Emerging antidepressants to treat major depressive disorder

Block, Samantha; Nemeroff, Charles B.

doi:10.1016/j.ajp.2014.09.001

Cited by 46 publications

(36 citation statements)

References 114 publications

(110 reference statements)

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“…Virtually all drugs used to treat depression target the same basic mechanisms identified serendipitously more than 60 years ago and these existing pharmacotherapies induce full remission in fewer than 50% of people (Block and Nemeroff, 2014). Depression is thought to arise from a complex interaction of biological, psychological and social factors and, consequently, finding a single target that causes depression in all individuals is unlikely.…”

Section: Introductionmentioning

confidence: 99%

Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility

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Cates

Purushothaman

et al. 2016

Neuron

307

322

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Summary Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here we performed RNA-sequencing on 4 brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery.

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Section: Introductionmentioning

confidence: 99%

Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility

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Cates

Purushothaman

et al. 2016

Neuron

307

322

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“…Virtually all drugs used to treat depression today target the same basic mechanisms identified more than 60 years ago, inducing full remission in fewer than 50% of affected individuals (2). Earlier treatments, such as tricyclic antidepressants (e.g.…”

Section: Introductionmentioning

confidence: 99%

Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles

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Purushothaman

et al. 2017

Biological Psychiatry

135

114

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Background Examining transcriptional regulation by antidepressants in key neural circuits implicated in depression, and understanding the relationship to transcriptional mechanisms of susceptibility and natural resilience, may help in the search for new therapeutics. Given the heterogeneity of treatment response in human populations, examining both treatment response and non-response is critical. Methods We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine, and a rapidly acting, non-monoamine-based antidepressant, ketamine, in mice subjected to chronic social defeat stress, a validated depression model, and used RNA-sequencing to analyze transcriptional profiles associated with susceptibility, resilience and antidepressant response and non-response in prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala. Results We identified similar numbers of responders and non-responders following ketamine or imipramine treatment. Ketamine induced more expression changes in hippocampus; imipramine induced more expression changes in nucleus accumbens and amygdala. Transcriptional profiles in treatment responders were most similar in PFC. Non-response reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptibility-associated transcriptional changes as well as induced resilience-associated transcription in PFC. Conclusions We generated a uniquely large resource of gene expression data in four inter-connected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by both antidepressant drugs and in both reversing susceptibility- and inducing resilience-associated molecular adaptations. In addition, we found region-specific effects of each drug suggesting both common and unique effects of imipramine versus ketamine.

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“…Neurostimulation and neuromodulation strategies (electroconvulsive therapy, repetitive transcranial magnetic stimulation, vagus nerve stimulation) are also available for subjects insufficiently responding to pharmacotherapy or psychosocial interventions [1,27–30]. …”

Section: Introductionmentioning

confidence: 99%

Investigational drugs in recent clinical trials for treatment-resistant depression

Garay

Zarate

Charpeaud³

et al. 2017

Expert Review of Neurotherapeutics

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Introduction The authors describe the medications for treatment-resistant depression (TRD) in phase II/III of clinical development in the EU and USA and provide an opinion on how current treatment can be improved in the near future. Areas covered Sixty-two trials were identified in US and EU clinical trial registries that included six investigational compounds in recent phase III development and 12 others in recent phase II clinical trials. Glutamatergic agents have been the focus of many studies. A single intravenous dose of the glutamatergic modulator ketamine produces a robust and rapid antidepressant effect in persons with TRD; this effect continues to remain significant for 1 week. This observation was a turning point that opened the way for other, more selective glutamatergic modulators (intranasal esketamine, AVP-786, AVP-923, AV-101, and rapastinel). Of the remaining compounds, monoclonal antibodies open highly innovative therapeutic options, based on new pathophysiological approaches to depression. Expert commentary Promising new agents are emerging for TRD treatment. Glutamatergic modulators likely represent a very promising alternative to monoaminergic antidepressant monotherapy. We could see the arrival of the first robust and rapid acting antidepressant drug in the near future, which would strongly facilitate the ultimate goal of recovery in persons with TRD.

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Emerging antidepressants to treat major depressive disorder

Cited by 46 publications

References 114 publications

Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility

Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility

Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles

Investigational drugs in recent clinical trials for treatment-resistant depression

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