Science, serotonin, and sadness: the biology of antidepressants: A series for the public

Wrobel, S. (2007). Science, serotonin, and sadness: the biology of antidepressants: A series for the public. The FASEB Journal, 21(13), 3404-3417.

Fluoxetine was trademarked as Prozac in 1988, arriving in the U.S.A. This new drug was critically acclaimed at the time and is still used by millions of people across nations. In the past, depression was viewed as a disease of the mind, soul and the heart and individuals who suffered it felt stereotyped and ashamed. Prozac changed that, by acting on the biochemical mechanism in the brain.

Prozac and other drugs that affect the reuptake process of serotonin (SSRI) weren't the first drugs that treated depression, but were the first to be designed specifically after the realization of how the brain and neurotransmitters work.

People with depression have reduced levels of serotonin in their brains. Selective serotonin reuptake inhibitor drugs correct this imbalance by not allowing the neurons to retake the serotonin, and thus leaving more of this neurotransmitter (NT) available for the brain to use. This created a new term, which the public knows, as "chemical imbalance" and changed the way it perceived depression.

Building on past clinical research, SSRI drugs raised more questions and opportunities for the future.

What is depression?

Often regarded as the common cold of psychotherapy, depression affects 5%-8% of the world population and prevents people from enjoying their lives, sometimes leading to suicidal thoughts and acts. Depression, in addition to the emotional and physical pain it causes, has a cost of 70 billion dollars per year for the economy.

Thankfully though, 80-90% of severely depressed patients can be treated with a combination of drugs and therapy. We owe the existence of these pharmacological interventions to the physicians and scientists who fought through years of research and did not give up at the first sign of unexpected results.

Depression: the real thing

Depression is endogenous, meaning that it has no clear precipitating event. Without treatment, symptoms of depression can persist for weeks, months, or years; however with adequate treatment those who suffer from depression often find relief. Anyone, at any age, can suffer from depression - worldwide, 5-8% of the population suffers from major depression, while 20% of the population has been affected by milder forms. Women are twice as likely as men to develop depression, probably due to hormones, and are particularly at risk after childbirth. However, men have been found to be four times as likely to commit suicide than women. The accepted explanation for depression is an imbalance in neurotransmitters, particularly serotonin. There is also a genetic component, as depression has been shown to run in families.

There are several forms of depression:

Major depressive disorder is severe enough to interfere with the ability to function in daily life, such as in sleep, work, and eating. Symptoms include feeling sad or fatigued for a long period of time, loss of interest in hobbies, feelings of guilt and hopelessness, and persistent physical ailments (such as digestive disorders and chronic pain) that do not respond to treatment.

Dysthymia is a less severe form of major depressive disorder, but can still affect daily function. People with dysthymia can also have major depressive episodes.

Bipolar disorder is characterised by cycling mood changes between mania and depression. While manic phases are happy and positive, thinking, social behaviour and judgment can still be impaired throughout. Left untreated, bipolar disorder can develop to psychosis.

Chance discovery meets scientific explanation

The history of neuropharmacology helps us understand that mental disorders are diseases of the brain. But in order to learn more about these disorders, scientists had to work hard to understand the brain and the nervous system. The physical and biochemical processes went beyond the scope of dualism, and scientists were forced to re-examine what they once accepted as a truth: that mind and boy were separate.

In the early 20th century, scientists established a basic understanding of how neurotransmitters convey signals through nerves. In the late 1940s and early 1950s, scientists several important neurotransmitters, as well as their levels and relation to certain behaviours:

• Norepinephrine: constriction of blood vessels, increase heart rate and blood pressure

• Dopamine: shortage of this NT is involved in Parkinson's Disease

• Serotonin: deeply connected to depression

Despite their research attempts, the first drugs to treat depression were discovered by chance in patients who were taking the drugs for other purposes. These drugs were far from perfect, but it was a pleasant surprise to observe that they worked for all patients with depression

Thorazine: A story of keen observation

In 1952, a chance discovery of a drug that worked against schizophrenia was made.

While in the search for anti-malarial products, French scientists (from the pharmaceutical firm, Rhone-Poulenc) researched phenothiazine, the basic foundation of methylene blue, which eventually lead to the discovery of its antihistaminic effects.

