It is Possible Find an Antidepressant with Faster Onset of Action? Ketamine: Promise or Reality?

Review Article

Ann Depress Anxiety. 2014;1(5): 1021.

It is Possible Find an Antidepressant with Faster Onset of Action? Ketamine: Promise or Reality?

Alamo C1, López-Muñoz F1,2,3* and García-García P1

1Department of Biomedical Sciences (Pharmacology Area), University of Alcalá, Madrid, Spain

2Faculty of Health Sciences, Camilo Jose Cela University, Madrid, Spain

3Neuropsychopharmacology Unit, Hospital 12 de Octubre Research Institute, Madrid, Spain

*Corresponding author: Lopez-Munoz F, Faculty of Health Sciences, Camilo Jose Cela University, C/ Castillo de Alarcon, 49, Urb. Villafranca del Castillo, 28692 Villanueva de la Cañada, Madrid, Spain

Received: Aug 26, 2014; Accepted: Sep 20, 2014; Published: Sep 24, 2014

Abstract

Monoaminergic antidepressants have a delay in the onset of response that needs alternatives. Sub anesthetic doses of ketamine, a NMDA receptor antagonist, show a rapid-acting antidepressant effect in Major Depressive Disorder (MDD) and in bipolar depression, and improve suicidal ideation. However, for ketamine routinely use as antidepressant, more clinical research on the relation risks and benefits is needed to decide if ketamine is a promise or a reality.

Keywords: Depression; Ketamine; Fast response; Antidepressant effect

Introduction

Major Depressive Disorder (MDD) is one of the most prevalent, serious and debilitating forms of mental illness with health, socioeconomic and familiar consequences [1]. In the last six decades, agents that modulate monoaminergic systems are widely used as antidepressants. However, these are limited in terms of overall efficacy and in the delay in the onset of antidepressant response [2-4]. Delay in antidepressant effect increase morbidity, suicidal ideation [5], psychosocial defeat, quality of life loss [6] and non adherence to treatment [7].

For these reasons, there is a growing interest in rapid-onset pharmacological alternatives [2].To carry out this mini-review, literature was retrieved (July 2014) from PubMed.gov and bibliographic funds of the Alcala University Library, using the keywords ketamine, rapid, fast or early antidepressant effect.

Current and past strategies to accelerate therapeutic response in depression

In despite that some meta-analysis [8-10], showed an improvement in the first week of classical and modern antidepressant treatment [6-11], response rates were generally small [6], not affect the core symptoms of depression and severe melancholic depression do not showed rapid response. An early antidepressant effect may be an artifact [12]. Thus, with very little controversy [6-11], a delay in antidepressant response for more than two weeks is generally accepted [2,3,7,13].

In order to try a rapid antidepressant response, agents not classified as antidepressants, as pindolol [14,15], mifepristone [16], metyrapone [17], methylphenidate [18,19], Thyrotropin-Releasing Hormone (TRH) [20,21],have been investigated with promising initial results but with limited clinical success. Recently, agomelatine, a melatonergic receptor agonist, with a non-monoaminergic profile [22-25], showed significant improvements in the core symptoms of depression within the first week of treatment [26]. However, clinical experience with this agent is limited.

On the other hand, some non-pharmacological interventions, as Electroconvulsive Therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), Deep Brain Stimulation (DBS) as well as “sleep deprivation” showed promising results on early response in depression, but these results needs to be confirmed with controlled clinical trials [6].

Ketamine: A non-monoaminergic pathway for fast antidepressant response

Rapid antidepressant response will require alternative mechanisms of action to “the monoamine hypothesis” [2,4,6]. Glutamatergic system has been shown to be a key pathway in the pathophysiology of a variety of central nervous diseases including MDD [4,27]. In fact, different antidepressants, as Monoamine-Oxidase Inhibitors (MAOIs), Selective Serotonin Reuptake Inhibitors (SSRIs), tricyclic antidepressants, desensitize the locus of glycine in NMDA receptors, down-regulating glutamatergic neurotransmission. This effect was the most sensitive predictor of antidepressant activity [28]. Moreover, NMDA receptor antagonists, as amantadine, or D-cycloserine, has provided conceptual, but limited, clinical support for glutamatergic hypothesis of depression [29,30].

