Intranasal esketamine and the dawn of precision psychiatry

Watts, Devon; Garcia, Frederico D.; Lacerda, Acioly L.T.; Mari, Jair de J.; Quarantini, Lucas C.; Kapczinski, Flávio

doi:10.1590/1516-4446-2021-0031

One in twenty individuals worldwide suffer from depression,¹,² and limited developments have been made in pharmacological treatments over the last four decades.³Current first-line treatment recommendations for major depressive disorder (MDD) involve medications that inhibit the reuptake of serotonin, norepinephrine, and dopamine through various mechanisms.⁴ However, as indicated in the STAR*D study, roughly one in three patients fail to achieve clinical remission through these medications.⁵ It is known that a sufficient clinical response to these medications can take an upwards of 8 to 12 weeks.⁶ Moreover, up to 15% of patients with MDD have a treatment-resistant form of the disorder.⁷ Altogether, this highlights the urgent need for rapid-acting antidepressants with a novel mechanism of action.

It has recently been shown that repeated infusions of ketamine have rapid, cumulative, and sustained antidepressant effects.⁸ It has also been shown that ketamine infusions can reduce suicidal ideation in treatment-resistant depression.⁹ This antidepressant effect persists in racemic formulations, such as esketamine,¹⁰ which shows non-inferiority to ketamine.¹¹ However, the exact mechanism underlying its rapid antidepressant and anti-suicidal effects remains unknown.

There is growing evidence that dysregulations in the glutamatergic and GABAergic systems are implicated in the pathophysiology of depression,¹² which provides an opportunity for novel drug design and the repurposing of existing drugs. Ketamine has been shown to modulate extrasynaptic GABA_A receptors in cortical neurons,¹³ and the rapid increase in glutamate that ketamine produces appears to be an essential component of its antidepressant effect.¹⁴

While many candidate pathways have been proposed to mediate the antidepressant effects of ketamine,¹⁵,¹⁶ few clinical trials have investigated biological predictors of treatment response. Among them, acute alterations in glutamate and glutamine levels, measured using in vivo magnetic resonance spectroscopy, appears to mediate the antidepressant effects of ketamine.¹⁷ However, no studies have yet identified a set of candidate biological markers that can predict treatment response to ketamine on an individual level. Clearly defined clinical markers in treatment-resistant depression coupled with effective, innovative, and fast acting treatments such as intranasal esketamine marks the dawn of precision psychiatry.¹⁸

Acknowledgements

FDG has received grants from Fundacão de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG; APQ-02572-16 and APQ-04347-17), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; 313944/2018-0), Emenda Parlamentar Federal (23970012), and Secretaria Nacional de Política sobre Drogas (01/2017). LCQ has received grants from Programa de Pesquisa para o SUS (CNPq/PPSUS/BA; 003/2017). FK has received grants from the Stanley Medical Research Institute (07TGF/1148), Instituto Nacional de Ciência e Tecnologia – Conselho Nacional de Desenvolvimento Científico e Tecnológico (INCT-CNPq; 465458/2014-9), and the Canadian Foundation for Innovation (CFI).

