Skip to main content
SpringerLink
Log in

Is There Anything Really Novel on the Antidepressant Horizon?

  • Mood Disorders (SM Strakowski, Section Editor)
  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

Abstract

Major depression represents one of the most disabling illnesses worldwide and current treatments are only partially effective. All antidepressant agents modulate the monoamine system, which likely accounts for the similar efficacy profile of available treatments. Herein we summarize the current state of depression therapeutics and assess the antidepressant development pipeline. Antidepressant response rates in controlled trials are estimated at ~54 % and real-world effectiveness data suggests a somewhat lower rate. Response rates are lower still in patients who have not responded to previous treatment attempts and meaningful advancements will likely come only from identification of mechanistically novel agents. Monoaminergic agents largely dominate the antidepressant development pipeline, however the glutamate neurotransmitter system represents a bright spot on the antidepressant horizon. We review in detail findings regarding the antidepressant effects of the glutamate N-methyl-d-aspartate receptor antagonist ketamine in order to highlight the promise of novel agents as future treatments for major depression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. World Health Organization. The global burden of disease: 2004 update. 2008.

  2. • Collins PY, Patel V, Joestl SS, et al. Grand challenges in global mental health. Nature. 2011;475:27–30. This article provides an overview of the global burden of mental health and highlights depressive disorders as the most disabling brain-based disorders worldwide.

    Article  PubMed  CAS  Google Scholar 

  3. Berton O, Nestler EJ. New approaches to antidepressant drug discovery: Beyond monoamines. Nat Rev Neurosci. 2006;7:137–51.

    Article  PubMed  CAS  Google Scholar 

  4. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455:894–902.

    Article  PubMed  CAS  Google Scholar 

  5. Manji HK, Quiroz JA, Sporn J, et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry. 2003;53:707–42.

    Article  PubMed  CAS  Google Scholar 

  6. Mathew SJ, Manji HK, Charney DS. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008;33:2080–92.

    Article  PubMed  CAS  Google Scholar 

  7. Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358:252–60.

    Article  PubMed  CAS  Google Scholar 

  8. Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: A patient-level meta-analysis. JAMA. 2010;303:47–53.

    Article  PubMed  CAS  Google Scholar 

  9. Undurraga J, Baldessarini RJ. Randomized, placebo-controlled trials of antidepressants for acute major depression: Thirty-year meta-analytic review. Neuropsychopharmacology. 2012;37:851–64.

    Article  PubMed  CAS  Google Scholar 

  10. Levkovitz Y, Tedeschini E, Papakostas GI. Efficacy of antidepressants for dysthymia: A meta-analysis of placebo-controlled randomized trials. J Clin Psychiatry. 2011;72:509–14.

    Article  PubMed  CAS  Google Scholar 

  11. Gartlehner G, Hansen RA, Morgan LC, et al. Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: An updated meta-analysis. Ann Intern Med. 2011;155:772–85.

    PubMed  Google Scholar 

  12. Lam RW, Kennedy SH, Grigoriadis S, et al. Canadian network for mood and anxiety treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults III. Pharmacotherapy. J Affect Disord. 2009;117:S26–43.

    Article  PubMed  Google Scholar 

  13. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice. Am J Psychiatry. 2006;163:28–40.

    Article  PubMed  Google Scholar 

  14. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry. 2006;163:1905–17.

    Article  PubMed  Google Scholar 

  15. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354:1231–42.

    Article  PubMed  CAS  Google Scholar 

  16. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:1243–52.

    Article  PubMed  CAS  Google Scholar 

  17. Rush AJ, Trivedi MH, Stewart JW, et al. Combining medications to enhance depression outcomes (CO-MED): Acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry. 2011;168:689–701.

    Article  PubMed  Google Scholar 

  18. Pharmaceutical Research and Manufacturers of America (PhRMA). Medicines in development for mental illness report 2012.

  19. Sanacora G, Zarate CA, Krystal JH, et al. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008;7:426–37.

    Article  PubMed  CAS  Google Scholar 

  20. Heninger GR, Delgado PL, Charney DS. The revised monoamine theory of depression: A modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry. 1996;29:2–11.

    Article  PubMed  CAS  Google Scholar 

  21. Ruhe HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: A meta-analysis of monoamine depletion studies. Mol Psychiatry. 2007;12:331–59.

    Article  PubMed  CAS  Google Scholar 

  22. Paul IA, Skolnick P. Glutamate and depression: Clinical and preclinical studies. Ann N Y Acad Sci. 2003;1003:250–72.

    Article  PubMed  CAS  Google Scholar 

  23. Skolnick P, Popik P, Trullas R. Glutamate-based antidepressants: 20 years on. Trends Pharmacol Sci. 2009;30:563–9.

    Article  PubMed  CAS  Google Scholar 

  24. Holtmaat A, Svoboda K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci. 2009;10:647–58.

    Article  PubMed  CAS  Google Scholar 

  25. Pittenger C, Duman RS. Stress, depression, and neuroplasticity: A convergence of mechanisms. Neuropsychopharmacology. 2008;33:88–109.

