The role of immunomodulators in treatment-resistant depression: case studies

Depression is a common mental disorder affecting more than 264 million people worldwide. The first-line treatment for most cases of depression are selective serotonin reuptake inhibitors (SSRIs), such as sertraline, reboxetine and fluoxetine. Recently, it has been found that one-quarter of depressed patients have excessive activation of the immune system. This potentially warrants sub-categorisation of depressed patients into inflammatory and non-inflammatory subtypes. Such a sub-category of depression already exists for those not responding to various traditional antidepressants and is known as treatment-resistant depression. Those with treatment-resistant depression are far more likely to have raised inflammatory markers relative to those whose depression is treatment-responsive. Chronic, low-level inflammation seems to trigger depression via a multitude of mechanisms. These include kynurenine pathway and microglial cell activation, resulting in a reduction in hippocampal volume. Raised inflammatory cytokines also cause perturbations in monoaminergic signalling, which perhaps explains the preponderance of treatment resistance in those patients with inflammatory depression. Therefore, if treatment-resistant depression and inflammatory depression are semi-synonymous then it should follow that anti-inflammatory drugs will display high efficacy in both sub-types. Ketamine is a drug recently approved for use in depression in the USA and displays a particularly good response rate in those patients with treatment resistance. It has been suggested that the antidepressant efficacy of ketamine results from its anti-inflammatory effects. Ketamine seems to produce anti-inflammatory effects via polarisation of monocytes to M2 macrophages. Furthermore, another anti-inflammatory drug with potential use in treatment-resistant depression is Celecoxib. Celecoxib is a long-acting, selective COX-2 inhibitor. Early clinical trials show that Celecoxib has an adjuvant effect with traditional antidepressants in treatment-resistant patients. This paper highlights the importance of classifying depressed patients into inflammatory and non-inflammatory subtypes; and how this may lead to the development of more targeted treatments for treatment-resistant depression.