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Brain-Derived Neurotrophic Factor Val66MetPolymorphism and Antidepressant Efficacy of Ketaminein Depressed Patients

To the Editor:

T he noncompetitive N-methyl-D-aspartate (NMDA) receptorantagonist ketamine shows rapid antidepressant efficacy—within 1 hour—in individuals with treatment-resistant major

epressive disorder (MDD) (1,2) and bipolar disorder (3). This rapidntidepressant effect is in stark contrast to the lag typically associ-ted with traditional monoamine-modulating medications, whichequire weeks to become effective. Ongoing studies are investigat-ng the cellular and molecular mechanisms underlying ketamine’seneficial effects (4,5), with a view to both expanding our under-tanding of affective disorders and developing effective, viable, andapid-acting treatments.

A recent series of elegant animal studies suggest that increasedrain-derived neurotrophic factor (BDNF) function is a necessaryomponent of the antidepressant response of ketamine and otherMDA antagonists (5). BDNF is critical to neuronal plasticity (6) and

hought to be strongly associated with the pathophysiology offfective disorders (7). In a recent issue of Biological Psychiatry, Liund colleagues (8) compared the role of the Val66Met (rs6265)ingle nucleotide polymorphism (SNP), a putatively functional poly-

orphism within the first exon of BDNF, and ketamine response.DNF knock-in mice (Val/Val, Val/Met, Met/Met) had differing levelsf prefrontal cortex synaptogenesis after drug administration on

he basis of this single polymorphism. Homozygous Val/Val micexhibited a stronger neural response than Met carriers, with ho-ozygous Met/Met carriers responding the least. Indeed, the anti-

epressant effects of ketamine in Met/Met mice were attenuated tohe extent that performance on the forced swim test remained ataseline levels, whereas Val carriers showed relative performancenhancements. Moreover, the increases in spine density that fol-

owed ketamine administration were more diminished in Met/Metice than in Val/Met mice (8).

Intrigued by these findings, we investigated whether the rs6265Val66Met SNP) is associated with response to ketamine in patientsxperiencing a major depressive episode. Homozygous Met carri-rs are rare in some human populations (�5%), thus our aim was toompare homozygous Val/Val individuals, who account for approx-

mately 60% of the European-ancestry population [HapMap],gainst Met carriers (both Val/Met and Met/Met). We hypothesizedhat patients carrying a BDNF Met substitution would show anttenuated antidepressant response to ketamine infusion com-ared with Val/Val patients.

The investigation was approved by the National Institute ofental Health (NIMH) and Yale Institutional Review Boards and

thics committees. All subjects provided written informed consent.ixty-two depressed patients (55% female patients, mean age:8.68, SD: 11.9; male patients, mean age: 43.3, SD: 13.2) receivedetamine infusion (.5 mg/kg over 40 min), as described in detaillsewhere (1). Eight subjects were infused onsite at Yale University

New Haven, Connecticut) in a single-blind lead-in infusion proce-ure (2); subjects infused at the NIMH (Bethesda, Maryland) partic-

pated in either an open-label or double-blind crossover setup1,3,9). Genetic analyses revealed that 41 individuals possessed theal/Val polymorphism; 21 carried either one (n � 19) or both (n � 2)et substitutions. Most subjects were of European ancestry (n �

8); four were of self-reported African ancestry, and all but one

escribed themselves as “non-Hispanic.” Hamilton Depression Rat- g

0006-3223/$36.00

ng Scale (HAM-D) (10) scores were obtained at baseline (same dayreinfusion) and throughout the study. For simplicity, scores areresented here at either 210 or 230 minutes postinfusion. Thearker was in Hardy-Weinberg equilibrium in this sample. Given

hat allele frequencies in rs6265 vary widely among continentalroups and because we did not have additional genotypes for partf the sample, we used self-reported race as a proxy for geneticncestry.