While the old compounds were too toxic for humans, a newly developed phenothiazine compound had positive effects on patients with Parkinson's, alluding that it had effects on the neurological system. In an attempt to minimise circulatory shock, Laborit, a French naval surgeon, discovered that promethiazine caused patients to relax and become sedated and began using it in combination with anesthesia. An improved version of the drug, chlorpromazine, was already in clinical trails and became a staple in Laborit's toolkit. He began encouraging his colleagues to use the drugs on psychiatric patients, often mixed with barbiturates or other sedatives. The effect of chlorpomazine was unclear until much later, when it was given to manic psychiatric patients on its own.

Later, the American pharmaceutical company, Smith-Kline & French (now Glaxo-Smith&Kline) brought the drug to the United States as Thorazine, and although they were unaware of how it worked, it relieved patients from their psychosis.

Thorazine was considered a "miracle drug" and is responsible for the discharge of more than half a million patients who were previously committed to mental asylums.

"Psychic Energizers": Tuberculosis leads to unexpected discovery and MAOIs

Having vast quantities of Hydrazine post WWII, in 1951 chemists at Hoffman-La Roche created the drugs isoniazid and iproniazid by structurally manipulating hydrazine, a chemical once used by the German military to propel rockets. Both were used to treat tuberculosis (TB).  The psychiatrist, Nathan Kline, claimed that the drug improved patients' mood and brought them happiness; and in 1957, after the release of several scientific papers describing the use of the drugs to treat depression, it became an accepted method of treatment for over 400 000 patients.

Iproniazid and other similar compounds were called "monoamine oxidase inhibitors" (MAOIs) because they worked by inhibiting monoamine oxidase, an enzyme that destroys monoamines, such as norepinepherine and serotonin. Iproniazid disappeared from use soon after, as it caused jaundice in many patients.

From Thorazine to Tricyclics

After the huge success of Thorazine, scientists had hope that a related drug like imipramine would be even more effective against psychosis. Unfortunately, this was not the case, however in 1958, Swiss clinical psychiatrist, Ronald Kuhn, discovered that imipramine caused drastic changes in depressed patients, causing their moods to improve. Eventually, in the 1950;s and 60's, Ciba-Geigy, a pharmaceutical manufacturer released Tofranil, the market brand of imipramine. Tofranil is considered a tricyclic antidepressant (TCA), because of it's structure, with three rings of atoms. Later, another TCA, Elavil was released, and by the 1970's, TCA's became the World Health Organisation's number one recommendation for the treatment of depression. TCAs would keep this status until the arrival of SSRIs.

Problems with lack of selectivity

While effective in treating depression, there were still several problems with MAOIs and TCAs. The most important one was that they did not alter neurotransmitters selectively, so while the symptoms of depression were eliminated, these drugs still caused unwanted side effects that were sometimes dangerous. MAOIs were discovered to cause migraines and high blood pressure, due to its interaction with tyramine, a substance found in foods like cheeses, wines, chocolate, and smoked or pickled meat. These side effects did not necessarily have an immediate onset and could last more than two weeks after the patients stopped taking the medication.

TCAs, like MAOIs, caused undesirable side effects due to the fact that they are non-selective, or "dirty" drugs. This means that they have an effect at sites in the neuron in addition to their intended sites of interaction. For example, its effect on the acetylcholine receptors caused conditions like dry mouth, constipation, and blurred vision. Another major problem with the use of TCAs is that the "clearing time" of the drugs varied from person to person, meaning that some patients could accumulate excessive amounts of the drugs in their bodies, even when taking modest doses. The symptoms of toxicity mimic those of depression, which sometimes led doctors to increase the dosage, making the problem worse. In some cases, the lethal dose for TCAs is only five times the therapeutic dose, and TCAs were the leading cause of death by overdose.