Ketamine, a dissociative anesthetic with hallucinogens properties, is a non-selective non-competitive high affinity of ionotropicglutamatergic NMDA receptors antagonist [31], that show a complex pharmacodynamic profile. Ketamine show preclinical antidepressant response in some predictive tasks [32,33]. Ketamine act primarily as NMDA antagonist and also interact with monoamine, nicotinic and muscarinic cholinergic receptors and opioids receptors [31,34]. Antagonism at NMDA receptor triggers a cascade of events responsible for the antidepressant response to ketamine. Thus, ketamine blocking primarily NMDA receptors increase glutamate synthesis and release that stimulate postsynaptic AMPA receptor. This stimulation increase expression of Akt/mTOR pathway (mammalian target of rapamycin) [35,36] and Brain-Derived Neurotrophic Factor (BDNF) [37]. These proteins are associated with neuronal growth, differentiation, synaptic plasticity, and general functioning of the neuron. Furthermore, ketamine has been shown to inhibit brain GSK-3 [38,39], a kinase that is also a target of mood stabilizing agents. Moreover, in the rapid mood elevation can be implicated the anti-inflammatory activity [40] or inhibition of nitric oxide synthesis [31] induced by ketamine. Thus, blockade of NMDA receptors by ketamine trigger AMPA receptors stimulation that seems to be essential for its antidepressant effects. In fact, AMPA receptor antagonists block ketamine antidepressant effects in animal models [29,31,41].

Ketamine: A prototype for rapid-acting antidepressant in depressed patients

The seminal study of Berman et al. was the first to show that a single low sub-anesthetic ketamine IV infusion (0.5 mg/kg/40 min.) produces a rapid antidepressant response within 4 hours that persist for at least 3 days [30]. Ketamine improve core symptoms of depression and these effects are disconnected from euphoria or “high” induced by this agent [30].These findings were replicated in 18 patients with treatment-resistant depression, which reported a more rapid response within 2 hours that persist for 7 days [42]. Several open and controlled trials confirm the rapid antidepressant actions of single infusion of ketamine [5,6,31,43]. Murrough et al. carry out the largest (n=73) randomized controlled trial of a single infusion of ketamine to date [44]. Ketamine, in comparison with midazolam, show a rapid and broad-spectrum antidepressant effect (response rates: 64% and 28% respectively). Ketamine, independently of antidepressant effect, reversed suicidal ideation. On the other hand, ketamine showed positive results in bipolar depression [45,46] and had significant efficacy in patients resistant to ECT [47].

Moreover, the efficacy of repeated administration of ketamine has been studied. Aan het Rot et al. showed significant improvement of symptoms following six infusions of ketamine over 11 days, although the 9 patients treated in this trial eventually relapsed 19 days after the final infusion [48]. These results were replicated by Murrough et al. in 24 patients with resistant depression. The overall response rate at study end was 70.8%. Among responders, median time to relapse following the last ketamine infusion was 18 days [49]. Recently, antidepressant effects were obtained in an open trial using repeated ketamine as augmenter in twelve patients that maintain stable doses of antidepressant regimen [50].

On the other hand, ketamine improve mood level and was well tolerated by intramuscular [51], sublingual [52] or intranasal [53,54] administration. Oral administration of ketamine improves depressive symptoms at day 14 of treatment [55]. These data open the option for a more practical use of ketamine, but more controlled studies are needed.

Clinical evidence support that low doses of single or repetitive ketamine infusion have a rapid-acting antidepressant effect in MDD and in bipolar depression and improve suicidal ideation. These effects were independent from euphoria or “high” induced by this agent. Ketamine superiority over standard antidepressants is unequivocal. The response rates with ketamine at 24 and 72 hours is superior to obtain with traditional monoaminergic antidepressants at 6-8 weeks of treatment [43,56]. However, many of the discussed studies in this review are methodological limited in regard to their sample size. A sample size of 102, 51 in each group, would be required within randomized controlled trials methodology to detect a moderate effect size of 0.5, with a power of 80% and 0.05 significance. But, none included a sample size in this size. The study by Murroughet al. [44] was the largest to date but still included only 47 patients treated with ketamine. Moreover, despite the fact that some clinical trials were made with the technique of double-blind, caution must therefore be taken in interpreting these results, although several authors identified the difficulties in blinding ketamine administration [43].

