European Journal of Pharmacology 771 (2016) 236–240 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar Perspective Novel approaches for the management of depressive disorders Manuella P. Kaster a, Morgana Moretti b, Mauricio P. Cunha a, Ana Lúcia S. Rodrigues a,n a Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, Brazil b Department of Nutrition, Center of Health Sciences, Federal University of Santa Catarina, Florianópolis, SC, Brazil article info abstract Article history: Major depressive disorder is a disabling psychiatric condition that causes a significant burden on in- Received 22 July 2015 dividuals and society. There is still a lack of a clear understanding of the neuropathological changes Received in revised form associated with this illness and the efficacy of antidepressants is still far from optimal. Research into 14 November 2015 antidepressant therapies has evolved from serendipitous observation in human trials, but more than 60 Accepted 14 December 2015 years after the first monoaminergic antidepressants emerged they remain the mainstay for treating Available online 15 December 2015 depression. However, glutamatergic modulators such as ketamine became the forefront of anti- Keywords: depressant exploration, especially for treatment-resistant depression and suicidal ideation. The gluta- Depression matergic hypothesis of depression is not new, however other NMDA receptor modulators do not seem to Antidepressants share the rapid and sustained effects of ketamine, suggesting that a unique combination of intracellular Glutamatergic system targets might be involved in its effect. Interestingly, inflammation can impact the glutamatergic system Inflammation enhancing excitotoxicity and decreasing neuroplasticity. The points of convergence between the in- flammatory and glutamatergic hypotheses of depression are not completely established, especially re- garding the effects of fast-acting antidepressants. In this review, we discuss the most recent research surrounding glutamatergic fast-acting antidepressants, capable of modulating cellular plasticity and synaptogenesis and the potential of anti-inflammatory compounds evaluated from a different perspec- tive. The combination of innovative ideas plus improvements on the discoveries made so far might lead to advances in antidepressant research with the promise of finding compounds that are both effective and fast-acting, even in patients who have tried other therapies with limited success. & 2015 Elsevier B.V. All rights reserved. 1. Major depressive disorder (MDD) – pathophysiology and and prefrontal cortex, leading to stimulation of intracellular sig- current antidepressant treatment naling pathways and consequent regulation of genes associated with neuroplasticity and cell survival (Castrén and Rantamaki, MDD causes profound socioeconomic burden and negative 2010). impact on functioning and quality of life of patients (Papakostas Inflammation has also emerged as an important etiologic fac- and Ionescu, 2015). Although there has been significant research tor, and thus a potential pharmacological target for MDD. Pro-in- directed towards understanding the biologic underpinnings of flammatory cytokines are increased in depressed patients (Dowlati MDD, there is not a complete consensus about the neurochemical et al., 2009) resulting in an imbalance in critical neuroactive alterations present in depressive individuals. The monoamine compounds and changes in brain structural and synaptic plasticity hypothesis of depression proposes that underactivity of mono- (Dantzer and Walker, 2014). Interestingly, antidepressant therapy may attenuate this inflammatory dysfunction in depressed in- amines may underlie the pathophysiology of this disorder dividuals (Lanquillon et al., 2000). Moreover, neuroinflammation is (Schildkraut, 1965). In addition, impairments on structural plasti- associated with increased extracellular glutamate levels, causing city and cellular resilience associated with reduced levels of brain- neurotoxicity that contributes to depressive symptoms (Sanacora derived neurotrophic factor (BDNF) have been implicated in the et al., 2012). pathophysiology of MDD (Sen et al., 2008). Chronic antidepressant Current antidepressant treatments are limited in both efficacy treatment increases BDNF levels, particularly in the hippocampus and tolerability. The drawbacks include delayed therapeutic onset and side effects that reduce adhesion to treatment (Papakostas n Corresponding author. and Ionescu, 2015). Approaches targeting new pathways have E-mail address: [email protected] (A.L.S. Rodrigues). been investigated and may represent a significant improvement in http://dx.doi.org/10.1016/j.ejphar.2015.12.029 