The path to selectivity

Julius Axelrod was interested in whether mental illness was caused by the imbalance of the hormone epinephrine. He began studying the enzymes released with norepinephrine, taking a close look at monoamine oxidase, an enzyme that was known to interfere with neurotransmitters. Many scientists at the time, including Axelrod, believed that monoamine oxidase destroyed neurotransmitters once they leave the neuron that produced it. However, going against this theory, one of Axelrod's colleagues discovered that even when monoamine oxidase was inhibited, norepinephrine was deactivated, indicating that it had another means of leaving the system. This very phenomenon could account for the fact that epinephrine was only ever detected at 3% in the body at any given time.

In order to investigate further, Axelrod designed an experiment that involved injecting radioactive norepinephrine into animals. First, he disabled monoamine oxidase in the animals' bodies; then he disabled their sympathetic system on one side of their bodies; and finally, he injected the radioactive norepinephrine. Axelrod found that norepinephrine was not present in the part where the sympathetic system was destroyed, but in the other side of the animals' bodies where the sympathetic system was intact, norepinephrine was present. Thus, the inactivation of this neurotransmitter could be accounted for by its uptake into the sympathetic nervous system.

In 1961, Axelrod declared that neurotransmitters go through a reuptake process, by which they are recaptured or taken back into the neuron, so that it can be recycled.

A neurotransmitter is either destroyed or goes through reuptake. In the following years, Axelrod and his colleagues discovered that TCAs block neurotransmitter reuptake, while other antidepressants inhibit the destruction of neurotransmitters by enzymes like MAO.

Basic biology to drug design: the SSRIs

Serotonin was connected to depression, as shown by its low concentrations in the cerebrospinal fluid of depressed patients. Treatment with precursors of serotonin revealed antidepressant qualities, and now, thanks to the discoveries of Axelrod, it was now possible to design a drug that could target specific neurotransmitter involved in depression (serotonin.)

Using newly established techniques, such as nuclear magnetic resonance and crystallographic analyses, scientists were able to analyze the structures of compounds and find their properties and biological activity. In 1960s, Bryan Molloy tried to find a new drug to treat depression, one that would not have such severe side effects, like those caused by TCAs and MAOIs. Molloy created a series of analogues, structural derivatives that may differ by at least one element, of the antihistamine, diphenhydramine.

Later one, Solomon Snyder, one of Axelrod's students, developed a method that would allow for the discrimination of the reuptake of serotonin, dopamine or norepinephrine in nerve cells. They centrifuged brain cells, separating out the nerve endings. It was found that the nerve endings continued to take up the neurotransmitters to which they were exposed, giving researchers a quick way of finding out which compounds might block neurotransmitters.

In 1972, fluoxetine was found to restrict the reuptake of serotonin. It was later trademarked by the name of Prozac in 1974. Fluoxetine succeeded in passing various clinical studies and had no known side-effects. Prozac was approved by the FDA in 1987, to be taken once a day to treat depression. It was also later found to be effective against OCD. In a short time after, five SSRIs were developed by other companies and used worldwide. The development of these SSRIs marked a shift in the pharmaceutical industry, one where the serendipitous process of discovery was replaced by rational drug development:

• identifying the enzyme or receptor involved in a disease

• identifying the molecular structure of that enzyme or receptor

• designing and synthesising a molecule that will bind tightly to that enzyme or receptor, changing its behaviour in the desired manner.

While many cheered, others worried

SSRIs have little side effects, due to their inhibition of reuptake for specific neurotransmitters. Another advantage was that they could be started from Day 1 of therapy, in contrast to the earlier TCAs and MAOIs, which had to be initiated a low, less than therapeutic levels.

On the other hand, SSRIs did have some side effects, including sleep disturbance, sexual dysfunction, and weight gain. Additionally, the greatness of SSRIs proved to be a double-edged sword, as the more useful they became, the more freely therapists prescribed and used them. Some feared that SSRIs would be used in instances beyond the treatment of depression, for example in people who wanted to change their personalities. The use of SSRIs for the treatment of depression remains controversial: Children and adolescents on SSRIs have been found to have a two-fold increased risk of suicidal tendencies.

The promise of the future, building on the past

Even today, drugs like TCAs, as well as a number of designer are prescribed and used increasingly. Using genetic identification, scientists can create specific drugs for patients. These drugs are often used in combination with cognitive-behavioral therapies treat depression.