Safety profile of ketamine and risk-benefits relation

Routinely use of ketamine as antidepressant can be considered only when tolerability and safety in humans will be established. At this moment, ketamine has a long track record of safety when administered as a surgical anesthetic [57]. However, less is known about single and repetitive infusion at sub anesthetic doses in less intensively monitored depressed patients. On the other hand, generalize the results of clinical trials to practice daily is difficult due to the restrictive criteria of exclusion, as acute suicidal risk, history of psychosis, unstable general medical conditions, substance abuse, abnormal ECGs, applied in studies [58].

Ketamine is one of several “club drugs” that is abused. Misuse of therapeutically relevant agents is a risk but not a new phenomenon in psychiatry (i.e. anticholinergic drugs, stimulants, benzodiazepines, opioids) and should not preclude their study as putative treatments [59].

In antidepressant clinical trials, the dissociative profile of ketamine, as perceptual disturbances, confusion, euphoria, dizziness and increased libido, appears to be similar to that observed in healthy subjects and ceased within 2hours following the infusion. Interesting, in clinical trials of MDD or bipolar patients, ketamine has not led the transition to mania [29,44,49,60].

Ketamine abuse is related with neural injuries, cognitive impairments, altered thought content as well as alteration of mnemonic functions [31,61,62]. Thus, testing the impact of chronic ketamine on these items in longer-term controlled studies is critical.

Distressing adverse events following ketamine infusion, as anxiety, might raise the risk of suicidal thinking [58] but clinical trials to date [43,44,49] support the premise that ketamine has rapid beneficial effects on suicidal cognition. However, this important issue will need careful prospective study in larger samples.

Although somatic adverse effects have generally been mild, 33% of patients have experienced brief changes in blood pressure and/or heart rate and two subjects required their infusions to be stopped for hemodynamic reasons [49]. Thus cardio respiratory monitoring is an essential component of risk management.

On the other hand, experimental and clinical reports of longterm ketamine induced ulcerative cystitis, increased frequencies of bladder carcinoma and kidney dysfunction need to be controlled with the repeated use of ketamine [31,59].

However, if these findings with ketamine could be directly compared with monoaminergic antidepressants, ketamine represent some advantages [28]. Thus, considering these methodological limitations, ketamine has shown evidence that it is safe for the treatment of depression [29].

Conclusion

Current ketamine research has been shown that significant clinical improvement in depression symptoms may occur within hours of drug administration. Moreover, ketamine show that a rapid antidepressant effect can be found beyond the monoaminergic mechanisms of current antidepressant medications that required weeks to months to produce benefits in responding patients. Ketamine is a promising tool to learn more about the pathophysiology of depression and develop more specific rapid-acting antidepressant treatments.

The literature demonstrates evidence supporting that a single intravenous sub anesthetic dose of ketamine exerts rapid antidepressant effects in patients with MDD, bipolar depression and reduces suicidal ideation.

Apparently, safety concerns associated with ketamine dictate a cautious approach to its application outside of research and more clinical research on the risks and benefits of ketamine use is indispensable. At this moment, in despite of tremendous excitement create by ketamine, their administration is not routinely recommended [58,63].

