenous catheter was inserted into an antecubital vein. After a period of rest, three blood samples were drawn at 20-min intervals between 2.30 p.m. and 4.30 p.m. The blood was immediately separated and the plasma frozen for later hormone analysis. Cortisol was measured by an enzyme-linked immunosorbent assay (Lewis and Elder, 1985)
Although cortisol levels in the bipolar (335 + 200 nmol/l) and unipolar patients (345 + 109 nmol/l) were similar, the bipolar patients had lower prolactin levels (156 _+64 mIU/l) than the unipolar patients (333 + 213 mIU/l) (Wilcoxon rank sum test, P < 0.01). Among the bipolar patients there was no relationship between cortisol and prolactin levels (r = 0.05, p NS). However, among the unipolar patients the prolactin and cortisol levels were significantly correlated (r = 0.46, P < 0.02). In the nine
.
.
Fig. 1. The relationships between simultaneous afternoon prolactin and cortisol levels in unipolar (r = 0.46, P -c0.02) and bipolar (r = 0.05, p NS) depressives.
191
unipolar males this correlation was similar (r = OSO), although it just failed to reach significance at P < 0.05 because of small numbers. In addition to the prolactin-cortisol correlation in unipolar depressives it should be noted that the three highest prolactin levels in the unipolar females occurred in the three who also had the highest cortisol levels. Furthermore, the one female patient with a prolactin level above the normal range of 500 mIU/l was the unipolar female patient with the highest cortisol level. Similarly, in the unipolar males, the three highest prolactin levels occurred in the three with the highest cortisol levels, and two of these prolactin levels were above the normal prolactin range of 400 mIU/l for males. The higher prolactin levels in the unipolar depressives and their cortisol-prolactin correlation did not appear to be due to age, sex, menopausal status or current psychotropic drugs. The prolactin and cortisol levels for each patient are shown in Fig. 1. Discussion The first finding from this study was that the unipolar depressed patients had higher afternoon basal prolactin levels than bipolar depressed patients. Furthermore, among the unipolar but not the bipolar patients, the prolactin and cortisol levels were significantly correlated. In our earlier study (Joyce et al., 1985, 1986), when baseline prolactin and cortisol levels at 4.00 p.m. were correlated, the sample of 20 depressed patients consisted of 18 unipolar depressed patients and two with an atypical bipolar disorder. Whether the two atypical bipolar patients are included or excluded from the earlier study leaves the cortisol-prolactin correlation essentially unaltered. The differences in prolactin levels between unipolar and bipolar depressed patients is consistent with the reported 24-h prolactin rhythms, in which bipolar patients had lower mean levels and also failed to show the expected nocturnal increase (Mendlewicz et al., 1980). It is possible, therefore, that some of the discrepancies in the literature on basal prolactin levels in depression arise from the failure to separate bipolar and unipolar depres-
sives. Furthermore, the results from this study are afternoon, not morning, levels and this could be another important variable in understanding the earlier discrepancies. Age and sex also affect prolactin levels, although in this study neither of these variables can explain the observed correlation of prolactin with cortisol in non-bipolar depression. It is interesting to note the reported differences in catecholamine and metabolite levels between bipolar and unipolar depression. For instance, bipolar depressives have lower urinary 3-methoxy4-hydroxyphenylglycol (MHPG) levels (Muscettola et al., 1984) and lower plasma norepinephrine levels (Roy et al., 1985; Rudorfer et al., 1985) than unipolar patients. Furthermore, among unipolar depressed patients, those with high urinary MHPG levels are those with high urinary cortisol excretion (Rosenbaum et al., 1983), and higher plasma norepinephrine levels occur in unipolar patients who do not suppress plasma cortisol following dexamethasone (Barnes et al., 1983; Roy et al., 1985; Joyce et al., 1986). This pattern of relationships with catecholamines in depression, namely lower levels in bipolar patients and among