For many depression patients treatment changes are required, including switching to another
antidepressant and addition of a second antidepressant or a non-antidepressant agent
("augmentation"). The need to modify treatment is usually necessary because of partial or no
response to first-line monotherapy or the failure to achieve remission although treatment
response (improvement) has been obtained. These caveats of presently available antidepressant
drugs highlight the need for innovative pharmacological treatment strategies. Recent data
suggest that N-methyl-D-aspartate receptor (NMDAR) antagonists and partial agonists at the
NMDAR-associated glycine binding site may represent a novel type of antidepressant
medications. These types of compounds protect vulnerable neurons against a variety of
insults, including stress-induced damage, and may serve to enhance and maintain normal
synaptic connectivity. In animal models, these compounds mimic the effects of clinically
effective antidepressants. Furthermore, down-regulation of the glycine site of the NMDAR was
found to be a common feature of currently used antidepressant medications. D-cycloserine (DCS
, Seromycin) is a broad spectrum antibiotic, in use for over thirty years against
tuberculosis, that acts as a partial agonist at the NMDAR-associated glycine site. Beneficial
antidepressant effects have been reported with 500-1000 mg/day DCS regimens in depressed
tuberculosis patients and recent preliminary findings suggest that DCS may also be beneficial
in the treatment of major depressive disorder. The antidepressant effects of DCS seem to
reflect consequences of its capacity to reduce NMDAR receptor function. In the present
project, it is proposed to assess, using a random assignment, parallel-group, double blind,
placebo controlled design, the effects of a NMDAR -antagonist DCS dose regimen, 250 --> 1000
mg/day for 6 wks, as adjuvant pharmacotherapy for treatment-resistant major depressive
disorder patients. The study methodology includes the assessment of DCS effects upon symptoms
profile, neurocognitive tests performance, amino acids serum levels, and brain
electrophysiology parameters associated with the prepulse inhibition-startle response
paradigm. It is hypothesized that significant beneficial DCS treatment effects will be
registered.
Phase:
Phase 2
Details
Lead Sponsor:
Herzog Hospital
Collaborator:
National Alliance for Research on Schizophrenia and Depression