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European Journal of Pharmacology 771 (2016) 236–240

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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 is still far from optimal. Research into 14 November 2015 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, modulators such as 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 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 , leading to stimulation of intracellular sig- current antidepressant treatment naling pathways and consequent regulation of 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 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 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- 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 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 , , CP-101,606 () 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 , 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 GLYX-13 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 , 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 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 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 capable of modulating pocampal increases on BDNF and progenitor cell proliferation. glutamatergic neurotransmission exhibit antidepressant effects in Also, the Ampalex elicited a rapid antidepressant effect animal models, such as (Manosso et al., 2015), when compare to fluoxetine (Knapp et al., 2002). Sleep depriva- (Cardoso et al., 2009), (Neis et al., 2015), ascorbic acid tion, which is capable of producing rapid antidepressant effects, (Moretti et al., 2011), creatine (Cunha et al., 2015a) and guanosine has similar effects on AMPA-mediated plasticity, suggesting that (Bettio et al., 2012). We showed that ascorbic acid, creatine and rapid enhancement of synaptic plasticity might represent the final guanosine exert antidepressant-like effects by inhibiting NMDA target for symptoms remission (Faraguna et al., 2008). receptors and activating mTOR signaling (Bettio et al., 2012, Cunha Despite similar properties of these compounds at NMDA neu- et al., 2015a,b, Moretti et al., 2014). The hippocampal phosphor- rotransmission, their inability to replicate the fast, robust and ylation of p70S6K, a downstream target to mTOR, and increased sustained antidepressant effect of ketamine may be due to doses, levels of PSD-95 were already observed 1 hour after a single ad- pharmacokinetic differences, and activation of different in- ministration of ascorbic acid or creatine in mice (Cunha et al., tracellular signaling pathways. 2015b, Moretti et al., 2014). Moreover, the mTOR inhibitor rapa- mycin abolished the antidepressant-like effect of ascorbic acid, creatine and guanosine in the tail suspension test (Bettio et al., 3. Anti-inflammatory agents for the management of MDD 2012, Cunha et al., 2015b, Moretti et al., 2014), suggesting that mTOR activation may be a key event underlying the anti- Depressive symptoms are commonly observed in patients with depressant effects of these compounds. inflammatory conditions (e.g. aging and obesity), inflammatory Although there is limited clinical evidence indicating the ben- diseases (e.g. atherosclerosis, congestive heart failure and rheu- eficial effects of these compounds for MDD, zinc supplementation matoid arthritis), and in patients undergoing im- was effective in combination with conventional antidepressants munotherapy (Capuron and Dantzer, 2003). The presence of (Lai et al., 2012). Regarding magnesium, although it still remains to asthma and arthritis was significantly higher in depressed in- be established if its administration elicits ketamine-like effects in dividuals (odds ratio (OR)¼1.53, 95% CI, 1.03–2.28; OR¼1.95, 95% behavioral paradigms, it is reported that ketamine increases brain CI, 1.17–3.25, respectively). Heart attack and were more magnesium levels (Murck, 2013). A randomized clinical trial prevalent in depressed patients when compared to controls showed that magnesium was as effective as imipramine for (OR¼3.76, 95% CI, 1.95–7.27; OR ¼2.83, 95% CI, 1.59–5.06, respec- treating MDD in diabetics (Barragán-Rodríguez et al., 2008). The tively) (Kim et al., 2015). Diabetes mellitus is also more prevalent antidepressant effect of agmatine was documented in a small in the depressed group (OR¼1.65, 95% CI, 0.93–2.92) and a meta- 238 M.P. Kaster et al. / European Journal of Pharmacology 771 (2016) 236–240 analysis of longitudinal studies demonstrated that obesity in- monoclonal antibodies (anti-TNF-α) and IDO inhibitor (1-methyl- creases the risk for MDD (OR¼1.55, 95% CI, 1.22–1.98) (Kim et al., ) produce robust antidepressant-like effects in pre- 2015; Luppino et al., 2010). Notably, MDD is associated with per- clinical models (Liu et al., 2015). Several studies have shown the ipheral increase on pro-inflammatory cytokines, such as tumor- effect of the nonsteroidal anti-inflammatory drugs (NSAIDs) necrosis factor-α (TNF-α) and interleukin-1β (Dowlati et al., 2009). acetylsalicylic acid and celecoxib as adjunctive antidepressant Collectively, these data suggest that the relationship between agents (Rosenblat et al., 2014). A meta-analysis exploring 14 ran- MDD and inflammation is bidirectional and driven by immune domized clinical trials concluded that NSAIDs and cytokine in- deregulation. hibitors reduce depressive symptoms as compared to placebo Depressed patients also show increased plasma ratio of ky- (Köhler et al., 2014). However, the best evidence available on the nurenine to tryptophan as a consequence of excessive activation of subject is for celecoxib. A recent meta-analysis showed that 4–6 the indoleamine 2,3-dioxygenase (IDO) by pro-in- weeks of treatment with celecoxib was associated with higher flammatory cytokines. IDO activation produces that, in response (OR¼6.6, 95% CI, 2.5–17.0) and higher remission rates turn, may be metabolized by perivascular and mi- (OR¼6.6, 95% CI, 2.7–15.9) in medicated MDD patients (Far- croglia to generate neuroactive glutamatergic compounds, such as idhosseini et al., 2014). It is still not established if these benefits , an NMDA receptor agonist, contributing to gluta- are limited to patients with increased peripheral inflammatory matergic excitotoxicity (Dantzer and Walker, 2014). Therefore, markers and there are no data to support the use of celecoxib or anti-inflammatory agents modulating pro-inflammatory cytokines other NSAIDs in antidepressant-resistant patients. levels, IDO activity, microglial activation and consequently gluta- Preclinical studies show that depressive behavior associated matergic excitotoxicity may be promising agents for MDD with inflammatory conditions involves increased glutamate levels treatment. in prefrontal cortex of mice (Martín-de-Saavedra et al., 2013). In Several anti-inflammatory strategies, such as , addition, increased levels of pro-inflammatory cytokines and