unipolar patients a relationship between catecholamine levels and cortisol hypersecretion, is similar to the pattern which we have now reported with prolactin levels. It is also of note that while a relationship between low CSF 5-hydroxyindoleacetic acid (5 HIAA) and violent suicide (Asberg et al., 1976; Brown et al., 1982) has been reported in unipolar depression, this relationship may not apply in bipolar depression (Roy-Byrne et al., 1983). Furthermore, differences between bipolar and unipolar depressed patients have also been noted in regard to platelet q-receptors (Kafka et al., 1986), CSF prostaglandin levels (Linnoila et al., 1983), in positron emission tomography studies of cerebral glucose uptake (Phelps et al., 1984; Buchsbaum et al., 1986), and in verbal memory deficits (Wolfe et al., 1987). Our knowledge of the neurotransmitter control of anterior pituitary hormone secretion is fragmentary and it is likely that multiple neurotransmitters (each the last neuron of a complex neural network) are involved in the release of each hormone. It is also possible that under differing conditions the same neurotransmitter (e.g.,
192
serotonin) could have both inhibitory and excitatory effects on release of the same hormone (e.g., ACTH) (Tuomisto and Manmsto, 1985). Furthermore, elevated glucocorticoid levels, as in depression, may in turn affect biogenic amine activity, and possibly in a biphasic manner (McEwen, 1987). Finally, it is well to appreciate the increasing multiplicity of receptor subtypes, and that a change in neurotransmitter activity at the hypothalamic-pituitary interface need not imply the same change in all other neural circuits which utilize the same neurotransmitter. These factors thus advise caution in extrapolating backwards from the measured neuroendocrine abnormalities to a potential neurotransmitter explanation of the abnormalities, however, hypotheses for future exploration need to be advanced. In the initial study in which we observed that afternoon prolactin and cortisol levels in non-bipolar depression were correlated, we hypothesized that this correlation could be explained by increased central cholinergic and/or serotonergic activity (Joyce et al., 1985). However, such an explanation would not explain the data in bipolar depression, indeed any simple hypothesis of central neurotransmitter control of neuroendocrine secretion will have difficulty in explaining the discrepant findings in unipolar and bipolar depression. Earlier in the discussion it was commented that the cortisol-prolactin findings appear similar to the cortisol-noradrenergic function findings; thus the obvious study would be to look at the correlation between prolactin and noradrenergic function in relationship to the bipolar-unipolar dichotomy and in terms of cortisol hypersecretion. If it could be shown that bipolar depression is associated with low noradrenergic function and low prolactin levels (independent of cortisol hypersecretion), but that in unipolar depression prolactin levels and noradrenergic function increase with increasing hypothalamic-pituitary-adrenal hyperactivity, then further refinement of an explanatory hypothesis may be more feasible. Assuming that prolactin levels and measures of noradrenergic function do correlate with each other, then one way of explaining this is that peripheral levels of noradrenergic activity influence prolactin levels by
a non-central mechanism (Tuomisto and Mannisto, 1985). Peripheral levels of noradrenergic activity may in turn largely be reflecting output of the sympathetic nervous system. If such an explanation is tenable then the question becomes why there is decreased sympathetic nervous system output in bipolar depression, while in unipolar depression this increases with increasing hypothalamic-pituitary-adrenal activity. Whatever the final explanation for the findings reported here, when considered in conjunction with other findings of differences between unipolar and bipolar depression, then further neurobiological studies need to pay careful attention to the unipolar-bipolar dichotomy. Conversely it may be possible to refine the clinical diagnosis of this dichotomy or predict a future bipolar outcome by using combinations of neurobiological measures which differ between unipolar and bipolar