Monitoring Ketamine Treatment Response in a Depressed Patient via Peripheral Mammalian Target of Rapamycin Activation
Publication: American Journal of Psychiatry
To the Editor: Most clinically used antidepressants target monoaminergic reuptake mechanisms. However, a limited efficacy and a delayed onset combined with several side effects make the currently available antidepressants less than ideal drugs. Treatment resistance occurs in approximately 15%–20% of depressed patients (1). To improve antidepressant drug efficacy, one line of research has focused on theN-methyl-d-aspartic acid (NMDA) receptor and its pathway in order to manipulate glutamatergic neurotransmission. One important signaling event following NMDA receptor stimulation is mammalian target of rapamycin (mTOR) activation that results in the protein's phosphorylation on serine residues 2481 and 2448. The ensuing signaling cascades are important for the induction of neuroplasticity (2).
Ketamine is a hypnotic and analgesic drug used in anesthesia. It is an NMDA receptor noncompetitive antagonist with functions in monoaminergic and cholinergic neuronal transmission. Ketamine improves depressive symptoms in patients with major depressive disorder who are resistant to conventional therapy (3).
Using the Western blot test analysis of peripheral mononuclear cell protein extracts, we provide for the first time evidence of increased mTOR phosphorylation in a depressed patient after (S)-ketamine treatment. The patient's depressive symptoms improved rapidly after an infusion of (S)-ketamine and did not return for 24 hours. These results are in line with animal data reporting rapid mTOR phosphorylation on serine residue 2448 in the prefrontal cortex of a rat after ketamine treatment (4). Our data provide preliminary evidence that findings in the rat have the potential to translate to clinical studies monitoring ketamine treatment response in patients.
Case Report
A 56-year-old woman with major depressive disorder showed considerable resistance to conventional antidepressive therapy. Over the course of a 9-month period of high-dosage standard antidepressant and augmentation treatments, including a combination of antidepressant drugs (citalopram, escitalopram, amitriptyline, clomipramine, venlafaxine, and moclobemide), atypical antipsychotics, and benzodiazepines, we observed no improvement of symptoms. Based on these negative results, we decided to give 0.25 mg/kg of (S)-ketamine intravenously with a 40-minute injection duration (3). Written informed consent was obtained from the patient after the procedure had been fully explained. Blood was collected at baseline and 10 minutes, 40 minutes, and 100 minutes after initiating the (S)-ketamine infusion. Before, during, and after the infusion, the patient was evaluated for depression using the Beck Depression Inventory (BDI), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Brief Psychiatric Rating Scale. The depressive and anxiety parameter scores rapidly improved after (S)-ketamine infusion, and the best results were observed at the end of the treatment (baseline scores: MADRS=29/BDI=18; posttreatment scores: MADRS=4/BDI=3). Acute dissociative symptoms monitored using the Clinician-Administered Dissociative States Scale were slightly elevated during the treatment (baseline=0, posttreatment=12) and returned to basal levels immediately after the end of treatment. No psychotic or delusional symptoms were recorded during or after the (S)-ketamine treatment.
In a Western blot analysis of peripheral blood cells, we observed a continued increase of mTOR phosphorylation on serine 2448 starting from baseline up to 100 minutes after the start of the (S)-ketamine infusion (Figure 1).
FIGURE 1. Western Blot Analysis of Peripheral Blood Cells in a Study of (S)-Ketamine Infusion for the Treatment of Depressive Symptomsa
a Blood mononuclear cell protein extracts were analyzed at baseline and 10 minutes, 40 minutes, and 100 minutes after the 40-minute (S)-ketamine infusion was begun. For comparison, protein extracts from HEK293 cells were analyzed on the same gel. The protein band is detected at the expected molecular weight of 250 kDa.
Footnote
Accepted for publication in March 2011.
References
1.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M: Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163:1905–1917
2.
Hoeffer CA, Klannm E: mTOR signaling: at the crossroads of plasticity, memory, and disease. Trends Neurosci 2009; 33:67–75
3.
Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK: A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63:856–864
4.
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS: mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329:959–964
Information & Authors
Information
Published In
History
Accepted: March 2011
Published online: 1 July 2011
Published in print: July 2011
Authors
Funding Information
The authors report no financial relationships with commercial interests.
Metrics & Citations
Metrics
Citations
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
View Options
View options
PDF/EPUB
View PDF/EPUBLogin options
Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.
Personal login Institutional Login Open Athens loginNot a subscriber?
PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.
Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).