Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies

• Published in: European neuropsychopharmacology Vol. 28; no. 4; pp. 457 - 482
• Main Authors: Artigas, F., Celada, P., Bortolozzi, A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2018
• Subjects: Animals; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - metabolism; Excitatory Amino Acid Agents - pharmacology; Excitatory Amino Acid Agents - therapeutic use; Glutamic Acid - metabolism; Humans; Ketamine; microRNA; MicroRNAs - metabolism; Prefrontal cortex; RNA Interference; Small interfering RNA; AchE; eEF2; RNA; TRD; Small interfering RNA; MDD; ncRNA; A1; MK-801; TRkB; DBS; shRNA; mTOR; EPSC; rACC; vACC; GluN; dsRNA; RNAi; IL; FST; PDE4; Akt-mTOR; i.v; fMRI; SSRI; mPFC; SERT; NA; TREK-1; CRF; dlPFC; PKR; pCPA; GABA; GluA1; 5-HT; PCP; HDAC5; RNA interference; DHK; mRNA; pgACC; SD; NH125; CSF; NMDA; miRNA; TLR; SWA; 5-HT1A receptor; MEF2; Egr1; RISC; BDNF; VEGF; AGO; siRNA; Prefrontal cortex; PrL; TASK3; GSK3β; AMPA receptor; Klf6; NMR; Ketamine; mGluR7; PSD95; SNRI; DAT; ECT; microRNA; NBQX
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2018.01.005

In the second part we focus on two treatment strategies that may overcome the main limitations of current antidepressant drugs. First, we review the experimental and clinical evidence supporting the use of glutamatergic drugs as fast-acting antidepressants. Secondly, we review the involvement of microRNAs (miRNAs) in the pathophysiology of major depressive disorder (MDD) and the use of small RNAs (e.g.., small interfering RNAs or siRNAs) to knockdown genes in monoaminergic and non-monoaminergic neurons and induce antidepressant-like responses in experimental animals. The development of glutamatergic agents is a promising venue for antidepressant drug development, given the antidepressant properties of the non-competitive NMDA receptor antagonist ketamine. Its unique properties appear to result from the activation of AMPA receptors by a metabolite [(2S,6S;2R,6R)-hydroxynorketamine (HNK)] and mTOR signaling. These effects increase synaptogenesis in prefrontal cortical pyramidal neurons and enhance serotonergic neurotransmission via descending inputs to the raphe nuclei. This view is supported by the cancellation of ketamine's antidepressant-like effects by inhibition of serotonin synthesis. We also review existing evidence supporting the involvement of miRNAs in MDD and the preclinical use of RNA interference (RNAi) strategies to target genes involved in antidepressant response. Many miRNAs have been associated to MDD, some of which e.g., miR-135 targets genes involved in antidepressant actions. Likewise, SSRI-conjugated siRNA evokes faster and/or more effective antidepressant-like responses. Intranasal application of sertraline-conjugated siRNAs directed to 5-HT1A receptors and SERT evoked much faster changes of pre- and postsynaptic antidepressant markers than those produced by fluoxetine.