depression. Acknowledgements This research was funded by grants from the Canterbury Medical Research Foundation, the New Zealand Lottery Board Medical Research Distribution Fund, and the Medical Research Council of New Zealand. We thank Mrs. Robyn Abbott for her assistance. References Asberg, M., Traskman, L. and Thonen, P. (1976) 5-HIAA in the cerebrospinal fluid: a biochemical suicide prediction? Arch. Gen. Psychiatry 33, 1193-1197. Atkinson, J.H., Kremer, E.F., Risch, SC. and Janowsky, D.S. (1986) Basal and post-dexamethasone cortisol and prolactin concentrations in depressed and non-depressed patients with chronic pain syndromes. Pain 25, 23-34. Barnes, R.F., Veith, R.C., Borson, S., Verhey, J., Raskind, M.A. and Halter, J.B. (1983) High levels of plasma catecholamines in dexamethasone-resistant depressed patients. Am. J. Psychiatry 140, 162331625. Brown, G.L., Ebert, M.E., Goyer, P.F., Jimerson, D.C., Klein, W.J., Bumrey, W.E. and Goodwin, F.K. (1983) Aggression, suicide and serotonin: relationships to CSF amine metabolites. Am. J. Psychiatry 139, 741-746. Buchsbaum, M.S., Wu, J., Delisi, L.E., Holcomb, H., Kessler, R., Johnson, J., King, A.C., Hazlett, E., Langston, K. and Post, R.M. (1986) Frontal cortex and basal ganglia metabolic rates assessed by positron emission tomography with [r8F]2-deoxyglucose in affective illness. J. Affect. Disord. 10, 137-152.
193 Carroll, B.J., Curtis, G.C., Davies, B.M., Mendels, J. and Sugarman, A.A. (1976) Urinary free cortisol excretion in depression. Psychol. Med. (London), 6, 43-50. Halbreich, U., Grunhaus, L. and Ben-David, M. (1979) Twenty-four-hour rhythm of prolactin in depressive patients. Arch. Gen. Psychiatry 36, 1183-1186. Halbreich, U., Asnis, G.M., Shindledecker, R., Zumoff, B. and Nathan, R.S. (1985) Cortisol secretion in endogenous depression. Arch. Gen. Psychiatry 42,. 904-908. Heninger, G.R., Chamey, D.S. and Stemberg, D.E. (1984) Serotonergic function in depression: prolactin response to intravenous tryptophan in depressed patients and healthy subjects. Arch. Gen. Psychiatry 41, 398-402. Johnson, G.F.S. (1982) Endocrine dysfunction in depression. In: P.J.V. Beumont and G.D. Burrows (Eds.), Handbook of Psychiatry and Endocrinology, Elsevier Biomedical Press, Amsterdam, pp. 239-266. Joyce, P.R. (1985) Neuroendocrine changes in depression. Aust. N.Z.J. Psychiatry 19, 120-127. Joyce, P.R., Donald, R.A. and Livesey, J.A. (1985) A relationship between prolactin levels and dexamethasone suppression test results in major depressive disorder. J. Affect. Disord. 8, 191-195. Joyce, P.R., Donald, R.A., Nicholls, M.G., Livesey, J.H. and Abbott, R.M. (1986) Endocrine and behavioural responses to methylphenidate in depression. Psychol. Med. (London) 16, 531-540. Judd, L.L., Risch, SC., Parker, DC., Janowsky, D.S., Segal, D.S. and Huey, L.Y. (1982) Blunted prolactin response: a neuroendocrine abnormality manifested by depressed patients. Arch. Gen. Psychiatry 39, 1413-1416. Kafka, MS., Numberger, J.I., Siever, L., Targum, S., Uhde, T.W. and Gershon, E.S. (1986) Alpha-2-adrenergic receptor function in patients with unipolar and bipolar affective disorders. J. Affect. Disord. 10, 163-169. Klein, H.E., Seibold, B., Bender, W., Nedopil, N., Albus, M. and Schmauss, M. (1984) Postdexamethasone prolactin and cortisol: a biological state variable in depression. Acta Psychiatr. Stand. 70, 239-247. Lewis, J.G. and Elder, P.A. (1985) An enzyme-linked immunosorbent assay (ELISA) for plasma cortisol. J. Steroid Biochem. 22, 673-676. Linkowski, P., Mendlewicz, J., Leclercq, R., Brasseur, M., Hubain, P., Golstein, J., Copinschi, G. and Van Cauter, E. (1985) The 24-hour profile of adrenocorticotropin and cortisol in major depressive illness. J. Clin. Endocrinol. Metab. 61, 429-434. Linnoila, M., Whorton, A.R., Rubinow, D.R., Cowdry, R.W., Ninan, P.T. and Waters, R.N. (1983) CSF prostaglandin levels in depressed and schizophrenic patients. Arch. Gen. Psychiatry 40, 405-406. Livesey, J.H. and Donald, R.A. (1981) Prevention of absorption losses during radioimmunoassay of polypeptide hormones. Effectiveness of albumins, gelatin, caseins, Tween 20 and plasma. Clin. Chim. Acta 123, 193-198. McEwen, B.S. (1987) Glucocorticoid-biogenic amine interactions in relation to mood and behaviour. B&hem. Pharmacol. 36, 1755-1763.
