Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, Increased Volumes of Thalamus, Amygdala, and Brainstem in a Drug-Naïve Patient With Major Depression

“Mr. D” is a 20-year-old, first-episode, drug-naïve nonpsychotic MDD patient with symptoms for 1 month (Hamilton Rating Scale for Depression [Ham-D] score: 25). He refused to take any psychotropic medication because of possible side effects. He just accepted non-pharmacological treatment, such as nutritional and food therapy. After negotiation, he agreed to take SB (500 mg/day) and also signed the informed consent after being notified about the characteristics and side effects of SB. His MDD symptoms improved within the initial 2 weeks of treatment (Ham-D score: 12) and he achieved partial remission after a 6-week therapy with SB (Ham-D score: 9), with residual symptoms of sleep disturbance, anergia, and anhedonia. No intolerable side effects were mentioned during SB therapy. He received structural magnetic resonance imaging (MRI) scanning (3T Siemens Version Scanner housed at magnetic resonance Center, National Yang Ming University) at baseline and the 6th week for the evaluation of brain volume changes after SB treatment. The pulse sequence of MRI scanning was three-dimensional fast-spoiled gradient-echo recovery (3D-FSPGR) T1W1 (TR: 25.30 msec; TE: 3.03 msec; slice thickness: 1 mm(no gap);192 slices; matrix: 224 × 256; field of view: 256 mm; number of excitations: 1). Structural MRI was preprocessed with FMRIB's Integrated Registration and Segmentation Tool function (FIRST Version 1.2) of FSL (FMRIB Software Library, Version 4.1.1) to perform subcortical brain segmentation using a shape and appearance model. The subcortical structures include hippocampus, amygdala, nucleus accumbens, thalamus, pallidum, lentiform nucleus, caudate, and putamen. The volumes of bilateral thalami, brainstem, and right amygdala increased after a 6-week therapy with SB (Table 1).

Subcortical structures are important regions for an etiological model of MDD. Sheline proposed that cortico-striato-limbic-pallidal-thalamic circuit of patients with MDD might suffer from the damage related to glucorticoid neurotoxicity and reduced neurogenesis due to stress.¹ DAAs, such as D-serine or D-cycloserine, would induce limited activations of glutamate receptors through glycine receptor partial agonist and might treat symptoms of depression or anxiety.² Scholpp et al. reported that neurogenesis of thalamus would be modulated by different gene expressions in the glutamatergic system, which might lead to the establishment of discrete neuronal domains in the thalamus.³ Hamani et al. found that neurogenesis occurred after stimulation of thalamus in rats treated with corticosterone, which is a model for MDD.⁴ In the meta-analysis of volumes of amygdala in MDD, unmedicated patients seem to have lower volumes of amygdala, and medicated patients seems to have increased volumes of amygdala. It suggests that antidepressant might increase neurogenesis by increasing release of brain-derived neurotrophic factor and protecting against glucocorticoid toxicity in the amygdala.⁵ Volumetric increases of brainstem in this patient might be related to glutamate-related neurotrophic effects,⁶ which would be associated with potential antidepressant effects of SB. We have reported a similar phenomenon with brainstem growth in the patients with MDD and panic disorder, which might be related to neurotrophic effects of antidepressant.⁷ Chronic stress will induce depression and excess of excitatory glutamatergic neurotoxicity toward amygdala. In this case, we found increased volumes of right amygdala after treatment with SB, which can prevent excitotoxicity-induced death and enhance neural plasticity through inhibition of astroglia DAO.⁸ SB also can inhibit DAAO and increase DAA, which will activate the inhibitory glycinergic receptor to control glutamatergic excitotoxicity and enhance synaptic plasticity.⁹ Also, glutamate can stimulate the division of human progenitor cells and induce neurogenesis of glial cells due to the increase of neurotrophic factor.⁶

I thank Professor Hsien-Yuan Lane of the Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan, and Professor Guochuan Emil Tsai of the Department of Psychiatry, Harbor-UCLA Medical Center, and the Los Angeles Biomedical Research Institute, Torrance, CA, USA, for their help.

We also acknowledge MR support from National Yang-Ming University, Taiwan, which is in part supported by the MOE plan for the top university. We also thank Miss Ruao-Ching Wang for MRI acquisition help and technical assistance.