Pharmacotherapy of major depressive disorder in older adults: from an evidence-informed stepwise algorithm to precision medicine.

The pharmacotherapy of late-life depression (LLD) is characterized by clinical complexity. Older adults are living longer with multimorbidity, frailty and polypharmacy, and are taking more CNS-active medications and substances. These add to the risk and complexity of adding or changing depression treatment. At the same time, there are more medication options for depression and the use of many of them entails balancing potentials risks and benefits. As a result, the pharmacotherapy of LLD should be guided by tools such as algorithms or decision trees to maximize effectiveness and minimize risks of depression treatment. We propose an evidence-informed stepwise algorithm, based on three decades of clinical trials. With this algorithm, treatment starts with serotonin-selective reuptake inhibitors because of their safety and ease of use. If the patient does not respond, the next step is switching to serotonin-norepinephrine reuptake inhibitors, followed by augmentation (with aripiprazole as the preferred agent). For older patients who do not tolerate or do not respond to traditional pharmacotherapy, treatment options include transcranial magnetic stimulation, ketamine, or electroconvulsive therapy. Psychotherapy can be used in combination with antidepressants at any point in this algorithm. We also discuss the need for precision medicine research to improve treatment outcomes in LLD, presenting two approaches. The first is a "lock and key" approach, in which some patients need a specific medication to treat their depression, which requires biotyping to predict. The second is a "simple vs. complex depression" approach, which posits that some with TRD have a more complex illness consisting of less intact brain structure and function and are unlikely to benefit from any traditional treatment; they require novel-mechanism treatments targeting their specific pathophysiology, such as impaired slow wave sleep or accelerated biological aging. In the coming years, we expect these two complementary approaches to improve the outcomes of the increasing population of older adults who suffer from depression.