HUMAN PSYCHOPHARMACOLOGY, VOL. 1, 47-48 (1986)

Platelet monoamine uptake in depression-a primary or secondary phenomenon? PAUL TURNER MD, FRCP Professor of Clinical Pharmacology, Department of Clinical Pharmacology, St. Bartholomew’s Hospital, London -- ECl, U K

The detection of autonomic abnormalities in patients with affective disorders has been of great interest to human psychopharmacologists because of their possible relevance to theories of pathogenesis which involve monoaminergic mechanisms. Among the abnormalities have been an increased pressor sensitivity to intravenous tyramine (Turner, 1980) , reduced salivation (Palmai et al., 1967), and changes in urinary excretion of monoamines and their metabolites (Green and Costain, 1979). Equally intriguing have been changes in pharmacological response demonstrated in isolated cells or subcellular fragments such as platelets. Reduced levels of 5-hydroxytryptamine (5HT) in serum or in whole blood from depressed patients were reported by Sarai and Kayano (1968), Gayford et al. (1973) and Coppen et af. (1976). As 5 H T in whole blood is almost entirely found within platelets, studies were made on platelet uptake of 5HT in depression, and two groups of workers published, almost simultaneously, results which demons- trated a reduction in platelet uptake in depressed patients compared with normal control subjects (Hallstrom et al., 1976, Tuomisto and Tukiainen, 1976). Kinetic analysis by Tuomisto and Tukiainen showed that the Vmax for 5HT uptake was significantly reduced. Hallstrom et al. (1976) also found that platelet dopamine uptake was reduced in platelets taken from depressed pa- tients. Coppen et af. (1978) confirmed these observations on 5 H T uptake, and Ehsanullah and Mulgirigama (1979) confirmed the reduction of both 5HT and dopamine uptake by platelets in depression. It is still uncertain whether or not 5HT and dopamine share the same uptake pathway within the human platelet (Gordon et af., 1978).

These observations were intriguing, for they appeared to suggest that peripheral mechanisms involving the handling of monoamines might reflect changes in central neurones consistent with the monoamine theory of affective disorders. Questions which they provoked included the

0885-622U86/010047-O2$05 .OO 0 1986 by John Wiley & Sons, Ltd.

possibility of a generalized membrane disorder of monoamine uptake, or the possibility that a circulating plasma factor might be responsible for inhibition of uptake.

Recent pharmacological studies into the influ- ence of corticosteroids on platelet monoamine uptake may provide an explanation for these observations. Chan and Lee (1985) have investi- gated the effects of chronic ACTH and dex- amethasone treatment on groups of rats and have shown that both treatments resulted in decreased platelet 5HT uptake, with decreased Vmax values. Furthermore, dexamethasone potentiated the effects of amitriptyline, imipramine and desipramine as 5HT uptake inhibitors in vitro.

It has been known for a long time that cortisol hypersecretion is a common feature of depressive illness (Everitt and Keverne, 1979), being most prominent in the afternoon and night when it is low in normal subjects.

Is the reduced platelet uptake of 5HT into platelets from depressed patients the result of some abnormality specific to the psychiatric disorder, or is it an epiphenomenon, secondary to the increased cortisol concentrations found in this condition? The definitive studies are yet to be done, namely to determine whether or not the plasma cortisol levels sustained in depressed patients are sufficient to produce the depression in platelet uptake of 5HT found in patient studies. Until this is done, however, the implications of platelet uptake studies in the pathogenesis of endogenous depression must remain in consider- able doubt.

REFERENCES Chan, M. and Lee, P. H. K. (1985). Serotonin uptake

and imipramine binding in rat platelet after chronic dexamethasone and amitriptyline treatment. Phar- macological Research Communications, 17, 615L632.

Coppen, A., Turner, P., Rowsell, A. R. and Padgham, C . (1976). 5-Hydroxytryptamine in the whole blood of patients with depressive illness. Postgraduate Medical Journal, 52, 156-158.

48 P. TURNER

Coppen, A., Swade, C. and Wood, K. (1978). Platelet 5-hydroxytryptamine and dopamine into blood platelets from depressed patients. British Journal of Clinical Pharmacology, 7, 434-435P.

Everitt, B. J. and Keverne, E. G. (1979). Models of depression based on behavioural observations of experimental animals. In: Psychopharmacology of Affective Disorders. Paykel, E. S . and Coppen, A. (Eds), Oxford University Press, Oxford. 41-59.

Gayford, J. J., Parker, A. L., Phillips, E. M. and Rowsell, A. R. (1973). Whole blood 5- hydroxytryptamine during treatment of endogenous depressive illness. British Journal of Psychiatry, 122,

Gordon, J. L., Olverman, H. J. and Drummond, A. H. J. (1978). Interaction of platelets with biogenic amines. In: Platelets: a multidisciplinary approach. de Gaetano, G. and Garattini, S. (Eds), Raven Press, New York 361-372.