    Article  PubMed  CAS  Google Scholar 

  26. •• Duman RS, Voleti B. Signaling pathways underlying the pathophysiology and treatment of depression: Novel mechanisms for rapid-acting agents. Trends Neurosci. 2012;35:47–56. This recent article provides an authoritative review of cellular mechanisms hypothesized to underlie the rapid antidepressant effects of ketamine.

    Article  PubMed  CAS  Google Scholar 

  27. Arnone D, McIntosh AM, Ebmeier KP, et al. Magnetic resonance imaging studies in unipolar depression: Systematic review and meta-regression analyses. Eur Neuropsychopharmacol. 2012;22:1–16.

    Article  PubMed  CAS  Google Scholar 

  28. •• Mathew SJ, Shah A, Lapidus K, et al. Ketamine for treatment-resistant unipolar depression: Current evidence. CNS Drugs. 2012;26:189–204. This recent article provides an authoritative review of the current evidence for the antidepressant efficacy of ketamine in human depression.

    Article  PubMed  CAS  Google Scholar 

  29. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–4.

    Article  PubMed  CAS  Google Scholar 

  30. Zarate Jr CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64.

    Article  PubMed  CAS  Google Scholar 

  31. Aan Het Rot M, Zarate CA Jr, Charney DS, et al. Ketamine for depression: Where do we go from here? Biol Psychiatry. 2012, in press.

  32. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793–802.

    Article  PubMed  CAS  Google Scholar 

  33. Zarate Jr CA, Brutsche NE, Ibrahim L, et al. Replication of ketamine's antidepressant efficacy in bipolar depression: A randomized controlled add-on trial. Biol Psychiatry. 2012;71:939–46.

    Article  PubMed  CAS  Google Scholar 

  34. • Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2012, in press. This study demonstrated the safety and efficacy in the largest sample to date of three times weekly ketamine infusions over two weeks in patients with treatment-resistant major depression.

  35. Price RB, Nock MK, Charney DS, et al. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66:522–6.

    Article  PubMed  CAS  Google Scholar 

  36. DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010;71:1605–11.

    Article  PubMed  CAS  Google Scholar 

  37. Larkin GL, Beautrais AL. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int J Neuropsychopharmacol. 2011;14:1127–31.

    Article  PubMed  CAS  Google Scholar 

  38. Mathew SJ, Murrough JW, Aan het Rot M, et al. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: A pilot randomized, placebo-controlled continuation trial. Int J Neuropsychopharmacol. 2010;13:71–82.

    Article  PubMed  CAS  Google Scholar 

  39. Ibrahim L, Diazgranados N, Franco-Chaves J, et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: Results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology. 2012;37:1526–33.

    Article  PubMed  CAS  Google Scholar 

  40. Aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67:139–45.

    Article  Google Scholar 

  41. Murrough JW, Perez AM, Mathew SJ, et al. A case of sustained remission following an acute course of ketamine in treatment-resistant depression. J Clin Psychiatry. 2011;72:414–5.

    Article  PubMed  Google Scholar 

  42. • Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. This report was among the first to demonstrate specific synaptic and intra-cellular messenger system alterations in association with a rapid antidepressant behavioral effect of ketamine in animals.

    Article  PubMed  CAS  Google Scholar 

  43. Li N, Liu RJ, Dwyer JM, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69:754–61.

    Article  PubMed  CAS  Google Scholar 

  44. • Autry AE, Adachi M, Nosyreva E, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475:91–5. This report provides important evidence for a role for BDNF in the rapid antidepressant response to ketamine in animal models.

    Article  PubMed  CAS  Google Scholar 

  45. Beurel E, Song L, Jope RS. Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry. 2011;16:1068–70.

    Article  PubMed  CAS  Google Scholar 

  46. Maeng S, Zarate Jr CA, Du J, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63:349–52.

    Article  PubMed  CAS  Google Scholar 

  47. Cornwell BR, Salvadore G, Furey M, et al. Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression. Biol Psychiatry. 2012, in press.

  48. Valentine GW, Mason GF, Gomez R, et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Res. 2011;191:122–7.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

Dr. Murrough is supported by a Career Development Award from the National Institute of Mental Health (K23MH094707) and by the Brain and Behavior Research Foundation (NARSAD Young Investigator Award) and the American Foundation for Suicide Prevention (Young Investigator Grant). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health, the National Institutes of Health or other funding agencies. In the past two years, Dr. Murrough has received research support from Evotec Neurosciences and Janssen Research & Development. Dr. Charney, Dean of Mount Sinai School of Medicine, has been named as an inventor on a use-patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the Food and Drug Administration for this indication, Dr. Charney and Mount Sinai School of Medicine could benefit financially.

Author information

Authors and Affiliations

  1. Mood and Anxiety Disorders Program, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1230, New York, NY, 10029, USA

    James W. Murrough & Dennis S. Charney

  2. Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA

    James W. Murrough & Dennis S. Charney

  3. Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY, USA

    Dennis S. Charney

  4. Office of the Dean, Mount Sinai School of Medicine, New York, NY, USA

    Dennis S. Charney

Authors
  1. James W. Murrough
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dennis S. Charney
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James W. Murrough.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Murrough, J.W., Charney, D.S. Is There Anything Really Novel on the Antidepressant Horizon?. Curr Psychiatry Rep 14, 643–649 (2012). https://doi.org/10.1007/s11920-012-0321-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11920-012-0321-8

Keywords

Search

Navigation