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

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.

The N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) are key regulators of many aspects of CNS function and have been implicated in the pathophysiology of a variety of diseases associated with glutamatergic neurotransmission, ranging from Alzheimer's disease to schizophrenia. Most recently, the clinical efficacy of the NMDAR channel blocker ketamine has highlighted the therapeutic potential of reducing NMDAR function in treatment-resistant depression.
NMDARs are tetrameric assemblies of different proteins and are activated by two distinct agonists acting at the glutamate and D-serine/glycine binding sites. This latter site was originally thought to be solely activated by glycine, but more recent evidence has demonstrated the importance of D-serine as a physiological activator at this site. The only enzyme known to generate D-serine is serine racemase (SR), a cytosolic enzyme primarily expressed in neurons. SR uses amino acid L-serine as substrate and converts it to D-serine through a racemerization reaction that is dependent on pyridoxal 5'-phophate. This 340-amino acid enzyme forms a homodimer with each monomer comprising a large domain and a flexible, small domain.
Reduced expression of SR, and consequently D-serine levels, not only affects NMDAR-mediated processes such as long-term potentiation, but also has behavioural consequences, including, for example, a resilience to the depression-like phenotype produced by chronic social defeat stress. Importantly, SR is primarily localised in the forebrain, which suggests that inhibition of this enzyme should preferentially affect NMDARs in the forebrain and not NMDARs in other brain regions, such as the cerebellum, which may mediate some of the side-effects associated with non-selective drugs, such as ketamine.

The output of this project could provide seeds towards drug development needed for treatment-resistant major depressive disorder. Pharmacological intervention using serine racemase inhibitors would offer a different mechanism of action to common antidepressants and provide relief to patients with unmet need. These patients would benefit from medicine that had a safer profile than ketamine and related drugs with the added convenience of being administered orally. Patients should be able to resume normal activities of daily living and reestablish and sustain productivity and social interactions. Beneficiaries also include those connected to the patients such as family members, caregivers and friends. Finally, society in general would benefit since it would reduce direct and indirect costs associated with treatment-resistant depression and contribute to society financially via workplace productivity.