Meltzer, H.Y., Fang, V.S., Tricou, B.J., Robertson, A. and Pryaka, S.K. (1982) Effect of dexamethasone on plasma prolactin and cortisol levels in psychiatric patients. Am. J. Psychiatry 139, 763-768. Mendlewicz, J., Van Cauter, E.. Linkowski, F., L’Hermite, M. and Robyn, C. (1980) The 24 hour profile of prolactin in depression. Life Sci. 27, 2015-2024. Muscettola, G., Potter, W.Z., Pickar, D. and Goodwin, F.K. (1984) Urinary 3-methoxy-4-hydroxyphenylglycol and major affective disorders. Arch. Gen. Psychiatry 41, 337-342. Pfohl, B., Sherman, B., Schlechte, J. and Stone, R. (1985) Pituitary-adrenal axis rhythm disturbances in psychiatric depression. Arch. Gen. Psychiatry 42, 897-903. Phelps, M.E., Mazziotta, J.C., Baxter, L. and Gemer, R. (1984) Positron emission tomographic study of affective disorders: problems and strategies. Ann. Neurol. 15 (Suppl.), S149-S156. Risch, SC., Kahn, N.H. and Murphy, D.L. (1981) Neurochemical mechanisms in the affective disorders and neuroendocrine correlates. J. Clin. Psychopharmacol. 1, 180-185. Robertson, A.G., Jackman, H. and Meltzer, H.Y. (1984) Prolactin response to morphine in depression. Psychiat. Res. 11, 353-364. Rosenbaum, A.H., Manna, T., Schatzberg, A.F., Orsulak, P.J., Jiang, N.-S., Cole, J.O. and Schildkraut, J.J. (1983) Toward a biochemical classification of depressive disorders, VII: Urinary free cortisol and urinary MHPG in depressions. Am. J. Psychiatry 140, 314-318. Roy, A., Pickar, D., Linnoila, M. and Potter, W.Z. (1985) Plasma norepinephrine levels in affective disorders. Arch. Gen. Psychiatry 42, 1181-1185. Roy-Byrne, P., Post, R.M., Rubinow, D.R., Linnoila, M., Savard, R. and Davis, D. (1983) CSF 5-HIAA and personal and family history of suicide in affectively ill patients: a negative study. Psychiat. Res. 10, 263-274. Rudorfer, M.V., Ross, R.J., Linnoila, M., Sherer, M.A. and Potter, W.Z. (1985) Exaggerated orthostatic responsivity of plasma norepinephrine in depression. Arch. Gen. Psychiatry 42, 1186-1192. Sachar, E., Hellman, L. and Roffwarg, H. (1973) Disrupted 24 hour patterns of cortisol secretion in psychotic depression. Arch. Gen. Psychiatry 28, 19-24. Siever, L.J., Murphy, D.L., Slater, S., De La Vega, E. and Lipper, S. (1984) Plasma prolactin changes following fenfluramine in depressed patients compared to controls: an evaluation of central serotonergic responsivity in depression. Life Sci. 34, 1029-1039. Tuomisto, J. and Mannisto, P. (1985) Neurotransmitter regulation of anterior pituitary hormones. Pharmacol. Rev. 37, 249-332. Wolfe, J., Granholm, E., Butters, N., Saunders, E. and Janowsky, D. (1987) Verbal memory deficits associated with major affective disorders: a comparison of unipolar and bipolar patients. J. Affect Disord. 13, 83-92.