0014-2999/& 2015 Elsevier B.V. All rights reserved. M.P. Kaster et al. / European Journal of Pharmacology 771 (2016) 236–240 237 the therapeutic armamentarium for treating MDD. number of subjects (Shopsin, 2013) and ascorbic acid was effective as adjuvant agent for MDD in pediatric patients (Amr et al., 2013). Antidepressant effects of creatine supplementation were also re- 2. The search for fast-acting antidepressants: targeting the ported in depressive patients (Allen, 2012). However, there are no glutamatergic system clinical studies evaluating the mood effects of guanosine. The antidepressant effects of other NMDA receptor antagonists Seminal work by Trullas and Skolnick (1990) was the first re- and glutamate-modulators such as MK-801, AP-7, RO25-6981, porting that NMDA receptor antagonists exhibit antidepressant amantadine, memantine, CP-101,606 (traxoprodil) and riluzole properties in preclinical models. After this observation, several were extensively studied in preclinical models (Dutta et al., 2015). laboratories demonstrated that functional antagonists at multiple Most of these agents fail to afford rapid and sustained anti- NMDA receptor sites including ligands at glutamate, polyamine, depressant effects (Dutta et al., 2015; Preskorn et al., 2008; Zarate glycine, bivalent cations and ionophore recognition sites are effi- et al., 2004). Some promising results were observed with the low- cacious in models of depression (Sanacora et al., 2012). trapping NMDA channel blocker AZD6765, which elicits rapid, but In the late 1990s reduction of NMDA receptor function was not sustained, antidepressant effects in treatment-resistant MDD recognized as a long-term adaptation associated with anti- patients (Zarate et al., 2013). However, the intracellular pathways depressant effects (Skolnick, 1999). A promising clinical study by involved in its effect are not established. Also, antidepressant-like Berman et al. (2000) showed that the non-competitive NMDA effect of the NMDA receptor glycine-site partial agonist GLYX-13 receptor antagonist ketamine induced a rapid and persistent an- requires AMPA receptor and mTOR activation, similar to ketamine tidepressant response in severe depressive patients. Evidence now (Lu et al., 2014). The antidepressant potential of GLYX-13 was indicates that ketamine inhibits NMDA receptors on GABAergic confirmed in a clinical trial, and a fast (2 h) and sustained remis- interneurons increasing glutamate release. The consequent acti- sion of depressive symptoms was observed without dissociative vation of AMPA receptors causes depolarization of postsynaptic effects (Moskal et al., 2014; Preskorn et al., 2015). CP-101,606, a neurons, leading to voltage-dependent calcium channel activation. selective NR2B receptor antagonist, produced symptoms’ remis- As a consequence, BDNF released from vesicles activates mTOR sion by day 5 in depressed patients unresponsive to paroxetine signaling. Finally, translation of synaptic proteins in prefrontal (Preskorn et al., 2008). However, the intracellular pathways asso- cortex, particularly those implicated in synaptogenesis, including ciated with this effect need to be elucidated in preclinical studies. PSD-95, synapsin and GluA1 is the final event associated with Metabotropic glutamate receptor modulators and AMPA re- ketamine’s rapid antidepressant effect (Li et al., 2010). ceptor potentiators also represent interesting targets in the search Although the discovery of ketamine for treating severe de- for novel fast-acting antidepressant compounds. The blockade of pressed patients has represented a significant advance in the field, presynaptic mGluR2/3 receptors regulates glutamate release and its abuse liability and potential neurotoxicity upon repeated use produces rapid behavioral responses that require activation of ei- has led to the interest in the development of safer fast-acting ther AMPA receptors or mTOR signaling (Dwyer et al., 2012). antidepressants (Abdallah et al., 2015). Considering that ketamine Specifically, LY341495, an mGlu2/3 receptor antagonist, reduced modulates the glutamatergic system, there has been increasing the time required for antidepressants to exert their effects by a interest in targeting this system for the development of novel fast- mechanism dependent on stimulation and expression of AMPA acting antidepressants. receptors in prefrontal cortex (Matrisciano et al., 2005). Moreover, Our research group has particular interest in antidepressant preclinical studies have shown that AMPA potentiators LY392098 effects afforded by some endogenous compounds that target the and LY451616 exhibit antidepressant effects associated with hip- glutamatergic system. Several compounds