References

¹ Steel Z, Marnane C, Iranpour C, Chey T, Jackson JW, Patel V, et al. The global prevalence of common mental disorders: a systematic review and meta-analysis 1980 – 2013. Int J Epidemiol. 2014;43:476-93.
² Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68:241-51.
³ Hyman SE. Psychiatric drug development: diagnosing a crisis. Cerebrum. 2013;2013:5.
⁴ Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. Pharmacological treatments. Can J Psychiatry. 2016;61:540-60.
⁵ Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps. Am J Psychiatry. 2006;163:1905-17.
⁶ Gelenberg AJ, Chesen CL. How fast are antidepressants? J Clin Psychiatry. 2000;61:712-21.
⁷ Berlim MT, Turecki G. Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry. 2007;52:46-54.
⁸ Phillips JL, Norris S, Talbot J, Hatchard T, Ortiz A, Birmingham M, et al. Single and repeated ketamine infusions for reduction of suicidal ideation in treatment-resistant depression. Neuropsychopharmacology. 2020;45:606-12.
⁹ Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019;176:401-9.
¹⁰ Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression a randomized clinical trial. JAMA Psychiatry. 2018;75:139-48.
¹¹ Correia-Melo FS, Leal GC, Vieira F, Jesus-Nunes AP, Mello RP, Magnavita G, et al. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: a randomized, double-blind, non-inferiority study. J Affect Disord. 2020;264:527-34.
¹² Duman RS, Sanacora G, Krystal JH. Review altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019;102:75-90.
¹³ Wang DS, Penna A, Orser BA. Ketamine increases the function of γ -aminobutyric acid type a receptors in hippocampal and cortical neurons. Anesthesiology. 2017;126:666-77.
¹⁴ Krystal JH, Sanacora G, Duman RS. Rapid-acting glutamatergic antidepressants – the path to ketamine and beyond. Biol Psychiatry. 2013;73:1133-41.
¹⁵ Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS. Ketamine: a paradigm shift for depression research and treatment. Neuron. 2019;101:774-8.
¹⁶ Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23:801-11.
¹⁷ Milak MS, Rashid R, Dong Z, Kegeles LS, Grunebaum MF, Ogden RT, et al. Assessment of relationship of ketamine dose with magnetic resonance spectroscopy of Glx and GABA responses in adults with major depression a randomized clinical trial. JAMA Netw Open. 2000;3:e2013211.
¹⁸ Passos IC, Ballester P, Rabelo-da-Ponte FD, Kapczinski F. Precision psychiatry: the future is now. Can J Psychiatry. 2021 Mar 24;706743721998044. doi: http://10.1177/0706743721998044 Online ahead of print.
» http://10.1177/0706743721998044

Publication Dates

Publication in this collection
21 July 2021
Date of issue
Mar-Abr 2022

History

Received
2 June 2021
Accepted
3 June 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

[1] ¹ Steel Z, Marnane C, Iranpour C, Chey T, Jackson JW, Patel V, et al. The global prevalence of common mental disorders: a systematic review and meta-analysis 1980 – 2013. Int J Epidemiol. 2014;43:476-93.

[2] ² Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68:241-51.

[3] ³ Hyman SE. Psychiatric drug development: diagnosing a crisis. Cerebrum. 2013;2013:5.

[4] ⁴ Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. Pharmacological treatments. Can J Psychiatry. 2016;61:540-60.

[5] ⁵ Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps. Am J Psychiatry. 2006;163:1905-17.

[6] ⁶ Gelenberg AJ, Chesen CL. How fast are antidepressants? J Clin Psychiatry. 2000;61:712-21.

[7] ⁷ Berlim MT, Turecki G. Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry. 2007;52:46-54.

[8] ⁸ Phillips JL, Norris S, Talbot J, Hatchard T, Ortiz A, Birmingham M, et al. Single and repeated ketamine infusions for reduction of suicidal ideation in treatment-resistant depression. Neuropsychopharmacology. 2020;45:606-12.

[9] ⁹ Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019;176:401-9.

[10] ¹⁰ Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression a randomized clinical trial. JAMA Psychiatry. 2018;75:139-48.

[11] ¹¹ Correia-Melo FS, Leal GC, Vieira F, Jesus-Nunes AP, Mello RP, Magnavita G, et al. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: a randomized, double-blind, non-inferiority study. J Affect Disord. 2020;264:527-34.

[12] ¹² Duman RS, Sanacora G, Krystal JH. Review altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019;102:75-90.

[13] ¹³ Wang DS, Penna A, Orser BA. Ketamine increases the function of γ -aminobutyric acid type a receptors in hippocampal and cortical neurons. Anesthesiology. 2017;126:666-77.

[14] ¹⁴ Krystal JH, Sanacora G, Duman RS. Rapid-acting glutamatergic antidepressants – the path to ketamine and beyond. Biol Psychiatry. 2013;73:1133-41.

[15] ¹⁵ Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS. Ketamine: a paradigm shift for depression research and treatment. Neuron. 2019;101:774-8.

[16] ¹⁶ Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23:801-11.

[17] ¹⁷ Milak MS, Rashid R, Dong Z, Kegeles LS, Grunebaum MF, Ogden RT, et al. Assessment of relationship of ketamine dose with magnetic resonance spectroscopy of Glx and GABA responses in adults with major depression a randomized clinical trial. JAMA Netw Open. 2000;3:e2013211.

[18] ¹⁸ Passos IC, Ballester P, Rabelo-da-Ponte FD, Kapczinski F. Precision psychiatry: the future is now. Can J Psychiatry. 2021 Mar 24;706743721998044. doi: http://10.1177/0706743721998044 Online ahead of print.
» http://10.1177/0706743721998044