In the fluorescent-lit hallways of psychiatry clinics, where patients shuffle in with years’ worth of unfulfilled prescriptions and dwindling hope, a silent frustration grows. Antidepressants are essentially ineffective for about 30% of individuals with major depressive disorder. Not at all. Nothing. Additionally, half of those who experience some relief during the first few months will relapse. For a class of medications that are prescribed to hundreds of millions of people worldwide, the actual sustained recovery rate from SSRIs alone is around 25%. This statistic is shocking when you consider it.
For decades, the majority of physicians have relied on a sophisticated but, as it turns out, likely insufficient explanation. When it was first put forth in the 1960s, the serotonin hypothesis—which holds that depression results from a chemical deficit that SSRIs fix by preventing serotonin from being reabsorbed in the brain—made intuitive sense. It provided patients with a narrative they could cling to. However, SSRIs should function much more consistently than they do if low serotonin were the true cause. According to some research, some depressed patients actually have higher serotonin levels. Additionally, in clinical comparisons, therapies that do not affect serotonin at all, such as exercise, some types of therapy, or even meditation, can yield results comparable to those of SSRIs. The analogy of a headache is appropriate in this situation: paracetamol relieves headaches, but no one seriously contends that a lack of paracetamol causes headaches.
Though understanding it has been a slow process, researchers now believe it to be more complex and, in some respects, more hopeful. According to a study by Silvia Poggini and her colleagues at the Istituto Superiore di Sanità in Rome that was published in the journal Brain, Behavior and Immunity, SSRIs might not function primarily through their chemical action on serotonin. Instead, they appear to enhance the brain’s neuroplasticity, or its ability to physically alter, rewire, and react to experience. According to this interpretation, SSRIs don’t actually treat depression; rather, they open a window that allows the brain to become more flexible and susceptible to the influences of one’s surroundings. Thus, the environment is very important. Mice administered SSRIs and subsequently housed in a serene, encouraging environment showed significant improvements in the Rome study. Those who received the same medications and were placed in a stressful environment worsened. The drug was the same. It didn’t work out.
This theory has been extended into human biology by Gitte Knudsen, a neurologist at the University of Copenhagen. In order to measure synaptic density in a living human brain without invasive surgery, her team used a specialized PET scanning technique that was developed in 2016 for a clinical trial. Over the next few weeks, participants who took the SSRI escitalopram demonstrated quantifiable increases in synaptic connections. They made more new connections the longer they used the drug. This could help to explain the long-standing mystery of why SSRIs take four to six weeks to have an impact on mood, even though their chemical action on serotonin occurs within days. It appears that rewiring the brain takes time.
It is now known that factors that standard SSRIs were never intended to address are involved in treatment-resistant depression, which is formally defined as a failure to improve after at least two adequate antidepressant trials. The hypothalamic-pituitary-adrenal axis is dysregulated by prolonged stress, which modifies the body’s stress adaptation system and makes depression more difficult to treat. People who do not respond to standard medication are disproportionately affected by inflammatory conditions, such as autoimmune diseases and thyroid disorders. The brain’s capacity to release a crucial growth protein in response to stress or medication is diminished by a particular variant known as BDNF Val66Met, which is present in about 30% of individuals. SSRIs might be attempting to open a door that biology has partially blocked for those people.
While millions of patients cycled through prescription after prescription and were discreetly informed that they had treatment-resistant depression as if that were an endpoint rather than a starting point, it is difficult to ignore how much of this was unknown, or at least not widely absorbed into clinical practice. The research is pointing in a more beneficial direction. In contrast to the six-to eight-week waiting period for SSRIs, esketamine nasal spray, which was approved by the FDA in 2019, can induce remission in some TRD patients within hours. Once stigmatized to the point of near obsolescence, electroconvulsive therapy is now regarded as one of the best treatments for severe cases. The range of options is gradually expanding, including deep brain stimulation, psilocybin trials, and repetitive transcranial magnetic stimulation.
However, the conditions surrounding the medication are something that cannot be prescribed, and this is what the more recent research keeps returning to. SSRIs might get the brain ready for change, but they don’t control how it happens. Antidepressants may work against, rather than for, a person who takes them while experiencing long-term stress, loneliness, or a truly hostile environment. Poggini’s comparison is accurate: SSRIs put you in the boat, but the journey is determined by the sea. There may be more to antidepressant failure than just pharmacological issues. Additionally, it’s a contextual issue, which medicine can at least begin to address.