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Noradrenergic Function and Clinical Outcome in Antidepressant Pharmacotherapy Helen L

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Noradrenergic Function and Clinical Outcome in Antidepressant Pharmacotherapy Helen L Noradrenergic Function and Clinical Outcome in Antidepressant Pharmacotherapy Helen L. Miller, M.D., R. David Ekstrom, M.A., M.P.H., George A. Mason, Ph.D., R. Bruce Lydiard, M.D., Ph.D., and Robert N. Golden, M.D. Controversy remains regarding the role of noradrenergic and at the conclusion of the treatment trial. Changes in systems in determining clinical response to antidepressant urinary excretion of 6-sulfatoxymelatonin distinguished pharmacotherapy. Pineal gland production of melatonin can antidepressant responders from nonresponders, with a serve as a physiologic index of noradrenergic function. The significant increase observed in the former group and a aim of this study was to examine the effects of significant decrease in the latter. The degree of clinical antidepressant treatment on 24-hour urinary excretion of response was correlated with the change in the principle metabolite of melatonin, 6-sulfatoxymelatonin 6-sulfatoxymelatonin excretion. These results suggest that in treatment responders and nonresponders. Twenty-four enhanced noradrenergic function may play an important outpatients meeting DSM-III-R criteria for Major role in determining clinical response to Depression received treatment with either fluvoxamine or antidepressant pharmacotherapy. imipramine for 6 weeks while participating in a placebo- [Neuropsychopharmacology 24:617–623, 2001] controlled double-blind clinical trial. Twenty-four hour © 2001 American College of Neuropsychopharmacology. excretion of 6-sulfatoxymelatonin was measured at baseline Published by Elsevier Science Inc. KEY WORDS: Antidepressants; Melatonin; Norepinephrine; a substantial minority do not, and insights regarding Pineal gland; Depression the necessary psychobiologic components of treatment response could help predict, and perhaps prevent, The introduction of effective antidepressant pharmaco- some cases of treatment failure. therapies in the 1950s revolutionized the treatment of Early observations focused attention on the role of mood disorders. However, despite several decades of norepinephrine (NE) in determining antidepressant re- research, the mechanisms of action of antidepressants sponse. All of the original antidepressants, including remain unclear. Elucidation of these mechanisms is of the tricyclic antidepressants (TCAs) and monoamine considerable clinical, as well as scientific, importance. oxidase inhibitors (MAOIs), enhance noradrenergic Although the majority of patients respond to treatment, neurotransmission, either directly or via active metabo- lites. Based on these observations, early theories of anti- depressant action proposed that clinical response is re- From the Department of Psychiatry (HLM, RDE, GAM, RNG), lated to increased noradrenergic activity in the brain University of North Carolina School of Medicine, Chapel Hill, (Schildkraut 1969). Later studies found that most anti- North Carolina, and the Department of Psychiatry (RBL), Medical depressants, including those with minimal direct bio- University of South Carolina, Charleston, South Carolina. Address correspondence to: Robert N. Golden, M.D., Psychiatry chemical effects on NE, can influence noradrenergic Department, Campus Box # 7160, University of North Carolina, systems. For example, lithium, electroconvulsive ther- Chapel Hill, NC 27599-7160. Tel.: 919-966-4738; Fax: 919-966-7659; apy, the dopamine reuptake inhibitor bupropion, and E-mail: [email protected] Received 2 August 2000; revised 28 October 2000; accepted 2 the serotonin (5-HT) reuptake inhibitor zimelidine all November 2000. decrease “whole-body norepinephrine turnover”; that NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 6 © 2001 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/01/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(00)00232-3 618 H.L. Miller et al. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 6 is, the 24-hour excretion of NE and its major metabo- n-acetyltransferase, the rate-limiting step in melatonin lites (Linnoila et al. 1983; Rudorfer et al. 1984; Golden et production) that lead to the synthesis of melatonin (Ax- al. 1988). Central NE turnover, as measured by cere- elrod 1974) (see Figure 1). Pharmacologic blockade of brospinal fluid concentrations of the NE metabolite ␤ARs suppresses melatonin production (Arendt et al. 3-methoxy-4-hydroxy-phenylglycol (MHPG), is also re- 1985; Cowen et al. 1983). Stimulation of ␣-adrenergic re- duced by a variety of antidepressants, including the ceptors potentiates the effects of ␤AR stimulation on 5-HT specific reuptake inhibitor zimelidine (Potter et al. melatonin synthesis (Klein et al. 1983; Sugden et