References

  1. Martin-Agueda B, Lopez-Munoz F, Rubio G, Guerra JA, Silva A, Alamo C. Management of depression in primary care: a survey of general practitioners in Spain. Gen Hosp Psychiatry. 2005; 27: 305-312.
  2. Alamo C, Lopez-Munoz F. New antidepressant drugs: beyond monoaminergic mechanisms. Curr Pharm Des. 2009; 15: 1559-1562.
  3. Lopez-Munoz F, Alamo C. Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. Curr Pharm Des. 2009; 15: 1563-1586.
  4. Lopez-Munoz F, Alamo C, eds. Neurobiology of Depression. Boca Raton: CRC Press Taylor & Francis Group. 2012.
  5. Browne CA, Lucki I. Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol. 2013; 4: 161.
  6. Machado-Vieira R, Baumann J, Wheeler-Castillo C, Latov D, Henter ID, Salvadore G, et al. The Timing of Antidepressant Effects: A Comparison of Diverse Pharmacological and Somatic Treatments. Pharmaceuticals. 2010; 3: 19-41.
  7. Blier P. The pharmacology of putative early-onset antidepressant strategies. Eur Neuropsychopharmacol. 2003; 13: 57-66.
  8. Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry. 2005; 66: 148-158.
  9. Papakostas GI, Perlis RH, Scalia MJ, Petersen TJ, Fava M. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol. 2006; 26: 56-60.
  10. Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry. 2006; 63: 1217-1223.
  11. Kasper S, Spadone C, Verpillat P, Angst J. Onset of action of escitalopram compared with other antidepressants: results of a pooled analysis. Int Clin Psychopharmacol. 2006; 21: 105-110.
  12. Parker G, Paterson A, Blanch B. Suggested early onset of true action of antidepressant drugs may be artefactual: a heuristic study. Int Clin Psychopharmacol. 2013; 28: 29-32.
  13. Stassen HH, Delini-Stula A, Angst J. Time course of improvement under antidepressant treatment: a survival-analytical approach. Eur Neuropsychopharmacol. 1993; 3: 127-135.
  14. Artigas F, Perez V, Alvarez E. Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch Gen Psychiatry. 1994; 51: 248-251.
  15. Artigas F. Developments in the field of antidepressants, where do we go now? Eur Neuropsychopharmacol. 2013.
  16. Carroll BJ, Rubin RT. Mifepristone in psychotic depression? Biol Psychiatry. 2008; 63: e1.
  17. Jahn H, Schick M, Kiefer F, Kellner M, Yassouridis A, Wiedemann K. Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial. Arch Gen Psychiatry. 2004; 61: 1235-1244.
  18. Gwirtsman HE, Szuba MP, Toren L, Feist M. The antidepressant response to tricyclics in major depressives is accelerated with adjunctive use of methylphenidate. Psychopharmacol Bull. 1994; 30: 157-164.
  19. Patkar AA, Masand PS, Pae CU, Peindl K, Hooper-Wood C, Mannelli P, et al. A randomized, double-blind, placebo-controlled trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. J Clin Psychopharmacol. 2006; 26: 653-656.
  20. Alamo C, Vallejo M, Cuenca E. [Effect of TRH on the catalepsy induced by various neuroleptics]. Arch Farmacol Toxicol. 1982; 8: 151-156.
  21. Kastin AJ, Ehrensing RH, Schalch DS, Anderson MS. Improvement in mental depression with decreased thyrotropin response after administration of thyrotropin-releasing hormone. Lancet. 1972; 2: 740-742.
  22. Alamo C, Garcia-García P. Lopez-Munoz F. Agomelatine: a differential approach to depression. Eur J Clin Pharmacol. 2010; 66: S12.
  23. Alamo C, Lopez-Munoz F. Optimizando el tratamiento de los pacientes deprimidos. Depresión y ritmos circadianos: relación farmacológica. El papel de la agomelatina. Rev PsiquiatrSaludMent (Barc.). 2010; 3: 3-11.
  24. Alamo C, Lopez-Munoz F, García-García P. Treatment of depression in elderly: The challenge to success. Int J Clin Psychiatry Mental Health. 2014; 2: 77-88.
  25. Srinivasan V, Zakaria R, Othman Z, Lauterbach EC, Acuna-Castroviejo D. Agomelatine in depressive disorders: its novel mechanisms of action. J Neuropsychiatry Clin Neurosci. 2012; 24: 290-308.
  26. Gorwood P. Restoring circadian rhythms: a new way to successfully manage depression. J Psychopharmacol. 2010; 24: 15-19.
  27. Stan TL, Alvarsson A, Branzell N, Sousa VC, Svenningsson P. NMDA receptor antagonists ketamine and Ro25-6981 inhibit evoked release of glutamate in vivo in the subiculum. Transl Psychiatry. 2014; 4: e395.
  28. Naughton M, Clarke G, O'Leary OF, Cryan JF, Dinan TG. A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action. J Affect Disord. 2014; 156: 24-35.
  29. Krystal JH, Sanacora G, Duman RS. Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry. 2013; 73: 1133-1141.
  30. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000; 47: 351-354.
  31. Hasselmann HW. Ketamine as antidepressant? Current state and future perspectives. Curr Neuropharmacol. 2014; 12: 57-70.
