Prozac, Paxil, Celexa, Zoloft, Lexapro. These so-called selective serotonin reuptake inhibitors (SSRIs) are among the most widely prescribed drugs in the U.S. Although they are typically used to treat depression and anxiety disorders, they are also prescribed off-label for conditions such as chronic pain, premature ejaculation, bulimia, irritable bowel syndrome, premenstrual syndrome and hot flashes.
Even if you have never taken an SSRI, chances are you know someone who has. About one in every 10 American adults is being prescribed one now. For women aged 40 to 59 years old, the proportion increases to one in four.
SSRIs block the body from reabsorbing serotonin, a neurotransmitter mostly found in the brain, spinal cord and digestive tract whose roles include regulation of mood, appetite, sexual function and sleep. Specifically, SSRIs bind to the protein that carries serotonin between nerve cells—called SERT, for serotonin transporter—intercepting it before it can escort the released neurotransmitter back into the cell. This action leaves more active serotonin in the body, a chemical effect that is supposed to spur feelings of happiness and well-being.
But there are hints that SSRIs are doing something other than simply boosting serotonin levels. First, people vary in their response to SSRIs: Studies have shown that the drugs are not very effective for mild to moderate depression, but work well when the disorder is severe. If low serotonin were the only culprit in depression, SSRIs would be more uniformly helpful in alleviating symptoms. Second, it takes weeks after starting an SSRI for depression and anxiety to lift even though changes in serotonin ought to happen pretty much right away.
Changing Emotional Bias
Some data suggest that SSRIs may also lessen negativity by calming the amygdala, a brain region that governs fear, among other emotions. People with depression and anxiety typically pay excessive attention to unpleasant social and environmental cues, which creates a “negative emotional bias” in the way they interpret their experiences, says psychopharmacologist Phil Cowen of the University of Oxford. In their brain, the amygdala is overactive whereas the prefrontal cortex, which keeps emotions in check, is unusually quiet. Neuroimaging studies indicate that SSRIs lessen these negative biases by inhibiting the amygdala and improving communication between the prefrontal cortex and the emotional processing areas, Cowen says.
SSRIs have also been found to stimulate nerve growth in the hippocampus, a brain structure involved in learning and memory. Imaging studies have indicated that people with depression may have fewer connections among neurons; so one theory suggests that SSRIs alleviate depression by encouraging neural growth and plasticity. Cowen hypothesizes that the new connections form as people with depression relearn old emotional associations in a way that puts their experiences in a more positive light. This learning might be necessary for recovery—and the time it takes to gain a new perspective might partly explain why SSRIs take so long to work.
SSRIs have various effects on other parts of the body, too. Sexual dysfunction, for example, may occur because the drugs limit tension in blood vessels, making it difficult to achieve genital arousal. One person’s side effect may be another’s salve, however: men suffering from premature ejaculation are sometimes prescribed SSRIs. SSRIs also alter appetite signaling, accounting for two other common side effects, nausea and weight gain. Relatedly, serotonin levels in the gut can trigger intestinal contractions and secretions, potentially explaining why SSRIs help ameliorate irritable bowel syndrome and other digestive disorders.