Journal of Affective Disorders, 14 (1988) 189-193 Elsevier
JAD 00528
The unipolar-bipolar depressive dichotomy and the relationship between afternoon prolactin and cortisol levels P.R. Joyce ‘, J.D. Sellman I, R.A. Donald
2, J.H. Livesey
2 and P.A. Elder 3
I Affective Disorders Unit, Sunnyside Hospital, Christchurch, New Zealand, ’ Department of Endocrinology, The Princess Margaret Hospital, Christchurch, New Zealand
and 3 Department
of Biochemistry,
Christchurch Hospital, Christchurch, New Zealand
(Received 15 June 1987) (Revision received 13 October 1987) (Accepted 22 October 1987)
Summary Afternoon prolactin and cortisol levels were measured in 29 patients suffering from a current major depressive episode. Among the 15 unipolar depressed patients the afternoon prolactin and cortisol levels were positively correlated, but 14 bipolar depressed patients did not show a similar relationship, and had prolactin levels lower than the unipolar patients. This finding adds to the growing list of ways in which the neurobiology of bipolar and unipolar depression may differ.
Key words: Unipolar
depression;
Bipolar
depression;
Introduction Multiple neuroendocrine abnormalities have been reported in many patients with major depressive disorders (Risch et al., 1981; Johnson, 1982; Joyce 1985), with cortisol hypersecretion the best documented abnormality (Sachar et al., 1973; Carroll et al., 1976; Halbreich et al., 1985; Linkowski et al., 1985; Pfohl et al., 1985). There are conflicting reports as to whether basal levels of prolactin in depression are higher, lower or similar to those in control subjects, but it does appear that the
Address for correspondence: Professor Peter Joyce, Department of Psychological Medicine, Christchurch School of Medicine, Christchurch Hospital, Christchurch, New Zealand. 0165-0327/88/$03.50
0 1988 Elsevier Science Publishers
Neurobiological
difference
24-h rhythm of prolactin is altered (Halbreich et al., 1979) with unipolar and bipolar depressed patients having differing prolactin rhythms (Mendlewicz et al., 1980). In addition to these abnormalities of prolactin rhythm, blunted prolactin responses to opiates (Judd et al., 1982; Robertson et al., 1984), tryptophan (Heninger et al., 1984) and fenfluramine (Siever et al., 1984) have been reported in major depression. As part of an earlier study of patients with unipolar depression we noted that afternoon prolactin levels correlated with post-dexamethasone cortisol levels (Joyce et al., 1985) and with the simultaneous afternoon cortisol levels (Joyce et al., 1986). Furthermore, other studies have suggested that there is a relationship in depressed patients between post-dexamethasone cortisol and post-
B.V. (Biomedical
Division)
190
dexamethasone prolactin levels (Meltzer et al., 1982; Klein et al., 1984; Atkinson et al., 1986), with the latter two studies also finding a correlation between post-dexamethasone prolactin and severity of depression which was more significant than with post-dexamethasone cortisol. In this study we wanted to establish whether we could replicate our earlier finding of a relationship between basal afternoon prolactin and cortisol levels, and to see whether a similar relationship occurs in both bipolar and non-bipolar depressed patients.
