1. Background
1.1 The fragile future of antidepressant development
New treatments for major depressive disorder (MDD) are necessary, considering the high prevalence of nonresponse to current antidepressants that largely target serotonin and norepinephrine transporters. However, the development of psychiatric drugs is considered high risk due to the high trial failure rate and the immense cost associated with an investigational program, especially in the current global economic climate. In fact, many pharmaceutical companies have restructured their pipelines to remove R&D into medications to treat MDD as well as other mental disorders. Both GlaxoSmithKline and AstraZeneca have announced their intention to scale back drug discovery research for some psychiatric disorders, including depression Citation[1]. The resulting decrease in the percentage of drugs in development for depression in the last few years contrasts with the Grand Challenges in Global Mental Health statement that 13% of the global burden of disease can be attributed to mental, neurological and substance-use disorders, exceeding both cardiovascular disease and cancer Citation[2].With the growing burden of psychiatric disorders, including depression, substantial reductions in research investment have the potential for immensely negative consequences, such as an increase in the incidence of treatment-resistant depression (TRD) and exacerbation of outcomes for comorbid conditions associated with unresolved MDD.
1.2 Global scope and new directions in antidepressant development
Since our last publication Citation[3], there have been few additions to the list of potential antidepressant targets. Among the more novel advances are investigations of sigma-1 receptor modulators, vasopressin receptor antagonists and further exploration of melatonin targets to restore circadian rhythm. There are also ongoing attempts to explore the efficacy of triple reuptake inhibitors (TRIs) targeting serotonin, norepinephrine and dopamine transporters.
Due to their physiologic conformation and action, sigma-1 receptors were initially misclassified as a subclass of opioid receptors and later NMDA receptors. It is now understood that they represent unique binding sites that, when bound to inositol receptors, result in the activation of the intramitochondrial tricarboxylic acid cycle, which essentially increases neuroprotection and neurite growth Citation[4]. Animal models of depression have demonstrated rapid antidepressant effects following even a single dose of a sigma-1 agonist such as SA4503 (cutamesine) Citation[5,6]. Furthermore, neurogenic properties of sigma-1 receptor agonists, including cutamesine, have been demonstrated Citation[7]. Research has also shown that existing antidepressants, such as fluvoxamine, as well as certain endogenous neurosteroids are sigma-1 agonists Citation[8-11].
Vasopressin is a small peptide that is thought to play an increasing role in depression during chronic stress, since vasopressin activates the hypothalamic–pituitary axis Citation[12]. Evidence suggests that levels of arginine vasopressin are higher in depressed patients compared with healthy controls Citation[13], and also this increase may be linked to psychomotor retardation during the day and increased motoric activity at night Citation[14]. However, considering this hormone is antidiuretic, clinical trials will have to demonstrate that there are no effects on kidney function.
Following the approval of agomelatine in many countries across Europe, Asia and Latin America, there are ongoing attempts to develop melatonergic agents for MDD, including tasimelteon and BCI-952. In the case of agomelatine, current preclinical evidence suggests that both melatonin agonism and antagonism of the 5HT2C receptors are required to produce antidepressant benefits Citation[15]. By contrast, tasimelteon targets only MT1 and MT2 receptors, while BCI-952 combines melatonin agonism with the 5HT1A agonism of buspirone.
The rationale for triple reuptake inhibition of serotonin, norepinephrine and dopamine depends on the belief that ‘multisystem' targeting may provide a broader spectrum of antidepressant effects, rather than relying on the reciprocal connections across these neurotransmitter systems Citation[16]. While two of the four TRIs previously listed in development failed, one is still in development (amitifadine), the status of the second is undisclosed (DOV 216,303) and four more are undergoing Phase I or II trials (BMS-820836, DOV 102,677, RG7166 SEP 228432).
Aside from mechanism of action, trends in drug development can reflect dosing strategies as well as indication. A greater number of augmentation therapies are being investigated from the outset of development, probably in an effort to achieve more rapid or increased antidepressant response. Another factor for the development of an augmentation therapy to an existing approved drug is the less stringent criteria for FDA or regulatory bodies, where only one adequate and well-controlled study may be required for approval Citation[17].
With respect to changes in indication, there is an increase in drugs being developed to target either depression or anxiety. Considering several first-line antidepressants are effective in treating anxiety, this shift to increase the likelihood of attaining a signal for either disorder seems prudent. Especially with the advent of DSM-5 and the proposal to restructure diagnostic criteria to include ‘mixed anxiety/depression' Citation[18], the need for medications to target both depression and anxiety will probably become more important for drug development in the near future. Additionally, there have been increases in the number of trials investigating TRD or ‘mild' TRD (previous nonresponse to one to two antidepressant trials), although this seems linked to the greater number of companies developing NMDA and mGluR antagonists. Given these agents require an intravenous drug delivery system, they are typically tested in more severe and resistant populations.
