The Revised Monoamine Theory of Depression: A Modulatory Role for Monoamines, Based on New Findings From Monoamine Depletion Experiments in Humans

Abstract

The original hypothesis that brain monoamine systems have a primary direct role in depression has been through several modifications during the past 30 years. In order to test this hypothesis and more fully characterize the role of serotonin and catecholamines in the pathophysiology of depression and the mechanism of action of antidepressant treatments, our research group has conducted a series of studies evaluating monoamine depletion induced brief clinical relapse following different types of antidepressant treatment of depressed patients. We have also studied the effects of monoamine depletion (SD) on depressive symptoms in depressed and recovered patients off medication and in healthy controls. Relapse to serotonin depletion or to catecholamine depletion (CD) was found to be specific to the type of antidepressant treatment, i.e., patients responding to selective serotonin reuptake inhibilitors relapsed more frequently following SD than CD and patients responding to selective catecholamine reuptake inhibitors relapsed more frequently following CD than SD. Neither CD or SD increased depressive symptoms in clinically ill patients off treatment, or produced clinical depression in normal controls. However, recovered patients with a prior history of depression had a relapse with SD. Patients with obsessive compulsive disorder who improved on SSRI treatment, did not have an increase in OCD symptoms but those with prior depressive symptoms did have an increase in depressive symptoms with SD. The findings that relapse during treatment is specific to the type of treatment and type of depletion, that neither SD or CD produced an increase in clinical depression in healthy controls or depressed patients off medication, and that recovered patients off medication have a return of symptoms following SD, forces a major revision of the current monoamine theories of depression. The new hypothesis most consistent with this new data is that the monoamine systems are only modulating "other" brain neurobiologic systems which have a more primary role in depression. The modulatory or "antidepressant" function of the monoamine systems appears to be only necessary during drug induced recovery and the maintenance of recovery after a prior episode. These clinical studies point to the need for more fundamental research on the interaction of monoamine systems with other brain neurobiologic mechanisms relevant to depression.

Differential Role of Galanin Receptors in the Regulation of Depression-Like Behavior and Monoamine/Stress-Related Genes at the Cell Body Level

“…It is generally assumed that dysfunctional monoaminergic transmission may underlie various symptoms of depression, including the susceptibility to stress (see Heninger et al, 1996;Mongeau et al, 1997;Holsboer, 2001;Morilak and Frazer, 2004). Since galanin and the galanin receptors are expressed in both the NA and 5-HT systems, it is possible that the role of galanin in depression-like behavior may, at least partially, be related to modulation of brain NA and/or 5-HT functions at the cell body level and/or their projection areas.…”

“…Dysfunctions of brain noradrenaline (NA) and serotonin (5-hydroxytryptamine, 5-HT) neurotransmission as a consequence of uncontrollable (chronic) stress are implicated in depression (see Weiss et al, 1981;Heninger et al, 1996;Holsboer, 2001). In fact, the current pharmacotherapy of depression is also mainly based on use of compounds correcting dysfunctions in monoaminergic transmission, including selective serotonin reuptake inhibitors (SSRIs) (see Frazer, 1997;Millan, 2004).…”

Evaluation of Antidepressant-related Behavioral Responses in Mice Lacking the Serotonin Transporter

“…In an interesting parallel in humans, depressed patients treated with serotonin reuptake inhibitors are prone to relapse if serotonin levels are pharmacologically depleted, but not if catecholamines are depleted. Conversely, catecholamine, but not serotonin, depletion produces relapse in patients that have been treated with norepinephrine reuptake inhibitors (Delgado et al 1990(Delgado et al , 1991Heninger et al 1996). On the basis of such findings, some authors have suggested that antidepressants that have varying affinity for noradrenergic versus serotonergic systems produce their behavioral effects via separate mechanisms (Page et al 1999).…”

Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

“…On the other hand, Delgado and co-workers have suggested that although both NE and serotonin (5-HT) mediate antidepressant responses, these actions are independent, that is, the depletion of one neurotransmitter had little effect on patients treated with an AD acting primarily on the other neurotransmitter (Delgado and Moreno, 2000;Heninger et al, 1996). Therefore, it was interesting to use the recently generated (Xu et al, 2000), genetically modified mice lacking the NET (NET À/À mice) for studying the role of the NET and the noradrenergic system in the actions of ADs, and to compare the effects of ADs with those described in previous studies carried out with mice lacking the 5-HT transporter (Holmes et al, 2002).…”