Emerging Mechanisms and Treatments for Depression Beyond Ssris and Snris
Total Page：16
File Type：pdf, Size：1020Kb
G Model BCP-12210; No. of Pages 17 Biochemical Pharmacology xxx (2015) xxx–xxx Contents lists available at ScienceDirect Biochemical Pharmacology jo urnal homepage: www.elsevier.com/locate/biochempharm Research update Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs a, b a Elena Dale *, Benny Bang-Andersen , Connie Sa´nchez a Lundbeck Research USA, Paramus, NJ 07652, USA b Lundbeck Research DK, Ottiliavej 9, 2500 Copenhagen, Valby, Denmark A R T I C L E I N F O A B S T R A C T Article history: The monoamine hypothesis has been the prevailing hypothesis of depression over the last several Received 23 December 2014 decades. It states that depression is associated with reduced monoamine function. Hence efforts to Accepted 13 March 2015 increase monoamine transmission by inhibiting serotonin (5-HT) and norepinephrine (NE) transporters Available online xxx has been a central theme in depression research since the 1960s. The selective 5-HT reuptake inhibitors (SSRIs) and 5-HT and NE reuptake inhibitors (SNRIs) that have emerged from this line of research are Keywords: currently first line treatment options for major depressive disorder (MDD). One of the recent trends in Depression antidepressant research has been to refine monoaminergic mechanisms by targeting monoaminergic Antidepressants receptors and additional transporters (e.g. with multimodal drugs and triple re-uptake inhibitors) or by Serotonin Glutamate adding atypical antipsychotics to SSRI or SNRI treatment. In addition, several other hypotheses of SSRI depression have been brought forward in pre-clinical and clinical research based on biological hallmarks of the disease and efficacy of pharmacological interventions. A central strategy has been to target glutamate receptors (for example, with intravenous infusions of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine). Other strategies have been based on modulation of cholinergic and g- aminobutyric acid (GABA)ergic transmission, neuronal plasticity, stress/hypothalamic pituitary adrenal(HPA)-axis, the reward system and neuroinflammation. Here we review the pharmacological profiles of compounds that derived from these strategies and have been recently tested in clinical trials with published results. In addition, we discuss putative treatments for depression that are being investigated at the preclinical level and outline future directions for antidepressant research. ß 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction NE and/or 5-HT transporters (NET and SERT, respectively). Furthermore, they have notable affinity for secondary receptor The selective serotonin (5-HT) reuptake inhibitor (SSRI) and 5- or transporter targets at clinically relevant doses. For example, HT and norepinephrine (NE) reuptake inhibitor (SNRI) antide- among the SSRIs paroxetine shows affinity for the NET and the pressants that were launched during the 1980s and 1990s are muscarinic cholinergic receptor, sertraline for the dopamine (DA) among the most successful drug treatments for psychiatric transporter (DAT), fluoxetine for the 5-HT2C receptor, citalopram disorders and still remain the first line treatments for major for the sigma1 and histamine (HA) H1 receptors, and escitalopram depressive disorder (MDD). Monoamine oxidase (MAO) inhibitors for the sigma1 receptor [1–3]. Similarly, SNRIs show differences in have also been used for the treatment of MDD, but to a lesser potency for SERT vs. NET with venlafaxine having a preference for extent. SSRIs and SNRIs are often presented as two major classes of SERT over NET, and duloxetine being a more balanced drug with antidepressants, with each class comprised of individual drugs that respect to 5-HT and NE reuptake inhibitory potencies [4]. These are highly similar. However, thorough pharmacological character- distinct pharmacological properties may lead to different clinical ization has shown that drugs from these two classes have different efficacy and/or tolerability profiles [4,5]. However, possibly due to levels of selectivity for their primary pharmacological target(s), i.e. a lack of validated biomarkers that can reliably predict a patient’s response to a given antidepressant, it appears that only 50% of patients diagnosed with MDD go into clinical remission using treatments from these two drug classes regardless of the drug * Corresponding author. Tel.: +1 201 350 0574; fax: +1 201 261 0623. chosen [6]. For four consecutive treatment steps, the overall E-mail address: [email protected] (E. Dale). http://dx.doi.org/10.1016/j.bcp.2015.03.011 0006-2952/ß 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Please cite this article in press as: Dale E, et al. Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol (2015), http://dx.doi.org/10.1016/j.bcp.2015.03.011 G Model BCP-12210; No. of Pages 17 2 E. Dale et al. / Biochemical Pharmacology xxx (2015) xxx–xxx cumulative remission rate is only 56% [6]. This leaves a large During the last decade there has been an increasing interest in group of patients who respond inadequately or not at all to targeting glutamate neurotransmission. The interest in gluta- extensive therapeutic intervention. Moreover, the therapeutic mate targets precipitated from the spectacular clinical finding response to SSRIs/SNRIs is often delayed, requiring several weeks that intravenous infusion of the N-methyl-D-aspartate (NMDA) of treatment. Many of the current antidepressants also have drug- receptor antagonist ketamine can produce an immediate related adverse effects, such as nausea and sexual dysfunction antidepressant effect in patients with treatment-resistant [7]. Thus, there is a large unmet need for additional treatment depression (TRD) [10]. Several other glutamate targets have options. been defined, some of which have been tested in the clinic and While the etiology and pathology underlying MDD still by large are discussed in Section 3. remain unknown, many hypotheses of depression have been The neuroplasticity hypothesis of depression links to the brought forward in antidepressant research. Several of these glutamate hypothesis. It is based on the observation that enhanced investigations have led to drug discovery efforts and in some cases neuronal plasticity (e.g. neurogenesis, dendritic branching, synap- advanced into drug development programs (Fig. 1, Tables 1 and 2). togenesis) appears to be a shared mechanism for antidepressants Interestingly, the rationale of these hypotheses often originated and that depression risk factors, such as stress, reduce neuroplas- from pharmacological manipulations performed in depressed ticity in the hippocampus and prefrontal cortex (PFC) (Fig. 1, [11]). patients and was not based on an understanding of the There have been extensive preclinical efforts to identify neuronal pathophysiology of disease. plasticity related drug targets (Table 1 and Section 5), but the Over the last 40–50 years the prevailing hypothesis of hypothesis has so far not been validated clinically. depression has been the monoamine hypothesis which included Additional hypotheses of depression have been based on the catecholamine [8] and 5-HT [9] hypotheses. It originated from modulation of cholinergic transmission, stress/hypothalamic mechanistic studies of the serendipitously discovered tricyclic pituitary adrenal (HPA)-axis, reward system, neuroinflammation antidepressants (TCA) and MAO inhibitors. SSRIs and SNRIs that and g-butyric acid (GABA) transmission (Fig. 1, Table 1). Com- came out of this line of research were conceived to mainly improve pounds that were generated to test these theories (e.g. cortioco- tolerability of TCAs. Since the discovery of SSRIs and SNRIs, one tropin releasing factor (CRF) antagonists, neurokinin (NK) strategy in antidepressant research has been to refine and expand antagonists, kappa-opioid antagonists, Tumor Necrosis Factor on the monoaminergic mechanisms by either targeting monoam- (TNF) a antibody) are discussed in Section 4. Compounds with inergic receptors or additional transporters in one molecule or by only preclinical mechanistic data are outlined in Table 1 and some augmenting the effects of SSRIs or SNRIs by adjunctive treatment of them are discussed in Section 5. Finally, possible future with another drug. The main objectives have been to improve directions for antidepressant research are discussed at the end efficacy and/or reduce the time to onset the therapeutic effect of of this review in Section 6. SSRIs and SNRIs. We review drug target profiles that came out of these efforts and have been tested in the clinic in Section 2 and 2. Refining and expanding monoaminergic mechanisms Table 2. Additional target profiles that have only been investigated beyond SSRIs and SNRIs in preclinical models are summarized in Table 1 and Section 5. Other research efforts have focused on hypotheses of Whereas a general increase in extracellular monoamine levels depression that go beyond the monoamines (Fig. 1, Table 1). via inhibition of monoamine transporters may trigger a dampening Fig. 1. Summary of current hypotheses of depression. Proposed hypotheses of depression and their associated drug targets are shown in the top oval. For a full list of drug targets see Table 1. Several biological processes involved in the etiology of depression are listed in the middle