A new study in mice suggests that serotonin deficiency may not play as influential a role in depression as has previously been thought.

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Because of the widespread use of Prozac, the theory that low levels of serotonin caused depression also rose in popularity.

Since the late 1980s, a popular theory has claimed that increasing levels of the signaling molecule serotonin is central to treating depression. This approach to treating depression is typified by the antidepressant Prozac, which works by boosting serotonin levels.

When Prozac was launched in the 1980s, it became a popular treatment for depression very quickly.

However, some experts credit Prozac’s popularity not to it being more effective than previous antidepressant medications – such as tricyclics, which work by blocking absorption of serotonin and norepinephrine in the brain – but because it had fewer side effects than other antidepressants.

Because of the widespread use of Prozac, the theory that low levels of serotonin caused depression also rose in popularity.

But was there sound evidence to support this theory? Many experts think not. As antidepressant researcher Alan Frazer, chair of the pharmacology department at the University of Texas Health Science Center at San Antonio, told NPR in a 2012 feature on the serotonin theory:

I don’t think there’s any convincing body of data that anybody has ever found that depression is associated to a significant extent with a loss of serotonin.”

In the same piece, Dr. Joseph Coyle, a professor of neuroscience at Harvard Medical School in Boston, MA, is quoted as saying: “Chemical imbalance is sort of last-century thinking. It’s much more complicated than that. It’s really an outmoded way of thinking.”

Fast facts about serotonin and depression
  • Tricyclics were the first antidepressants, trialled in the late 1950s, and initiated the theory that chemical imbalance caused depression
  • In the 1990s, Pedro Delgado, chair of the University of Texas’ psychiatry department, conducted a study that found depleting human subjects of serotonin did not cause them to become depressed
  • Depression is said to be the world’s leading cause of disability. The World Health Organization (WHO) estimate that more than 350 million people suffer from it.

Now, studies show that 60-70% of depressed patients do not respond to Prozac or similar drugs.

Therefore, the researchers behind the new study – from the John D. Dingell VA Medical Center and Wayne State University School of Medicine, both in Detroit, MI – wanted to see what role, if any, serotonin plays in depression.

The team developed mice that lacked the ability to produce serotonin and used a variety of tests to investigate whether the mice displayed symptoms of depression.

The researchers found that the mice showed heightened compulsivity and aggression, but they did not display symptoms of depression.

Also, when put under stress, there was no difference in behaviors between the mice that lacked serotonin and a control group of normal mice. A similar proportion of normal mice and serotonin-lacking mice responded therapeutically to antidepressant medications.

The researchers conclude that serotonin may not be a dominant factor in depression, with risk for the condition being comprised instead of a range of different factors. The study’s results – which are published in the journal ACS Chemical Neuroscience – could “dramatically alter” the development of future antidepressants, the researchers state.