  32. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA receptor blockade at rest triggers rapid behavioral antidepressant responses. Nature. 2011; 475: 91-95.
  33. Ates-Alagoz Z, Adejare A. NMDA Receptor Antagonists for Treatment of Depression. Pharmaceuticals (Basel). 2013; 6: 480-499.
  34. Mathew SJ, Shah A, Lapidus K, Clark C, Jarun N, Ostermeyer B, et al. Ketamine for treatment-resistant unipolar depression: current evidence. CNS Drugs. 2012; 26: 189-204.
  35. Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology. 2012; 62: 35-41.
  36. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010; 329: 959-964.
  37. Akinfiresoye L, Tizabi Y. Antidepressant effects of AMPA and ketamine combination: role of hippocampal BDNF, synapsin, and mTOR. Psychopharmacology (Berl). 2013; 230: 291-298.
  38. 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: 1068-1070.
  39. Liu RJ, Fuchikami M, Dwyer JM, Lepack AE, Duman RS, Aghajanian GK. GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology. 2013; 38: 2268-2277.
  40. Yang JJ, Zhou ZQ, Yang C. Letter to the editor: does ketamine exert a fast-acting antidepressant effect via inhibition of pro-inflammatory cytokines? Psychol Med. 2011; 41: 1787.
  41. Zunszain PA, Horowitz MA, Cattaneo A, Lupi MM, Pariante CM. Ketamine: synaptogenesis, immunomodulation and glycogen synthase kinase-3 as underlying mechanisms of its antidepressant properties. Mol Psychiatry. 2013; 18: 1236–1241.
  42. Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006; 63: 856-864.
  43. Caddy C, Giaroli G, White TP, Shergil SS, Tracy DK. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Ther Adv Psychopharmacol. 2014; 4: 75–99.
  44. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013; 170: 1134-1142.
  45. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, 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.
  46. Zarate CA, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, et al. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012; 71: 939-946.
  47. Ibrahim L, Diazgranados N, Luckenbaugh DA, Machado-Vieira R, Baumann J, Mallinger AG, et al. Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35: 1155-1159.
  48. Aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010; 67: 139-145.
  49. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, Aan het Rot M, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013; 74: 250-256.
  50. Shiroma PR, Johns B, Kuskowski M, Wels J, Thuras P, Albott CS, et al. Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. J Affect Disord. 2014; 155: 123-129.
  51. Chilukuri H, Reddy NP, Pathapati RM, Manu AN, Jollu S, Shaik AB. Acute antidepressant effects of intramuscular versus intravenous ketamine. Indian J Psychol Med. 2014; 36: 71-76.
  52. Lara DR, Bisol LW, Munari LR. Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. Int J Neuropsychopharmacol. 2013; 16: 2111-2117.
  53. Papolos DF, Teicher MH, Faedda GL, Murphy P, Mattis S. Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype. J Affect Disord. 2013; 147: 431-436.
  54. Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, et al. A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder. Biol Psychiatry. 2014.
  55. Irwin SA, Iglewicz A, Nelesen RA, Lo JY, Carr CH, Romero SD, et al. Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept trial. J Palliat Med. 2013; 16: 958-965.
  56. Aan Het Rot M, Zarate CA, Charney DS, Mathew SJ. Ketamine for depression: where do we go from here? Biol Psychiatry. 2012; 72: 537-547.
  57. Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth. 1989; 36: 186-197.
  58. Rush AJ. Ketamine for Treatment-Resistant Depression: Ready or Not for Clinical Use? Am J Psychiatry. 2013; 170: 1079-1081.
  59. Li JH, Vicknasingam B, Cheung YW, Zhou W, Nurhidayat AW, Jarlais DC, et al. To use or not to use: an update on licit and illicit ketamine use. Subst Abuse Rehabil. 2011; 2: 11-20.
  60. Salvadore G, Singh JB. Ketamine as a fast acting antidepressant: current knowledge and open questions. CNS Neurosci Ther. 2013; 19: 428-436.
  61. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. Sub anesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994; 51: 199-214.
  62. Morgan CJ, Curran HV. Independent Scientific Committee on Drugs. Ketamine use: a review. Addiction. 2012; 107: 27-38.
  63. Schatzberg AF. A word to the wise about ketamine. Am J Psychiatry. 2014; 171: 262-264.

Download PDF

Citation: Alamo C, López-Muñoz F and García-García P. It is Possible Find an Antidepressant with Faster Onset of Action? Ketamine: Promise or Reality?. Ann Depress Anxiety. 2014;1(5): 1021. ISSN:2381-8883

Home
Journal Scope
Online First
Current Issue
Editorial Board
Instruction for Authors
Submit Your Article
Contact Us