which has an inter-assay coefficient of variation of less than 11%. Prolactin was measured by radioimmunoassay (Livesey and Donald, 1982) which has a current inter-assay coefficient of variation of 13%. The hormone levels from the three separate samples were averaged to give simultaneous mean afternoon cortisol and prolactin levels. Results are expressed as mean k standard deviation. Relationships between cortisol and prolactin levels were calculated using a Kendall rank correlation. Results
Patients and methods Twenty-nine consenting patients meeting the DSM-III criteria for a current major depressive episode participated in this study. Twenty-one of the patients were hospitalized and had been inpatients for at least 5 days prior to testing. The other eight patients were outpatients attending the affective disorders unit. Fourteen of the patients met DSM-III criteria for bipolar affective disorder, and the other 15 had no history of mania and were designated as unipolar. The bipolar patients had a mean age of 41 years (+14) (range 22-64) and the unipolar patients had a mean age of 44 years (&20) (range 21-78). Nine of the bipolar and nine of the unipolar patients were males, and of the 11 females six were postmenopausal. Patients were physically healthy and without evidence of any known factors which would alter cortisol or prolactin levels. All patients were on stable dosage of tricyclic antidepressants and/or lithium, but had been off neuroleptics for at least 1 month. Patients followed their normal diets and routines and reported for neuroendocrine evaluation in the afternoon. The patient then either sat in a comfortable chair or reclined on a bed; an indwelling intravenous catheter was inserted into an antecubital vein. After a period of rest, three blood samples were drawn at 20-min intervals between 2.30 p.m. and 4.30 p.m. The blood was immediately separated and the plasma frozen for later hormone analysis. Cortisol was measured by an enzyme-linked immunosorbent assay (Lewis and Elder, 1985)
Although cortisol levels in the bipolar (335 + 200 nmol/l) and unipolar patients (345 + 109 nmol/l) were similar, the bipolar patients had lower prolactin levels (156 _+64 mIU/l) than the unipolar patients (333 + 213 mIU/l) (Wilcoxon rank sum test, P < 0.01). Among the bipolar patients there was no relationship between cortisol and prolactin levels (r = 0.05, p NS). However, among the unipolar patients the prolactin and cortisol levels were significantly correlated (r = 0.46, P < 0.02). In the nine
.
.
Fig. 1. The relationships between simultaneous afternoon prolactin and cortisol levels in unipolar (r = 0.46, P -c0.02) and bipolar (r = 0.05, p NS) depressives.
191
unipolar males this correlation was similar (r = OSO), although it just failed to reach significance at P < 0.05 because of small numbers. In addition to the prolactin-cortisol correlation in unipolar depressives it should be noted that the three highest prolactin levels in the unipolar females occurred in the three who also had the highest cortisol levels. Furthermore, the one female patient with a prolactin level above the normal range of 500 mIU/l was the unipolar female patient with the highest cortisol level. Similarly, in the unipolar males, the three highest prolactin levels occurred in the three with the highest cortisol levels, and two of these prolactin levels were above the normal prolactin range of 400 mIU/l for males. The higher prolactin levels in the unipolar depressives and their cortisol-prolactin correlation did not appear to be due to age, sex, menopausal status or current psychotropic drugs. The prolactin and cortisol levels for each patient are shown in Fig. 1. Discussion The first finding from this study was that the unipolar depressed patients had higher afternoon basal prolactin levels than bipolar depressed patients. Furthermore, among the unipolar but not the bipolar patients, the prolactin and cortisol levels were significantly correlated. In our earlier study (Joyce et al., 1985, 1986), when baseline prolactin and cortisol levels at 4.00 p.m. were correlated, the sample of 20 depressed patients consisted of 18 unipolar depressed patients and two with an atypical bipolar disorder. Whether the two atypical bipolar patients are included or excluded from the earlier study leaves the cortisol-prolactin correlation essentially unaltered. The differences in prolactin levels between unipolar and bipolar depressed patients is consistent with the reported 24-h prolactin rhythms, in which bipolar patients had lower mean levels and also failed to show the expected nocturnal increase (Mendlewicz et al., 1980). It is possible, therefore, that some of the discrepancies in the literature on basal prolactin levels in depression arise from the failure to separate bipolar and unipolar depres-