Glutamatergic Modulators

Fig. 1. Potential strategies for the management of MDD targeting glutamatergic modulation and inflammation. Several studies have suggested that the ketamine and some glutamatergic agents, including ascorbic acid, creatine, zinc, guanosine, as well as mGluR2/3 antagonist LY341495, and NMDA receptor glycine site functional partial agonist GLYX-13 which modulate the glutamatergic system may cause antidepressant effects. These compounds may cause stimulation of mTOR activity and synthesis of synaptic proteins (such as PSD-95 and GluA1), leading to synaptogenesis. This mechanism is particularly well established for ketamine and remains to be investigated for the other mentioned glutamatergic modulators. Furthermore, proinflammatory cytokines induce IDO activation, which in turn increase the levels of kynurenine (KYN) and its toxic metabolite quinolinic acid, an NMDA receptor agonist that mediates excitotoxicity. Ketamine and other anti-inflammatory drugs may decrease the levels of pro-inflammatory cytokines, KYN and its metabolites. IDO inhibitors decrease KYN levels and microglial activation and exert antidepressant effects. Akt¼ B; BDNF¼brain- derived neurotrophic factor; ERK¼extracellular signal-regulated kinase; HAAO¼3-hydroxyanthranilate 3,4-dioxygenase; IDO¼indoleamine 2,3-dioxygenase; KY- NU¼kynureninase; KMO¼kynurenine 3-monooxygenase; MEK ¼ mitogen-activated protein kinase kinase; mTORC1¼mammalian target of rapamycin complex 1; NMDAR¼N-methyl-D-aspartate receptor; PI3K¼phosphoinositide 3 kinase; TrkB¼tropomyosin receptor kinase B. M.P. Kaster et al. / European Journal of Pharmacology 771 (2016) 236–240 239 quinolinic acid in cerebrospinal fluid were reported in medication- 2012. Guanosine produces an antidepressant-like effect through the modula- free suicide attempters (Erhardt et al., 2013). It is proposed that tion of NMDA receptors, -cGMP and PI3K/mTOR pathways. Behav. 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