2. Competitive environment
In updating the table of drugs in development from 2009 () and listing new drugs in development (), there was a great deal of difficulty in acquiring data on trials. This was particularly the case after company mergers, where drugs were either renamed or the trial data were never released. In these instances we have specified that the stage of development is unclear. Below we describe the current competitive environment based on the data made available through press releases, online reports, news articles and scientific journals. Searches on all drugs identified in the 2009 publication and new drugs in development using key words ‘depression,' ‘major depressive disorder' and ‘major depression' (timeframe 2008 – 1 February 2012) were conducted in www.clinicaltrials.gov. This information was cross-referenced with online tables of drugs in development for depression (e.g., http://www.neurotransmitter.net/newdrugs.html). Subsequently, all drugs were searched in PubMed or Google Scholar for published data. Online press releases and news articles were gathered for all identified drugs and companies.
Table 1. Updated list of drugs in development.
Table 2. List of new drugs in development since 2009*.
2.1 Monoamines
The mainstay of antidepressant development continues to be in the area of monoaminergic function. While new treatment avenues need to be explored, the multitude of research demonstrating changes in monoamine transmission during depression suggests this area could still be fruitful, but is in need of further refinement. For example, the recently FDA-approved antidepressant, vilazodone (Viibryd) Citation[19], may be more effective due to the addition of 5HT1A agonism. Considering there are more than 10 known serotonin receptor subtypes, along with norepinephrine and dopamine receptor subtypes, theoretically, there may be an ideal combination of action to achieve optimal antidepressant activity within and across neurotransmitter systems. Furthermore, more monoamine agents are reaching Phase IV. Of the 31 monoamine agents in development, 6 are approved (agomelatine, desvenlafaxine, transdermal selegiline, trazodone XR, vilazodone and CPI-300), 6 have failed, with the others either still or possibly in development. Vortioxetine (LuAA21004) will be submitted to the FDA for approval in 2012, given positive trial results Citation[20,21]. To the best of our knowledge, there are no other drugs in development with alternative mechanisms of action that are close to approval. However, this could be due to the fact that drugs with alternative actions have not been in development as long as monoamine agents and so the science has not been refined as much.
2.2 Amino acids
The main setbacks for the development of glutamatergic agents continue to be the risk of psychotomimetic side effects and the route of delivery (intravenous). Ketamine is still undergoing clinical trials and positive findings have been reported Citation[22,23], although traxoprodil was discontinued, despite positive trial results, based on side effects. While there is more development of mGluR antagonists, AstraZeneca discontinued AZD2066 (mGluR5 antagonist) for unspecified reasons. Of the 12 drugs in development, there are several that do not have data available, so it is uncertain whether they are still in development (MK-0657, farampator, RG7090, R228060/YKP10A).
2.3 Neuropeptides
Development of neuropeptide agents continues to be unimpressive. Of the 13 in development, 9 failed to meet efficacy endpoints. Orvepitant, an NK1 antagonist, appeared to meet endpoint, but the Phase II trial was terminated due to possible risk of seizures Citation[24]. Mifepristone trials are ongoing despite three failed studies. Trials using the V1b antagonist (AB-436) an opioid/buprenorphine agent (ALKS-5461) and a sigma-1 receptor agonist (cutamesine) appear to be ongoing and may provide a new avenue for success.
2.4 Neurotrophic factors
Neurogenic drugs continue to be developed; however, some of these drugs are not primarily neurogenic and have other mechanisms. As such, investigational agents with another main mechanism of action were placed in the respective table section. There are currently three drugs in development for their neurogenic properties including BCI-540, BCI-952 (melatonin and buspirone), BCI-224 (muscarinic receptor antagonist).
The development program in MDD for rolipram has been discontinued.
2.5 Cytokines
There are five anti-inflammatory agents listed as possible antidepressants. Both infliximab and cimicoxib have completed their trials, and data are pending release. While losmapimod was discontinued due to a failed proof-of-concept study, pioglitazone, a drug FDA approved to treat diabetes, has reported positive Phase II results in a small RCT. Etanercept does not have any trials ongoing in an MDD sample, although a decrease in depression symptoms was observed in patients with rheumatoid arthritis and psoriasis Citation[25,26].
2.6 Acetylcholine
The pursuit of an acetylcholine drug has yet to produce a viable agent. The first two Phase III flexible dose studies using mecamylamine failed and Pfizer's CP-601927 was discontinued due to lack of efficacy. Intravenous scopolamine has demonstrated efficacy Citation[27,28], and the NIMH is spearheading three ongoing trials, although the method of delivery will limit its use. Sabcomeline (BCI-952) is a new agent, and Phase II trials have not yet begun.
