Skeptics of the most commonly prescribed antidepressants—the selective serotonin reuptake inhibitors (SSRIs)—often cite the fact that it takes four to six weeks for these medications to kick in as a reason to think that SSRIs don't really work. Or if they work, skeptics argue, it's not because depressed or anxious individuals have low serotonin levels in the brain.
SSRIs are commonly believed to work by blocking the serotonin transporter—a molecule that carries serotonin back into brain's cells. When serotonin is inside a brain cell, it does not do anything good or bad. For it to work as a neurotransmitter that can help activate brain signaling, it needs to be on the outside of the brain's neurons. If SSRIs work by blocking the serotonin transporter, they will result in more serotonin sitting on the outside of the neurons (or, more specifically, in the gap between two neurons), where it can do its job.


Although serotonin has multiple functions in the brain, one of them is to keep us calm and content. So, when too little serotonin is active outside our brain cells, we become nervous, unhappy or unable to feel any pleasure. Blocking the transporter that inactivates serotonin can thus restore our brain's levels of active serotonin and once again make us calm and content.
Those who are skeptical of SSRIs and of the whole idea that low serotonin levels in the brain can be a reason we suffer from anxiety and depression occasionally make mention of the long time it takes for SSRIs to work.


It is certainly peculiar that SSRIs do not work instantaneously after popping the first pill. After all, SSRIs are not the only drugs to block the serotonin transporter. Street drugs like cocaine and ecstacy also reportedly block the serotonin transporter. But it does not take four to six weeks for cocaine or ecstacy to have a noticeable effect on us.
Some skeptics think that this difference between street drugs like cocaine and SSRIs is strong evidence that depression and anxiety are not due to too low serotonin levels in the brain but rather to something else altogether. When SSRIs work, they say, (which they do—roughly—for 30 percent of depressed/anxious people who take them), it is because the SSRIs activate some other brain system after increasing serotonin for weeks or months.


There is, however, a different explanation of why SSRIs, unlike cocaine and ecstacy, take so long to kick in. Consider an analogy. Let's say you go to a dietician and set up a new meal plan in an effort to shed weight. You and your dietician come up with a good regimen that is likely to work. However, your refrigerator and freezer are stocked with the foods you and your family used to eat. Since you do not want to waste the food you already have, you decide to finish it before starting your new and healthier eating habits. Because you have a lot of food in your house, it takes a few weeks before you have replaced most of it with healthier alternatives. So, your weight remains stable for a while. After a month or so, however, you start to lose weight. This is the time when most of the old foods in your house have been replaced by healthier alternatives.


More resent research suggests an analogous explanation of why SSRIs don't kick in right away. The reason suggested is that SSRIs don't target the serotonin transporter directly. Although some SSRIs (for instance, Lexapro) bind directly to the transporter, the direct binding is not the underlying mechanism of action. Instead antidepressants target our DNA, in particular the genes that code for the serotonin transporter. They make these genes less active, so fewer serotonin transporter molecules are available in the brain. This, it is argued, explains the delayed action of antidepressants. Since our brain has plenty of active serotonin transporter molecules when we start taking antidepressants, it takes a while before a suppression of the genes that code for the transporter has an effect on serotonin in the brain. When we start taking the medication, our brain is like a refrigerator stocked with our old food choices. It takes a few weeks for us to get through that food and replace it with the healthier alternatives that can ultimately stabilize us and make us function optimally.