Inhibitors of serine racemase as novel therapeutics for treatment-resistant depression

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Major depressive disorder (MDD) is a disorder that causes persistent feelings of sadness, low self-esteem and apathy and in 2-8% of adults it leads to suicide. According to the World Health Organisation, MDD is the second leading cause of global disability, with an estimated economic burden of ~$210 billion in the US alone. The standard treatment for MDD is anti-depressant drugs, such as serotonin-reuptake inhibitors. However, around one-third of patients do not respond to these common antidepressants. In these treatment-resistant depression patients, the experimental use of the intravenous anaesthetic ketamine has shown promising results as has a related drug called esketamine which is administered via the nose. Nevertheless, ketamine has several serious side effects including psychosis, cognitive and physical impairment and it is also a recreational drug with potential for addiction. Therefore, a drug that works on the same protein as ketamine but has a very different mechanism of action will likely have a safer profile which along with an easier route of administration would make it much better tolerated than ketamine by this patient population. Common antidepressants, which modulate levels of the so-called "mood chemical" serotonin whereas ketamine acts by altering the function of a different chemical in the brain, glutamate. Hence, ketamine works by blocking the effects of glutamate at proteins called N-methyl-D-aspartate receptors (NMDARs). However, in addition to glutamate, NMDARs also require a second chemical, D-serine to perform their function. Consequently, we hypothesise that by reducing the amount of D-serine in the brain by inhibiting the protein that makes it (serine racemase) we should be able to alter the function of NMDARs in a manner analogous to how ketamine produces its therapeutic benefits in treatment-resistant depression. Importantly, however, the different mechanism of action of a serine racemase inhibitor drug means that it will be a safer therapeutic option than ketamine since its restricted distribution in the brain means that is will not produce the unpleasant side-effects associated with ketamine.