3. Conclusion
Successes in antidepressant development over the past 3 years still reflect a refinement of monoaminergic targets: agomelatine combines 5HT2C antagonism with MT1 and MT2 agonism (approved since 2009); vilazodone acts as a 5HT1A partial agonist and 5HT reuptake inhibition (approved 2011 in US); and vortioxetine has affinity for 5HT1A,1B, 3 and 7 in addition to the serotonin transporter (US filing anticipated in 2012). Other recently approved drugs represent modifications to earlier antidepressants: Oleptro (trazodone XR) and Forfivo XL (bupropion 450 mg). While the amino acid targets still attract considerable interest, to date there are no obvious candidates for approval, and multiple attempts to demonstrate an antidepressant signal and a favorable safety profile with neuropeptides have failed.
Overall, antidepressant drug development has suffered from failure to establish valid biomarkers of response that may reflect subtypes of depression with distinct therapeutic targets. With better patient characterization, some of the previously failed investigated agents may have succeeded. Further research needs to bridge diagnostic specificity with alternative mechanisms of action in order to produce viable investigational compounds.
Declaration of interest
SH Kennedy has received honoraria or grant funding from AstraZeneca, Bristol-Meyers Squibb, Clera, Inc., Eli Lilly, GlaxoSmithKline, Lundbeck, Pfizer, Servier, and St. Jude Medical in the last 3 years. SJR has no disclosures to report.
Bibliography
- Boseley S. June 13 2011. Research into brain disorders under threat as drug firms pull out. In guardian.co.uk. Available from: http://www.guardian.co.uk/science/2011/jun/13/research-brain-disorders-under-threat [Retrieved 2 February 2012]
- Collins PY, Patel V, Joestl SS, Grand challenges in global mental health. Nature 2011;475:27-30
- Kennedy SH, Rizvi SJ. Emerging drugs for major depressive disorder. Exp Opin Emerging Drugs 2009;14:1-15
- Hayashi T, Su TP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 2007;131:596-610
- Lucas G, Rymar VV, Sadikot AF, Debonnel G. Further evidence for an antidepressant potential of the selective sigma1 agonist SA 4503: electrophysiological, morphological and behavioural studies. Int J Neuropsychopharmacol 2008;11:485-95
- Tottori K, Miwa T, Uwahodo Y, Antidepressant-like responses to the combined sigma and 5-HT1A receptor agonist OPC-14523. Neuropharmacology 2001;41:976-88
- Nishimura T, Ishima T, Iyo M, Hashimoto K. Potentiation of nerve growth factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP3 receptors and cellular signaling pathways. PLoS One 2008;3:e2558
- Villard V, Meunier J, Chevallier N, Maurice T. Pharmacological interaction with the sigma1 (tau1)-receptor in the acute behavioral effects of antidepressants. J Pharmacol Sci 2011;115:279-92
- Ishikawa M, Ishiwata K, Ishii K, High occupancy of sigma-1 receptors in the human brain after single oral administration of fluvoxamine: a positron emission tomography study using [11C]SA4503. Biol Psychiatry 2007;62:878-83
- Nakano M, Osada K, Misonoo A, Fluvoxamine and sigma-1 receptor agonists dehydroepiandrosterone (DHEA)-sulfate induces the Ser473-phosphorylation of Akt-1 in PC12 cells. Life Sci 2010;86:309-14
- Urani A, Roman FJ, Phan VL, The antidepressant-like effect induced by sigma(1)-receptor agonists and neuroactive steroids in mice submitted to the forced swimming test. J Pharmacol Exp Ther 2001;298:1269-79
- De Wied D, Diamant M, Fodor M. Central nervous system effects of the neurohypophyseal hormones and related peptides. Front Neuroendocrinol 1993;14:251-302
- van Londen L, Goekoop JG, van Kempen GM, Plasma levels of arginine vasopressin elevated in patients with major depression. Neuropsychopharmacol 1997;17:284-92
- van Londen L, Kerkhof GA, van den Berg F, Plasma arginine vasopressin and motor activity in major depression. Biol Psychiatry 1998;43:196-204
- Racagni G, Riva MA, Molteni R, Mode of action of agomelatine: synergy between melatonergic and 5-HT(2C) receptors. World J Biol Psychiatry 2011;12:574-87
- Guiard BP, El Mansari M, Blier P. Prospect of a dopamine contribution in the next generation of antidepressant drugs: the triple reuptake inhibitors. Curr Drug Targets 2009;10:1069-84
- Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products. Guidance for Industry. Food and Drug Administration, 1998. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078749.pdf [Last accessed 6 February 2012]
- First MB. DSM-5 proposals for mood disorders: a cost-benefit analysis. Curr Opin Psychiatry 2011;24:1-9
