Novel rapid-acting antidepressants: molecular and cellular signaling mechanisms

Thomas, Alexandra M.; Duman, Ronald S.

doi:10.1042/ns20170010

Cited by 10 publications

(5 citation statements)

References 61 publications

(79 reference statements)

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“…Rapid-acting antidepressant agents share some key neurobiological pathways, which probably mediate their antidepressant-like effects [ 79 ]. By altering glutamate transmission, they enhance mTOR signalling, which leads to increased BDNF levels, a process strongly connected to enhanced synaptic activity and plasticity in the prefrontal cortex (PFC).…”

Section: Gender-specific Differences In the Molecular Mechanisms Omentioning

confidence: 99%

Decoding the Mechanism of Action of Rapid-Acting Antidepressant Treatment Strategies: Does Gender Matter?

Herzog

Wegener

Lieb

et al. 2019

IJMS

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Gender differences play a pivotal role in the pathophysiology and treatment of major depressive disorder. This is strongly supported by a mean 2:1 female-male ratio of depression consistently observed throughout studies in developed nations. Considering the urgent need to tailor individualized treatment strategies to fight depression more efficiently, a more precise understanding of gender-specific aspects in the pathophysiology and treatment of depressive disorders is fundamental. However, current treatment guidelines almost entirely neglect gender as a potentially relevant factor. Similarly, the vast majority of animal experiments analysing antidepressant treatment in rodent models exclusively uses male animals and does not consider gender-specific effects. Based on the growing interest in innovative and rapid-acting treatment approaches in depression, such as the administration of ketamine, its metabolites or electroconvulsive therapy, this review article summarizes the evidence supporting the importance of gender in modulating response to rapid acting antidepressant treatment. We provide an overview on the current state of knowledge and propose a framework for rodent experiments to ultimately decode gender-dependent differences in molecular and behavioural mechanisms involved in shaping treatment response.

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Section: Gender-specific Differences In the Molecular Mechanisms Omentioning

confidence: 99%

Decoding the Mechanism of Action of Rapid-Acting Antidepressant Treatment Strategies: Does Gender Matter?

Herzog

Wegener

Lieb

et al. 2019

IJMS

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“…Also, their effectiveness is still questioned. It is now accepted that conventional monopharmacotherapy (with the use of single antidepressant) can be effective only in 60–80% of patients [7, 8]. For this reason, development of new and definitely better drugs is undoubtedly a huge challenge for modern psychiatry [9].…”

Section: Introductionmentioning

confidence: 99%

Neuronal life or death linked to depression treatment: the interplay between drugs and their stress-related outcomes relate to single or combined drug therapies

et al. 2019

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Depression is a serious medical condition, typically treated by antidepressants. Conventional monotherapy can be effective only in 60–80% of patients, thus modern psychiatry deals with the challenge of new methods development. At the same moment, interactions between antidepressants and the occurrence of potential side effects raise serious concerns, which are even more exacerbated by the lack of relevant data on exact molecular mechanisms. Therefore, the aims of the study were to provide up-to-date information on the relative mechanisms of action of single antidepressants and their combinations. In this study, we evaluated the effect of single and combined antidepressants administration on mouse hippocampal neurons after 48 and 96 h in terms of cellular and biochemical features in vitro. We show for the first time that co-treatment with amitriptyline/imipramine + fluoxetine initiates in cells adaptation mechanisms which allow cells to adjust to stress and finally exerts less toxic events than in cells treated with single antidepressants. Antidepressants treatment induces in neuronal cells oxidative and nitrosative stress, which leads to micronuclei and double-strand DNA brakes formation. At this point, two different mechanistic events are initiated in cells treated with single and combined antidepressants. Single antidepressants (amitriptyline, imipramine or fluoxetine) activate cell cycle arrest resulting in proliferation inhibition. On the other hand, treatment with combined antidepressants (amitriptyline/imipramine + fluoxetine) initiates p16-dependent cell cycle arrest, overexpression of telomere maintenance proteins and finally restoration of proliferation. In conclusion, our findings may pave the way to better understanding of the stress-related effects on neurons associated with mono- and combined therapy with antidepressants.

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“…Changes in S6 phosphorylation are associated with activation of the mammalian target of rapamycin (mTOR) signaling cascade; mTOR activates the translational regulator ribosomal protein S6 kinase 1 (S6K1), which in turn activates ribosomal protein S6 by phosphorylation at serine S240/244 (Roux et al, 2007 ). The mTOR-p70S6K pathway has been linked to protein synthesis and structural changes in the mPFC that underlie the therapeutic effects of novel rapid-acting antidepressants (Li et al, 2010 ; Dwyer et al, 2015 ; Thomas and Duman, 2017 ).…”

Section: Mechanisms Underlying the Therapeutic Effects Of Fear Extincmentioning

confidence: 99%

“…Because these pathways mediate long-lasting plastic changes associated with extinction memory, they may also be involved in the lasting therapeutic effects of extinction. Indeed, several of these same signaling pathways have been implicated in the mechanisms of action of both traditional and novel rapid-acting antidepressant drugs (Autry et al, 2011 ; Thomas and Duman, 2017 ). Identification of upstream factors and signaling pathways that initiate extinction-mediated protein synthesis, and downstream factors and pathways that mediate the resulting plasticity underlying its beneficial effects, may lead to the discovery of novel therapeutic targets and strategies to enhance the beneficial effects of extinction, and by translational extension, enhance the therapeutic efficacy of CBT for PTSD.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

A Rodent Model of Exposure Therapy: The Use of Fear Extinction as a Therapeutic Intervention for PTSD

Paredes

Morilak

2019

Front. Behav. Neurosci.

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The symptoms of post-traumatic stress disorder (PTSD) include cognitive impairment related to medial prefrontal cortical dysfunction. Indeed, a deficit of cognitive flexibility, i.e., an inability to modify previously learned thoughts and behaviors based on changes in the environment, may underlie many of the other symptoms of PTSD, such as changes in mood, hyper-arousal, intrusive thoughts, exaggerated and over-generalized fear, and avoidance behavior. Cognitive-behavioral therapies target the cognitive dysfunction observed in PTSD patients, training them to recalibrate stress-related perceptions, interpretations and responses. Preclinically, the extinction of conditioned fear bears resemblance to one form of cognitive therapy, exposure therapy, whereby an individual learns, through repeated exposure to a fear-provoking stimulus in a safe environment, that the stimulus no longer signals imminent threat, and their fear response is suppressed. In this review article, we highlight recent findings from our lab using fear extinction as a preclinical model of exposure therapy in rodents exposed to chronic unpredictable stress (CUS). We specifically focus on the therapeutic effects of extinction on stress-compromised set-shifting as a measure of cognitive flexibility, and active vs. passive coping behavior as a measure of avoidance. Finally, we discuss mechanisms involving activity and plasticity in the medial prefrontal cortex (mPFC) necessary for the therapeutic effects of extinction on cognitive flexibility and active coping.

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Novel rapid-acting antidepressants: molecular and cellular signaling mechanisms

Cited by 10 publications

References 61 publications

Decoding the Mechanism of Action of Rapid-Acting Antidepressant Treatment Strategies: Does Gender Matter?

Decoding the Mechanism of Action of Rapid-Acting Antidepressant Treatment Strategies: Does Gender Matter?

Neuronal life or death linked to depression treatment: the interplay between drugs and their stress-related outcomes relate to single or combined drug therapies

A Rodent Model of Exposure Therapy: The Use of Fear Extinction as a Therapeutic Intervention for PTSD

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