To test the association between rs6265 and ketamine treatmentutcome, we implemented a general linear model with change inAM-D score from baseline to 210/230 minutes as the dependentariable, and genotype (under a dominant model), primary diagno-is (MDD/bipolar disorder), self-reported race, and center of originYale/NIMH) as independent variables. The last three independentariables were used to account for potential confounders (e.g.,iagnosis, population stratification, differences in ketamine proto-ol implementation). Our results (F � 5.59, df � 4, p � .0007) areonsistent with recently reported studies (8). This model accountedor 28% of the variance in ketamine response in this sample. Meanaseline and endpoint HAM-D scores for Met carriers were 22.9 (SD:.7) and 17.8 (SD: 9.7), respectively. Mean baseline and endpointcores for Val carriers were 20.8 (SD: 4.8) and 12.2 (SD: 5.4), respec-ively. The mean percent change in scores (improvement) was 24%SD: 31) for the Met carriers, and 41% (SD: 24) for the Val carriers. Inhe Caucasian group only (n � 58), the mean change was 20% (SD:1) for the Met carriers (n � 18) and 40% (SD: 24) for the Val carriers

n � 40).Our results suggest that MDD patients with the Val/Val BDNF

llele at rs6265 are more likely to exhibit increased antidepres-ant response to ketamine than Met carriers. Liu and colleagues8) alluded to the possibility that the weakened antidepressantesponse to ketamine infusion typically seen in approximately0% of patients might be related to the Val66Met polymorphism.ur finding is consistent with their hypothesis that rs6265 geno-

ypes could help separate ketamine responders from non-esponders. They also suggested that it may be possible to administerDNF-enhancing compounds to Met allele-carrying patients be-ore administering ketamine. Standard antidepressants, electro-onvulsive therapy, and brain stimulation techniques such asranscranial magnetic stimulation all increase BDNF levels11,12); exercise also has BDNF secretion-enhancing effects (13).n contrast, a previous report that included the large STAR*Dohort found no association between traditional antidepres-ants and rs6265 (14). This suggests that the Val66Met variant

ay play a different role in patients treated with traditionalntidepressants as opposed to those treated with rapid-actingntidepressants such as ketamine.

Limitations of the study include small sample size and our inabil-ty to correct for population stratification. The results await replica-ion. Nevertheless, taken in conjunction with the findings of Liu andolleagues (8), these results add weight to novel hypotheses that

ink the BDNF (7) and glutamatergic (15) theories of depression anduggest that future studies should explore the long-term effects ofhe BDNF Val66Met variant. Ketamine’s rapid antidepressant effectsuggest that glutamatergic system alterations may operate up-tream, thus expanding monoaminergic theories of depression.uture pharmacogenetic research is needed to determine whetherenetic variation in the BDNF gene should be included in ketamine

reatment study designs and whether administration of BDNF-en-ancing compounds or interventions before drug infusion may

mprove treatment outcome in individuals with treatment-resistant

enotypes.

BIOL PSYCHIATRY 2012;72:e27–e28© 2012 Society of Biological Psychiatry

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e28 BIOL PSYCHIATRY 2012;72:e27–e28 Correspondence

Gonzalo Lajea

Níall Lallyb

Daniel Mathewsc

Nancy Brutschec

Anat Chemerinskia

Nirmala Akulaa

Benjamin Kelmendid

Arthur Simend

Francis J. McMahona

Gerard Sanacorad

Carlos Zarate Jr.c*

aHuman Genetics Branch, Division of Intramural Research Programs, NationalInstitute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda,Maryland; bInstitute of Cognitive Neuroscience, University College London,London, United Kingdom; cExperimental Therapeutics and PathophysiologyBranch, Division of Intramural Research Programs, NIMH, NIH, Bethesda,Maryland; dYale University School of Medicine, Department of Psychiatry, NewHaven, Connecticut.

*Corresponding author E-mail: zaratec@mail.nih.gov.Authors GL and NL contributed equally to this work.

This study was funded in part by the Intramural Research Program of the NationalInstitute of Mental Health (NIMH), National Institutes of Health, by Grant No.K99MH085098 to Gonzalo Laje; by a National Alliance for Research on Schizophrenia andDepression Independent Investigator Award to Francis McMahon and Carlos Zarate Jr.;and by the Brain and Behavior Award for Bipolar Disorder Mood Research. The content ofthis publication does not necessarily reflect the views or policies of the U.S. Department ofHealth and Human Services nor does mention of trade names, commercial products, ororganizations imply endorsement by the U.S. Government.

