Science, serotonin, and sadness: the biology of antidepressants A series for the public - Wrobel - 2018 - Article

What is depression?

Everyone one feels sad or blue from time to time, especially after, for instance, the loss of a beloved one. But individuals with depression are dealing with a very different situation, one that is persistent, severe, and debilitating. Depression is considered endogenous, which means that is has no clear precipitating event. Without treatment, depressive symptoms can last weeks, months, or even years. Worldwide, approximately five to eight percent of the population suffers from depression, with estimations up to 20 percent for people suffering from milder forms of the disease. With treatment, most people (about 80 to 90 percent), even with severe forms of depression, can be helped. Treatment occurs usually with drugs, often in combination with non-pharmacologic interventions, such as counseling or psychotherapy.

Like other diseases, depression comes in different forms. Major Depressive Disorder is a severe form that interferes with daily functioning. It hinders one's ability to work, study, sleep, eat, and enjoy once pleasurable activities. Dysthymia is a less severe form of depression (at a single time point), but more chronic, thus lasting much longer. Bipolar disorder, also called manic-depressive illness is characterized by cycling mood changes, in which one moves from a severe high (mania) to a severe low (depression).

How did drugs redefine depression?

Not so long ago, depression was regarded as an affliction of the human heart, mind, and soul. When an individual with depressive symptoms went to the psychiatrist, the psychiatrists would suggest that the person was repressing anger toward others and turning it toward themselves. The psychiatrist may also have asked if the individual had felt unloved by his or her mother. In those days, there was much of a stigma and blame associated to being depressed.

Nowadays, thanks to Prozac and other Selective Serotonin Reuptake Inhibitor (SSRI) drugs, there is a shift toward "chemical imbalance". Depression now is at least partially explained in a biological manner. That is, (major) depression is now understood as a biological brain disorder involving chemical imbalance in the neurotransmitters. Neurotransmitters are chemical messengers that transmit signals between brain cells. This shift is especially due to the entrance of Prozac. Prozac entered the pharmaceutical market in the United States in 1988. Such SSRIs focus on serotonin and inhibit is recapture by the nerve cells, alleviating the shortage in serotonin and leaving more of the mood-enhancing chemical outside the neuron, therefore available for the brain to use.

What is the history of antidepressant drugs?

Antipsychotic: Thorazine

Before Prozac, Thorazine was introduced at the pharmaceutical market. Although at that time it was unclear how Thorazine worked, some patients who had delusions and hallucinations for decades, emerged from their psychoses for the first time by taking this drug. However, later some troublesome side effects appeared, in particular abnormal movements and muscular rigidity. These side effects would become important clues both to how the drugs worked and to what could cause a disease with symptoms very similar to these side effects of Thorazine: Parkinson's disease. Arvid Carlsson, a Swedish pharmacologists, discovered that Thorazine was preventing dopamine from binding to its receptor. This finding led to important developments of medication with dopamine as a treatment for Parkinson's disease. It also led Carlsson to win the Nobel Prize in 2000.

Antidepressant: MAOI and TCA

After the success of Thorazine, scientists hoped to find a structurally-related drug that might work even more effectively against psychosis. They studied tricyclics (TCAs) with Tofranil being the first and trademark of the TCAs. However, the TCAs proved problematic. They were unselective, meaning that they have prominent actions at sites next to the site that produces the intended therapeutic effect. This resulted in side effects such as heart palpitations, dry mouth, blurred vision, constipation, and urinary retention. In addition, it appeared that they drugs could accumulate in the body, even when given modest dosages. The body is unable to quickly "clear" these drugs.

Antidepressant: SSRI

The path to selectivity began. A pioneer in this field was Julius Axelrod. He made two extraordinary discoveries. First, he identified an enzyme called catechol-O-methyltransferase that inactivates the transmitter norepinephrine, differently than does the enzyme called monoamine oxidase (MAO). Second, and most importantly, he discovered that neurotransmitters are not always inactivated by breaking them down. Sometimes, neurotransmitters are sucked back into the nerve from which they originated, and reused. Axelrod called this mechanism reuptake. This discovery had important implications for how antidepressants might work by preventing reuptake and hence correcting a deficiency of a needed neurotransmitter in the brain. Understanding this mechanism of reuptake allowed researchers to design and engineer a drug that would act only upon the neurotransmitters that created the desired effect relative to depression, and leave alone the neurotransmitters that could case unwanted side-effects if changed. This, in combination with the finding that serotonin was the neurotransmitter of choice, led to the development of Prozac and other SSRI's.