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.
- SourceAvailable from: Jing Wang
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- "Monoamine-based antidepressants, fortuitously discovered from clinical observations in the 1950s, represent a milestone in the treatment of depression    . Moreover, they provide clues to the biological basis of depression. "
ABSTRACT: Depression is a devastating psychiatric disorder widely attributed to deficient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4-8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplification. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant efficacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modified indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.Neuroscience Bulletin 02/2015; 31(1):75-86. DOI:10.1007/s12264-014-1484-6 · 2.51 Impact Factor
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- "It is the leading cause of disability in the U.S. for individuals aged 15e44 (WHO, 2008). It is well known that the pathophysiology of MDD involves a monoaminergic dysfunction (Elhwuegi, 2004; Heninger et al., 1996). Although most antidepressant drugs act acutely on the monoaminergic system by increasing its synaptic availability, the clinical effects of the antidepressant drugs are only observed 2e3 weeks after the onset of treatment (Gourion, 2008). "
ABSTRACT: Agmatine is an endogenous neuromodulator which, based on animal and human studies, is a putative novel antidepressant drug. In this study, we investigated the ability of sub-chronic (21 days) p.o. agmatine administration to produce an antidepressant-like effect in the tail suspension test and examined the hippocampal cell signaling pathways implicated in such an effect. Agmatine at doses of 0.01 and 0.1 mg/kg (p.o.) produced a significant antidepressant-like effect in the tail suspension test and no effect in the open-field test. Additionally, agmatine (0.001-0.1 mg/kg, p.o.) increased the phosphorylation of protein kinase A substrates (237-258% of control), protein kinase B/Akt (Ser(473)) (116-127% of control), glycogen synthase kinase-3β (Ser(9)) (110-113% of control), extracellular signal-regulated kinases 1/2 (119-137% and 121-138% of control, respectively) and cAMP response elements (Ser(133)) (127-152% of control), and brain-derived-neurotrophic factor (137-175% of control) immunocontent in a dose-dependent manner in the hippocampus. Agmatine (0.001-0.1 mg/kg, p.o.) also reduced the c-jun N-terminal kinase 1/2 phosphorylation (77-71% and 65-51% of control, respectively). Neither protein kinase C nor p38(MAPK) phosphorylation was altered under any experimental conditions. Taken together, the present study extends the available data on the mechanisms that underlie the antidepressant action of agmatine by showing an antidepressant-like effect following sub-chronic administration. In addition, our results are the first to demonstrate the ability of agmatine to elicit the activation of cellular signaling pathways associated with neuroplasticity/cell survival and the inhibition of signaling pathways associated with cell death in the hippocampus.Journal of Psychiatric Research 08/2014; 58. DOI:10.1016/j.jpsychires.2014.07.024 · 3.96 Impact Factor
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- "Depression, the predominant form of affective or mood disorders,1 is one of the leading causes of disease burden worldwide, with a great impact on the health status.2 Major drawbacks with currently used antidepressants, which mostly target the monoamines, are that therapeutic effect is only manifested after weeks of treatment and that many patients do not respond to them.3 Therefore, the development of novel fast antidepressants, with alternative mechanisms of action, is a crucial goal in depression research. "
ABSTRACT: Preclinical and clinical data have identified ketamine, a non-selective NMDAR (N-methyl-D-aspartate receptor) antagonist, as a promising medication for patients who do not respond to treatment with monoamine-based antidepressants. Moreover, unlike the current monoamine-based antidepressants, ketamine has a long-lasting effect already after a single dose. The mechanisms of ketamine action remain to be fully understood. Using a recently developed microelectrode array (MEA), which allows sub-second measurements of fluctuating glutamate concentrations, we studied here the effects of in vivo local application of the ketamine and of the N2B subunit-specific antagonist Ro25-6981 upon evoked glutamate release. Both ligands inhibit glutamate release in subregions of the hippocampus and prefrontal cortex. Likewise, acute systemic ketamine treatment, at an antidepressant dose, caused a reduction in evoked glutamate release in the subiculum. We suggest that the effects of ketamine and Ro25-6981 in the subiculum could involve blockade of presynaptic NMDA receptors containing N2B subunits.Translational Psychiatry 06/2014; 4(6):e395. DOI:10.1038/tp.2014.39 · 5.62 Impact Factor