sives. Furthermore, the results from this study are afternoon, not morning, levels and this could be another important variable in understanding the earlier discrepancies. Age and sex also affect prolactin levels, although in this study neither of these variables can explain the observed correlation of prolactin with cortisol in non-bipolar depression. It is interesting to note the reported differences in catecholamine and metabolite levels between bipolar and unipolar depression. For instance, bipolar depressives have lower urinary 3-methoxy4-hydroxyphenylglycol (MHPG) levels (Muscettola et al., 1984) and lower plasma norepinephrine levels (Roy et al., 1985; Rudorfer et al., 1985) than unipolar patients. Furthermore, among unipolar depressed patients, those with high urinary MHPG levels are those with high urinary cortisol excretion (Rosenbaum et al., 1983), and higher plasma norepinephrine levels occur in unipolar patients who do not suppress plasma cortisol following dexamethasone (Barnes et al., 1983; Roy et al., 1985; Joyce et al., 1986). This pattern of relationships with catecholamines in depression, namely lower levels in bipolar patients and among unipolar patients a relationship between catecholamine levels and cortisol hypersecretion, is similar to the pattern which we have now reported with prolactin levels. It is also of note that while a relationship between low CSF 5-hydroxyindoleacetic acid (5 HIAA) and violent suicide (Asberg et al., 1976; Brown et al., 1982) has been reported in unipolar depression, this relationship may not apply in bipolar depression (Roy-Byrne et al., 1983). Furthermore, differences between bipolar and unipolar depressed patients have also been noted in regard to platelet q-receptors (Kafka et al., 1986), CSF prostaglandin levels (Linnoila et al., 1983), in positron emission tomography studies of cerebral glucose uptake (Phelps et al., 1984; Buchsbaum et al., 1986), and in verbal memory deficits (Wolfe et al., 1987). Our knowledge of the neurotransmitter control of anterior pituitary hormone secretion is fragmentary and it is likely that multiple neurotransmitters (each the last neuron of a complex neural network) are involved in the release of each hormone. It is also possible that under differing conditions the same neurotransmitter (e.g.,
192
serotonin) could have both inhibitory and excitatory effects on release of the same hormone (e.g., ACTH) (Tuomisto and Manmsto, 1985). Furthermore, elevated glucocorticoid levels, as in depression, may in turn affect biogenic amine activity, and possibly in a biphasic manner (McEwen, 1987). Finally, it is well to appreciate the increasing multiplicity of receptor subtypes, and that a change in neurotransmitter activity at the hypothalamic-pituitary interface need not imply the same change in all other neural circuits which utilize the same neurotransmitter. These factors thus advise caution in extrapolating backwards from the measured neuroendocrine abnormalities to a potential neurotransmitter explanation of the abnormalities, however, hypotheses for future exploration need to be advanced. In the initial study in which we observed that afternoon prolactin and cortisol levels in non-bipolar depression were correlated, we hypothesized that this correlation could be explained by increased central cholinergic and/or serotonergic activity (Joyce et al., 1985). However, such an explanation would not explain the data in bipolar depression, indeed any simple hypothesis of central neurotransmitter control of neuroendocrine secretion will have difficulty in explaining the discrepant findings in unipolar and bipolar depression. Earlier in the discussion it was commented that the cortisol-prolactin findings appear similar to the cortisol-noradrenergic function findings; thus the obvious study would be to look at the correlation between prolactin and noradrenergic function in relationship to the bipolar-unipolar dichotomy and in terms of cortisol hypersecretion. If it could be shown that bipolar depression is associated with low noradrenergic function and low prolactin levels (independent of cortisol hypersecretion), but that in unipolar depression prolactin levels and noradrenergic function increase with increasing hypothalamic-pituitary-adrenal hyperactivity, then further refinement of an explanatory hypothesis may be more feasible. Assuming that prolactin levels and measures of noradrenergic function do correlate with each other, then one way of explaining this is that peripheral levels of noradrenergic activity influence prolactin levels by
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