Triple reuptake inhibitors for treating subtypes of major depressive disorder: the monoamine hypothesis revisited

Prins, Jolanda; Olivier, Berend; Korte, S. Mechiel

doi:10.1517/13543784.2011.594039

Cited by 89 publications

(60 citation statements)

References 243 publications

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“…Most present treatment options for depression are based on the monoamine hypothesis, and aim to increase the availability of monoamines, such as serotonin, in the synaptic cleft (Prins et al, 2011;Rush et al, 2006). However, the late onset of therapeutic effects as well as unsatisfactory relapse rates and side effects illustrates the need for improved therapeutics (Thase, 2006).…”

Section: Introductionmentioning

confidence: 99%

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

Wagner

Hartmann

Labermaier

et al. 2014

Neuropsychopharmacol

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Stress-induced psychiatric disorders, such as depression, have recently been linked to changes in glutamate transmission in the central nervous system. Glutamate signaling is mediated by a range of receptors, including metabotropic glutamate receptors (mGluRs). In particular, mGluR subtype 5 (mGluR5) is highly implicated in stress-induced psychopathology. The major scaffold protein Homer1 critically interacts with mGluR5 and has also been linked to several psychopathologies. Yet, the specific role of Homer1 in this context remains poorly understood. We used chronic social defeat stress as an established animal model of depression and investigated changes in transcription of Homer1a and Homer1b/c isoforms and functional coupling of Homer1 to mGluR5. Next, we investigated the consequences of Homer1 deletion, overexpression of Homer1a, and chronic administration of the mGluR5 inverse agonist CTEP (2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine) on the effects of chronic stress. In mice exposed to chronic stress, Homer1b/c, but not Homer1a, mRNA was upregulated and, accordingly, Homer1/mGluR5 coupling was disrupted. We found a marked hyperactivity behavior as well as a dysregulated hypothalamic-pituitary-adrenal axis activity in chronically stressed Homer1 knockout (KO) mice. Chronic administration of the selective and orally bioavailable mGluR5 inverse agonist, CTEP, was able to recover behavioral alterations induced by chronic stress, whereas overexpression of Homer1a in the hippocampus led to an increased vulnerability to chronic stress, reflected in an increased physiological response to stress as well as enhanced depression-like behavior. Overall, our results implicate the glutamatergic system in the emergence of stress-induced psychiatric disorders, and support the Homer1/mGluR5 complex as a target for the development of novel antidepressant agents.

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Section: Introductionmentioning

confidence: 99%

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

Wagner

Hartmann

Labermaier

et al. 2014

Neuropsychopharmacol

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“…Thus, the increases in DA observed are more likely an indirect effect of the increases in 5-HT and NA levels. Indeed, increased DA has been reported in the prefrontal cortex following NRI treatment [21,22].…”

Section: Acute Duloxetine Treatmentmentioning

confidence: 99%

Preclinical discovery of duloxetine for the treatment of depression

Torres-Sánchez

Pérez-Caballero

Micó

et al. 2012

Expert Opinion on Drug Discovery

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“…A new era in the antidepressant therapy was ushered on the premise that a broader spectrum inhibition of the three major MAT would lead to enhanced efficacy and faster antidepressant response. Moreover, TRIs should be able to address broad range of depressive symptoms including anhedonia and also exhibit reduced side effects, which are associated with currently available antidepressants [84].…”

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confidence: 99%

Triple Reuptake Inhibitors as Potential Next-Generation Antidepressants: A New Hope?

Santra

Dutta

2015

Future Med. Chem.

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The current therapy for depression is less than ideal with remission rates of only 25–35% and a slow onset of action with other associated side effects. The persistence of anhedonia originating from depressed dopaminergic activity is one of the most treatment-resistant symptoms of depression. Therefore, it has been hypothesized that triple reuptake inhibitors (TRIs) with potency to block dopamine reuptake in addition to serotonin and norepinephrine transporters should produce higher efficacy. The current review comprehensively describes the development of TRIs and discusses the importance of evaluation of in vivo transporter occupancy of TRIs, which should correlate with efficacy in humans.

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Triple reuptake inhibitors for treating subtypes of major depressive disorder: the monoamine hypothesis revisited

Cited by 89 publications

References 243 publications

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

Preclinical discovery of duloxetine for the treatment of depression

Triple Reuptake Inhibitors as Potential Next-Generation Antidepressants: A New Hope?

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