Jasper Stevens (1), Anantha Shekhar (2), Amit Anand (3), Robert R. Bies (1)
(1) Division of Clinical Pharmacology, Indiana University School of Medicine Indianapolis, IN, US; (2) Department of Psychiatry, Indiana University School of Medicine, IN, US; (3) Department of Psychiatry and Radiology, Indiana University School of Medicine, IN, US
Objectives: Presynaptic- and postsynaptic glutamatergic modulation is associated with anti-depressant activity that takes several weeks to reach a maximal full effect [1]. Limiting mood elevation after single drug administration may be the result of compensatory synaptic processes [2, 3]. Therefore, using augmentation treatment with agents having presynaptic- and postsynaptic effects on the glutamatergic system (lamotrigine and memantine, respectively), this study aims to evaluate the effect of augmentation therapy on the rate of change in mood elevation in patients with bipolar depression.
Methods: In a recent pilot study [4], 29 bipolar depression outpatients on a stable lamotrigine dose regimen received placebo or memantine pills daily (titrated up by 5 mg per week to 20 mg) in a randomized, double blind, parallel group, 8-week study. Patients were evaluated weekly using the 17-item Hamilton Depression Rating Score (HDRS) and all data were analyzed simultaneously. In this study, linear-, exponential-, maximal effect-, Gompertz- and inverse Bateman functions were evaluated using a Bayesian approach population pharmacodynamic model framework. In these models, differences in parameters were examined across the memantine and placebo augmentation groups.
Results: A Gompertz function with a treatment switch on the parameter describing the speed of HDSR decline best described the data. Between subject variability was identified on baseline HDRS and amplitude of score improvement.
Conclusions: This pharmacodynamic approach identified an increased speed of response after memantine augmentation, compared to placebo augmentation in bipolar depression patients.
References:
[1] Cryan JF, O'Leary OF. Neuroscience. A glutamate pathway to faster-acting antidepressants? Science 2010; 329: 913-4.
[2] Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 1997; 17: 2921-7.
[3] Naskar R, Vorwerk CK, Dreyer EB. Concurrent downregulation of a glutamate transporter and receptor in glaucoma. Invest Ophthalmol Vis Sci 2000; 41: 1940-4.
[4] Anand A, Gunn, AD, Barkay G, Karne H, Nurnberger JI, Mathew SJ, Ghosh S. Early antidepressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression. Bipolar Disorders; in press.
Reference: PAGE 21 () Abstr 2387 [www.page-meeting.org/?abstract=2387]
Poster: Other Drug/Disease Modelling