Ioline Henter (NIMH) provided excellent editorial assistance.Dr. Laje, Mr. Lally, Dr. Mathews, Ms. Brutsche, Ms. Chemerinski, Dr. Akula, Dr. Kelmendi,

and Dr. McMahon report no biomedical financial interests or potential conflicts of interest.Dr. Zarate is listed as a coinventor on a patent application for the use of ketamine and itsmetabolites in major depression. Dr. Zarate has assigned his rights in the patent to the U.S.government but will share a percentage of any royalties that may be received by thegovernment. Dr. Sanacora has received consulting fees from Abbott Laboratories,AstraZeneca, Avanier Pharmaceuticals, Bristol-Myers Squibb, Evotec, Eli Lilly & Co., Hoff-man La-Roche, Novartis, and Novum Pharmaceuticals over the last 24 months. He has alsoreceived additional grant support from AstraZeneca, Bristol-Myers Squibb, Hoffman La-Roche, Merck & Co., and Sunovion Inc over the past 24 months. In addition, he is a coinven-tor on a filed patent application by Yale University (PCTWO06108055A1). Dr. Simen iscurrently a full time employee of Merck & Co.

1. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, LuckenbaughDA, et al. (2006): A randomized trial of an N-methyl-D-aspartate antag-onist in treatment-resistant major depression. Arch Gen Psychiatry 63:

856 – 864. h

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2. Valentine GW, Mason GF, Gomez R, Fasula M, Watzl J, Pittman B, et al.(2011): The antidepressant effect of ketamine is not associated withchanges in occipital amino acid neurotransmitter content as measuredby [(1)H]-MRS. Psychiatry Res 191:122–127.

3. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, KhalifeS, et al. (2010): A randomized add-on trial of an N-methyl-D-aspartateantagonist in treatment-resistant bipolar depression. Arch Gen Psychia-try 67:793– 802.

4. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. (2010): mTOR-dependent synapse formation underlies the rapid antidepressant ef-fects of NMDA antagonists. Science 329:959 –964.

5. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. (2011):NMDA receptor blockade at rest triggers rapid behavioural antidepres-sant responses. Nature 475:91–95.

6. Pattwell SS, Bath KG, Perez-Castro R, Lee FS, Chao MV, Ninan I (2012): TheBDNF Val66Met polymorphism impairs synaptic transmission and plas-ticity in the infralimbic medial prefrontal cortex. J Neuroscience 32:2410 –2421.

7. Martinowich K, Manji H, Lu B (2007): New insights into BDNF function indepression and anxiety. Nat Neuroscience 10:1089 –1093.

8. Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK (2011):Brain-derived neurotrophic factor Val66Met allele impairs basal andketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychia-try 71:996 –1005.

9. Ibrahim L, Diazgranados N, Franco-Chaves J, Brutsche N, Henter ID,Kronstein P, et al. (2012): Course of improvement in depressive symp-toms to a single intravenous infusion of ketamine vs add-on riluzole:Results from a 4-week, double-blind, placebo-controlled study. Neuro-psychopharmacology 37:1526 –1533.

0. Hamilton M (1960): A rating scale for depression. J Neurol NeurosurgPsychiatry 23:56 – 62.

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2. Muller MB, Toschi N, Kresse AE, Post A, Keck ME (2000): Long-termrepetitive transcranial magnetic stimulation increases the expression ofbrain-derived neurotrophic factor and cholecystokinin mRNA, but notneuropeptide tyrosine mRNA in specific areas of rat brain. Neuropsycho-pharmacology 23:205–215.

3. Gomez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR (2002): Volun-tary exercise induces a BDNF-mediated mechanism that promotes neu-roplasticity. J Neurophysiology 88:2187–2195.

4. Domschke K, Lawford B, Laje G, Berger K, Young R, Morris P, et al. (2010):Brain-derived neurotrophic factor (BDNF) gene: No major impact onantidepressant treatment response. Int J Neuropsychopharmacology 13:93–101.

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ttp://dx.doi.org/10.1016/j.biopsych.2012.05.031