New research on how SSRIs work, and some ideas for making the wait a little easier.
When my doctor told me that the antidepressant, she had just described would take up to six weeks to take maximum effect, I didn’t know what to say. It had taken all the energy I had just to make that appointment and show up to it. I had no idea how to think about, let alone make it through, six more weeks of anxiety and exhaustion.
More than a decade later, those six weeks now appear as just a blip on the arc of a lifetime. But in the throes of depression, the prescription to wait weeks for relief is hard to hear.
Why do the most prescribed antidepressants — selective serotonin reuptake inhibitors, or SSRIs — take so long to work? And how do they work? Answers to these questions have proven surprisingly elusive, but new research has brought us closer to a full understanding and pave the way for insights into what causes depression to begin with
Can you hear me now?
Nerves communicate to each other by releasing chemical signals — including serotonin — at small connections called “synapses” between the nerves. While the brain sends some signals to the body by way of the bloodstream with hormones that hang around for minutes to days, signals sent through nerves (whether to other parts of the brain or other parts of the body, like muscles) need to be brief.
Imagine a symphony where every note played by every instrument lasted for 5 minutes. The result would be a cacophony — not music. In the same way, nerve signals need to be snappy if you are going to, say, run down the street or process a constant stream of visual data from your eyes.
Nerves accomplish this instantaneous signaling by slurping their chemical signals back up right after they release them — a process called “reuptake”. SSRIs slow down this reuptake process to make the signals sent by some nerves a little longer and a little louder.
Simple enough, right? Not exactly. Although SSRIs alleviate depression for many people, it has proved difficult to determine how nerve signaling with serotonin is involved in depression in the first place. And as a result, we don’t know for sure how SSRIs treat depression. If SSRIs work simply by turning up the volume on nerve signals, one might expect them to work quickly.
But they don’t — as I and countless other patients can tell you from first-hand experience.
Gitte Moos Knudson, MD, professor of neurobiology at Copenhagen University Hospital, looked at the effects of SSRIs from a new angle. Her lab wondered if SSRIs stimulate the formation of new synapses between neurons — rather than simply turning up the volume at existing synapses. Their new research, published this month in the journal Molecular Psychiatry, demonstrated that this is in fact the case.
Treatment with the SSRI escitalopram (brand name Lexapro) in healthy volunteers resulted in the formation of new nerve connections within large regions of the brain.
Rather than making each instrument in the brain symphony play louder and longer, escitalopram seemed to add more instruments to the orchestra.
“We found that with those taking the SSRI, over time there was a gradual increase in synapses in the neocortex and the hippocampus of the brain, compared to those taking placebo,” said Knudson, in a statement. “We did not see any effect in those taking placebo.”
Forming new brain connections takes time. Knudson’s study found an increase in synapses over the course of 5 weeks. Whether this process continues after 5 weeks remains an open question and was not addressed in this study.
“I wouldn’t say that it is the final answer, but it is a candidate mechanism that many scientists find plausible,” Knudson told me.
Not only does this research suggest how SSRIs work, but it also may help explain why depression occurs in the first place. Future studies can look more closely at where these new connections are being formed, which may help us understand which brain regions are involved in depression.
One size does not fit all
However, SSRIs work, they do not work for everyone. Different studies give different response rates, largely due to variations in the definition of “response”. But in general terms, any given patient has around a 50% chance of responding to any particular SSRI. (Why people respond differently to different SSRIs remains another scientific mystery.) And a significant proportion of patients will not respond at all even after trying several different SSRIs.
I asked Knudsen why that might be. “Patients with major depressive disorder have (kind of) similar symptoms, but many of us believe that depression has many different causes and that should be treated differently. I think this is a likely reason why the patients respond differently.”
Identifying different sub-types of depression and tailoring therapy accordingly is a young and important area of research.
Don’t wait for it
While all this research may advance the field and open the way to new and better treatments in the future, it provides little comfort to those suffering symptoms of depression who are waiting for their medication to take effect right now.
If you are one of those individuals, here is a list of some things you can do — based on a combination of personal experience and what experts in the field suggest — while you wait.
- Give yourself credit for getting to this point. Making an appointment and going to the doctor can be a monumental task when you are depressed. By taking these steps, you have already achieved something important for yourself. You have already demonstrated hope and resilience by reaching out to your doctor. Continue to nurture that sense of hope for the future.
- Take part in other therapeutic activities that have scientifically proven benefits for depression. This includes exercise and meditation. “I fully understand that it can be painful to wait for the therapeutic effect to set in,” said Knudson. “Neuroplasticity is also promoted by physical exercise, so my advice is to try and get some exercise outdoors, e.g., taking a walk in a park or in the forest.”
- Open your mind to the placebo effect. Around 35% of patients with depression improve significantly just by taking an inactive placebo tablet in randomized, controlled trials. This demonstrates that a combination of time and positive thinking is truly helpful for many people. So remind yourself each day that it is possible that you will feel a little better today even if your new medication has not kicked in yet.
- Minimize self-medication. Mind-altering substances like marijuana or alcohol, while providing short-term relief, can exacerbate depression and may interact in undesirable ways with antidepressant medication.
Finally, make a plan. Using the suggestions above and others from friends, family, and healthcare professionals, map out a schedule for yourself. Choose one therapeutic strategy per week for the next 5 weeks, and then spend 15–30 minutes per day focused on that activity or thought pattern.
These activities may help on their own, or at least help run out the clock while your new medication kicks in. Hopefully both.
Michael J McCluskey 