Page 305 - merged

S071-1 (Coordinator)

The Effects of Ketamine Dosage and Bdnf Gene Polymorphism on Prefrontal
Metabolism and Antidepressant Responses in Medication-Resistant Depression:
A Randomized Placebo-Controlled Imaging Study

Cheng-Ta Li1, Tung-Ping Su2, Ya-Mei Bai2, Mu-Hong Chen2, Wei-Chen Lin2, Ren-Shyan Liu3,
Chen-Ji Hong2

1Dept. Psychiatry, Taipei Veterans General Hospital, Taiwan 2Taipei Veterans General Hospital, Taiwan 3National
PET/Cyclotron Center, Taipei Veterans General Hospital, Taiwan

Background/Objective: Robust and rapid antidepressant effects of low-dose ketamine, an
antagonist on N-methyl-D-aspartate receptors for glutamate, have been shown in several randomized,
controlled studies. Preclinical data revealed that the rapid antidepressant effects were
mTOR-dependent, which peaks 30-60 minutes following ketamine injection, leading to new spine
synapses in the prefrontal cortex (PFC) of rat. BDNF gene polymorphism seems to involve in the
ketamine-related antidepressant responses. Low-dose ketamine rapidly activated PFC activations in
heathy individuals. However, whether ketamine’s antidepressant mechanisms on treatment-resistant
depression (TRD) involved a rapid change in the PFC function and the PFC-limbic network and
whether BDNF gene polymorphism plays a role in the ketamine-related antidepressant responses
remain to be determined.

Method: A group of 48 TRD patients were recruited and randomized to 3 groups [A: 0.2
kg/mg-ketamine; B: 0.5 kg/mg-ketamine; C: normal saline (NS); 16 patients were included in each
group]. Regional glucose metabolism was measured by 18F-FDG positron-emission-tomography,
before and immediately after 40-minute ketamine or saline infusion, and was corrected for injected
dose and body weight. Region-of-interest (ROI) analysis (a-priori regions: PFC and amygdala) and
whole-brain voxelwise analysis(FWE-corrected p<0.001) were investigated and correlated with
antidepressant responses.

Result: The ROI and voxelwise analysis consistently revealed that group-A and group-B, but not
group-C, had a metabolic increase of PFC and a decrease of amygdala 40 minutes after injection.
Such pattern of normalization in the PFC-amygdala circuit was seen in both responders and
non-responders. Metabolic increase in the PFC was significantly correlated with the fast
antidepressant responses to ketamine(r = -0.356, p = 0.013). BDNF Val66Val polymorphism did not
show better antidepressant outcome than other polymorphisms; instead, Met/Met carriers activated
PFC metabolism than Val/Met and Val/Val carriers.

Conclusion: Ketamine’s rapid antidepressant effects involved PFC activation and a normalization of
the PFC-amygdala dysregulation. In Asians, BDNF gene polymorphism modulated the initial PFC
response following ketamine treatment.