al. 1985). Based on these observations, it seems that in- 1984; Sugden et al. 1985). Thus, pineal gland melatonin creased noradrenergic function is an integral component production can provide a physiologic index of norad- of antidepressant treatments. renergic activity. In this regard, Axelrod has referred to On the other hand, a wide variety of antidepressants, the pineal gland as a “biochemical transducer,” in rec- including tricyclic NE and 5-HT reuptake inhibitors, ognition of its capacity to convert noradrenergic activ- monoamine oxidase inhibitors, and repeated electro- ity into the production of melatonin (Axelrod 1974). convulsive shock, down-regulate the density of ␤-adr- Pineal gland activity can be assessed by repeated mea- energic receptor (␤AR) ligand-binding sites in limbic suring of plasma melatonin concentration over a 24-hour brain regions, including the cerebral cortex and the hip- period and calculating the area under the curve for such pocampus (Vetulani and Sulser 1975; Banerjee et al. samples. Alternatively, urinary excretion of the principal 1977; Sugrue 1983). Furthermore, nearly all antidepres- metabolite of melatonin can provide a more practical ap- sants diminish the ability of ␤ARs to stimulate adeny- proach for determining net pineal gland activity in psy- late cyclase-mediated cAMP production in these re- chiatric populations. Melatonin is metabolized in the gions (Vetulani and Sulser 1975; Charney et al. 1981), liver, and approximately 85% is excreted as the sulfated and the time course for these receptor changes is consis- (6-sulfatoxymelatonin) and glucuronidated conjugates of tent with the time course for clinical response to antide- 6-hydroxymelatonin (Arendt et al. 1985; Markey et al. pressant treatment. Together, these observations have 1985). There is a robust correlation between nocturnal been cited as support for an alternative hypothesis of plasma melatonin concentrations and urinary excretion antidepressant action, which proposes that ␤AR recep- of 6-sulfatoxymelatonin (6-s-melatonin) (Arendt et al. tor down-regulation, and the consequent decrease in nor- 1985), and intra-individual excretion rates of urinary me- adrenergic function, is responsible for antidepressant latonin metabolites are consistent over time (Bojkowski action (Sulser et al. 1978; Charney et al. 1981). In addi- et al. 1987). Thus, measurement of 24-hour urinary excre- tion, antidepressants decrease tyrosine hydroxylase tion of 6-s-melatonin provides an index for assessing and tyrosine hydroxylase mRNA following chronic ad- changes in noradrenergic function, and can thereby ministration (Nestler et al. 1990), and chronic exposure serve as a useful tool for examining the net effect of anti- to either desipramine or electroshock decreases norepi- depressant treatment on noradrenergic systems. nephrine transporter binding (Bauer and Tejani-Butt In an earlier study, we found that diverse antide- 1992). These observations lend further support to the pressant pharmacotherapies, including the norepineph- hypothesis that antidepressant response is linked to de- rine reuptake inhibitor desipramine, the monoamine creased noradrenergic function (Owens 1996, 1997). oxidase inhibitors clorgiline and tranylcypromine, and There are limits to our ability to resolve these con- the dopamine reuptake inhibitor bupropion, enhance flicting theories of antidepressant mechanism of action 6-hydroxymelatonin output, while diminishing whole by means of approaches that examine isolated, static body norepinephrine turnover (Golden et al. 1988). components of the dynamic NE neurotransmitter sys- However, that study did not examine the relationship tem. The most careful exploration of presynaptic events between these changes in noradrenergic systems and or postsynaptic responses will not completely clarify clinical response. In the current study, we explore the the net physiologic effects of antidepressant treatments relationship between clinical response and changes in in humans. Rather, what is needed is a physiologic gauge 6-s-melatonin output in depressed patients participat- of over-all noradrenergic function that integrates pre- ing in a controlled trial of a serotonin selective reuptake synaptic and postsynaptic events, including those inhibitor, fluvoxamine, and the tricyclic imipramine. events that are “downstream” from receptors, and can be applied to clinical studies (Golden and Potter 1986). Pineal gland production of melatonin is, in many METHODS ways, well suited to serve this purpose. The pineal gland is unique in that, unlike other endocrine organs All subjects gave oral and written informed consent be- in the human body, it is regulated primarily by neural fore entry in the study. Patients meeting DSM-III-R crite- (sympathetic) input and does not seem to be affected by ria for Major Depression were randomly
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