Green, A. R. and Costain, D. W. (1979). The biochemistry of depression. In: Psychopharmacology

597-598.

of Affective Disorders. Paykel, E. S. and Coppen, A. (Eds), Oxford University Press, Oxford, L4-40.

Halhtrom, C. 0. S . , Linford Rees, W., Pare, C. M. B., Trenchard, A. and Turner, P. (1976). Platelet uptake of 5-hydroxytryptamine and dopamine in depression. Postgraduate Medical Journal, 52, Suppl. 3, 4044.

Palmai, G . , Blackwell, B., Maxwell, A. E:. and Morgenstern, F. (1967). Patterns of salivary flow in depressive illness and during treatment. British Journal of Psychiatry, 113, 1297-1308.

Saria, K. and Kayano, M. (1968). The level and diurnal rhythm of serum serotonin in manic-depressive patients. Folia in Psychiatry and Neurology of Japan,

Tuomisto, J. and Tukiainen, E. (1976) Decreased uptake of 5-hydroxytryptamine in blood platelets from depressed patients. Nature, 262, 596-597.

Turner, P. (1980). Tests of autonomic function in assessing centrally acting drugs. British Journal of Clinical Pharmacology, 10, 93-99.

22, 271-281.

F’rofessor Turner’s Comments were shown to Dr. Healy;* here is Dr. Healy’s response.

Professor Turner’s healthy scepticism is to be welcomed. Unquestionably, we should spend more time attempting to relegate our findings to the status of epiphenomena and less trumpeting flimsy evidence in support of currently fashion- able theories of pathogenesis. That we do not do so makes our discipline “all-too” human psychopharmacology .

Nevertheless, apart from apparent support for particular hypotheses, studies of peripheral vari- ables in affective disorders are worth pursuing as they may yield diagnostic markers. Trait markers have immediate pathogenetic implications, albeit of obscure significance. State markers on the other hand may be of use, even though subse- quently shown to be epiphenomenal. For exam- ple plasma steroids or catecholamines are com- monly altered by food deprivation, which may lead to elevations of platelet adrenoceptor num- ber or abnormal dexamethasone suppression responses in patients unaware of weight loss. Subjective awareness of neurovegetative dysfunc- tion is imprecise and unreliable and biological markers may help determine whether a patient has the abnormality in question, irrespective of its nosological implication.

Professor Turner suggests that all peripheral markers may be influenced by the hypersecretion of cortisol found in depression. This argument however is double edged. While amine systems may be influenced by cortisol, cortisol hypersecretion must itself stem from some abnor- mality of aminergic (or other) neurotransmitters impinging on hypothalamic or pituitary neurones. Hence the rationale for investigating peripheral

receptors and uptake systems in the hope of detecting abnormalities common to central and peripheral systems. Specifically Professor Turner suggests that the decreased platelet 5HT uptake reported in depression may stem from cortisol hypersecretion, citing Chan & Lee (1985). However, there is more extensive support for the opposite contention: that cortisol increases platelet 5HT uptake (Lee and Chan, 1985; Tukianen, 1981; Vermes et al., 1976). As cortisol is secreted in excess in depression, reports of a lowering of platelet 5HT uptake represent a significant discrepancy. Such a finding may be useful identifying those patients with a particular affective psychosis and may indicate that a generalised transport or receptor abnormality exists in depressed patients.

REFERENCES Chan, M.,-Lee, P. H. K. (1985). Serotonin uptake and

imipramine binding in rat platelets after chronic dexamethasone and amitriptyline treatment. Phar- macologic Research Communications, 17, 619-632.

Lee, P. H. K., Chan, M. (1985). Changes induced by corticosterone and adrenalectorny in synaptosomal and platelet uptake and binding of 5HT. Neurophar- macology, 24, 1043-1050.

Tukianen, E. (1981). Effects of hypophysectomy and adrenalectomy on 5-hydroxytryptamine uptake by rat hypothalamic synaptosornes and blood platelets. Acta Pharmacologia et Toxicologia, 48, 139-144.

Vermes, I. , Smelik, P. G. , Mulder, A. H. (1976). Effects of hypophysectomy, adrenalectomy and corticosterone treatment on uptake and release of putative central neurotransmitters by rat hypothala- mic tissue in vitro. Life Sciences, 19, 1719-1726.

‘David Healy, MB, MRCPsych, Clinical Research Associate, Dept. of Psychiatry, Addenbrooke’s Hospital, Cambridge, CB2 2QQ. UK.