The latest worldwide survey of global health underscores the devastating impact of depression. Depression was ranked as the 3rd highest cause of disability across all illnesses, resulting in approximately 43 million years lost to disability (YLD). In only a single year, 264 million people suffer from depression, and 800,000 lives are lost to suicide. Narrowing in on the United States, almost 7% of adults experience an episode of depression each year, costing an estimated $210.5 billion due to the combination of treatment costs and productivity loss. Consistent with this enormous disease burden, the NIH has spent over $22 billion on depression research over the last 20 years – more than for any other mental illness, including addiction, schizophrenia, or autism. But despite this massive investment, only 1 in 3 patients substantially responds to currently available medication or psychotherapy treatments.

Why are we stuck? The modern practices of psychiatry and psychology are grounded in neuroscience and biology. We understand that synaptic connections serve as the currency of neural communication, and that strengthening or weakening these connections can facilitate learning new behavioral strategies and ways of looking at the world. Through studies in both animal models and humans, we have discovered that emotional states are encoded in complex neural network activity patterns, and that directly changing these patterns via brain stimulation can shift mood. We also know that disruption of these delicately balanced networks can lead to neuropsychiatric illness.

Based on this understanding that psychiatric symptoms are rooted in biology, all existing drug therapies for depression target biological mechanisms. Selective serotonin reuptake inhibitors (SSRIs) bind to the serotonin transporter, leading to increased serotonin concentration in the synaptic cleft and a cascade of downstream functional and structural consequences. Although the exact mechanism of action of the fast-acting antidepressant ketamine is still being investigated, it is known to be an NMDA-receptor antagonist. Brexanolone, which is the newest FDA-approved antidepressant for the indication of post-partum depression, is a neuroactive steroid that is a positive allosteric modulator of the GABA receptor. We have now even solved the crystal structures of psychiatric drugs binding to their targeted receptors. Since at least the 1960’s, with the first indications that alterations in levels of catecholamines such as dopamine can lead to depressed mood, we have known that depression is biologically based, and that treatments need to address these underlying biological problems.

Yet, these biologically based treatments are not being matched to the biology of the human beings they’re being used in. According to standard treatment guidelines currently recommended by the American Psychiatric Association, the first-line pharmacotherapeutic treatment for depression is a randomly selected SSRI. And if that doesn’t work, the next step is switching to another randomly selected SSRI, followed by augmentation with an additional agent or switching to an alternative medication class. It is a brute force process guided almost exclusively by qualitative data and subjective self-report. And the impact of each new medication change can take between 2-6 months to assess. This current state of affairs leads to time lost for both patients and their loved ones, unnecessary side effects, discouragement, and – perhaps most importantly – continued progression towards end-stage illness.

What needs to change? To make meaningful change, we need to match treatments to the specific biology of the people receiving them.