- Laughren TP, Gobburu J, Temple RJ, Vilazodone: clinical basis for the US Food and Drug Administration's approval of a new antidepressant. J Clin Psychiatry 2011;72:1166-73
- Baldwin DS, Loft H, Dragheim M. A randomised, double-blind, placebo controlled, duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in acute treatment of major depressive disorder (MDD). Eur Neuropsychopharmacol 2011;http://dx.doi.org/10.1016/j.euroneuro.2011.11.008 [Epub ahead of print]
- Alvarez E, Perez V, Dragheim M, A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder. Int J Neuropsychopharmacol 2011; DOI: 10.1017/S1461145711001027 [Epub ahead of print]
- Aan het Rot M, Collins KA, Murrough JW, Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 2010;67:139-45
- Diazgranados N, Ibrahim L, Brutsche NE, A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010;67:793-802
- A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Fixed Dose Study Evaluating the Efficacy and Safety of Orvepitant in Subjects with Major Depressive Disorder. GlaxoSmithKline, 2010. Available from: http://www.gsk-clinicalstudyregister.com/result_comp_list.jsp?compound=orvepitant&studyType=All&phase=All&population=All&marketing=All [Last accessed 23 January 2012]
- Dauden E, Griffiths CE, Ortonne JP, Improvements in patient-reported outcomes in moderate-to-severe psoriasis patients receiving continuous or paused etanercept treatment over 54 weeks: the CRYSTEL study. J Eur Acad Dermatol Venereol 2009;23:1374-82
- Kekow J, Moots R, Khandker R, Improvements in patient-reported outcomes, symptoms of depression and anxiety, and their association with clinical remission among patients with moderate-to-severe active early rheumatoid arthritis. Rheumatology (Oxford) 2011;50:401-9
- Drevets WC, Furey ML. Replication of scopolamine's antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial. Biol Psychiatry 2010;67:432-8
- Furey ML, Khanna A, Hoffman EM, Drevets WC. Scopolamine produces larger antidepressant and antianxiety effects in women than in men. Neuropsychopharmacology 2010;35:2479-88
- Nichols AI, Focht K, Jiang Q, Pharmacokinetics of venlafaxine extended release 75 mg and desvenlafaxine 50 mg in healthy CYP2D6 extensive and poor metabolizers: a randomized, open-label, two-period, parallel-group, crossover study. Clin Drug Investig 2011;31:155-67
- Fabre LF, Brown CS, Smith LC, Derogatis LR. Gepirone-ER treatment of hypoactive sexual desire disorder (HSDD) associated with depression in women. J Sex Med 2011;8:1411-19
- Fabre LF, Smith LC, DeRogatis LR. Gepirone-ER treatment of low sexual desire associated with depression in women as measured by the DeRogatis Inventory of Sexual Function (DISF) fantasy/cognition (desire) domain–a post hoc analysis. J Sex Med 2011;8:2569-81
- Fabre LF, Clayton AH, Smith LC, The effect of gepirone-er in the treatment of sexual dysfunction in depressed men. J Sex Med 2012;9:821-9
- Tran P, Skolnick P, Czobor P, Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial. J Psychiatr Res 2012;46:64-71
- Learned S, Graff O, Roychowdhury S, Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials. J Psychopharmacol 2011; doi: 10.1177/0269881111424931 [Epub ahead of print]
- Dube S, Dellva MA, Jones M, A study of the effects of LY2216684, a selective norepinephrine reuptake inhibitor, in the treatment of major depression. J Psychiatr Res 2010;44:356-63
- Pangallo B, Dellva MA, D'Souza DN, A randomized, double-blind study comparing LY2216684 and placebo in the treatment of major depressive disorder. J Psychiatr Res 2011;45:748-55
- Gandey A. Pramipexole lawsuits a wake-up call for prescribers. 2010. Available from: www.medscape.com/viewarticle/734153 [Last accessed 23 January 2012]
- Coric V, Feldman HH, Oren DA, Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depress Anxiety 2010;27:417-25
- Blasey CM, Block TS, Belanoff JK, Roe RL. Efficacy and safety of mifepristone for the treatment of psychotic depression. J Clin Psychopharmacol 2011;31:436-40
- Mathew SJ, Vythilingam M, Murrough JW, A selective neurokinin-1 receptor antagonist in chronic PTSD: a randomized, double-blind, placebo-controlled, proof-of-concept trial. Eur Neuropsychopharmacol 2011;21:221-9
- Wade AG, Crawford GM, Nemeroff CB, Citalopram plus low-dose pipamperone versus citalopram plus placebo in patients with major depressive disorder: an 8-week, double-blind, randomized study on magnitude and timing of clinical response. Psychol Med 2011;41:2089-97
- Binneman B, Feltner D, Kolluri S, A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry 2008;165:617-20
- Keller M, Montgomery S, Ball W, Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry 2006;59:216-23