Improving the long-term response to antidepressants by establishing an individualized platform based on variability...

Despite the availability of multiple interventions, treatment-resistant depression (TRD) is still a major clinical challenge that has multiple factors associated with its development. Depression is a highly dynamic condition, and both the triggers which underlie its pathogenesis and the loss of response to drugs continuously change. These, along with large interpatient and intrapatient unpredictability, further complicate overcoming decreased response to drugs which may worsen the prognosis in some patients.

In this review, we discuss mechanisms associated with loss of response to antidepressants and focus on the potential role of the autonomic nervous system and chronobiology in the pathogenesis of the disease and subsequent response to therapy.

We introduce a novel treatment strategy which is based on individualized variability and guided by chronotherapy regimens. We also suggest the implementation of a personalized algorithm which comprises quantifiable signatures associated with the mechanisms of the disease and which underlie the loss of response to drugs. To overcome the deleterious compensatory responses in a highly dynamic system in patients with depression, we propose a closed-loop therapeutic regimen tailored to patients that enables improved responses to current therapies.

Implementing guided algorithms tailored to patients are expected to shed light on some of the mechanisms involved in the development of TRD, and will enable the development of new therapeutic strategies for improving the long-term drug response.