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Visions Journal

A reminder that this article from our magazine Visions was published more than 1 year ago. It is here for reference only. Some information in it may no longer be current. It also represents the point of the view of the author only. See the author box at the bottom of the article for more about the contributor.

From Happenstance to Targeted Investigation

A brief history of mental health meds

Debbie Thompson and Angus Kinkade

Reprinted from the "Medications" issue of Visions Journal, 2007, 4 (2)

The early development of medications for mental illness involved more luck than formal scientific method. It’s surprising how many of these medications have been discovered by chance.

The journey from dyes to antipsychotic agents

In 1950, the first antipsychotic agent, chlorpromazine, was identified. But the development of this first mental health medication unwittingly began in 1876, with a dye called methylene blue. A staining agent used in laboratory procedures, methylene blue was also thought, by researchers looking for alternatives to quinine, to effectively treat malaria symptoms. A search for other chemicals with properties similar to methylene blue identified various agents with antihistamine effects.

None of this development had a mental health focus. Some time later, however, physicians combined antihistamines with anesthetics to facilitate anesthesia in surgery. They discovered that this combination had a powerful calming effect. The success of this combination encouraged researchers to look further for similar compounds. One of these was chlorpromazine.

Chlorpromazine had a calming effect, without sedating the patient or causing them to lose consciousness. Patients receiving chlorpromazine were less excitable and their thoughts less chaotic than they were when they didn’t take any medication.

By early 1970, chlorpromazine was the most widely used antipsychotic medication. The search for similar medications continued, and over the next 30 years, 40 antipsychotic agents were developed. Although each of these agents had similar effects, they had different chemistry, potency and side effects.

The widespread use of chlorpromazine and related medications resulted in a dramatic decrease in hospitalizations. The large institutions, which used to hold hundreds or thousands of patients, gradually decreased in size as medication allowed more and more patients to live in their communities. Chlorpromazine greatly improved the quality of life for patients with mental illness.

Between 1975 and 1990, research into antipsychotic medications stalled. No new antipsychotic agents were identified or released during that time period.

In 1988, however, a group of researchers remembered clozapine, an old antipsychotic agent that was effective in patients with treatment-resistant schizophrenia. Clozapine was first identified and studied in early 1960, but research was stopped because of reports of a serious side effect (i.e., lowered white blood cell count). Reinvestigation of the medication showed that clozapine was helpful in reducing positive† (hallucinations, delusions, etc.) and negative† (withdrawal, apathy, etc) symptoms of schizophrenia. To reduce the risk from side effects, clozapine’s re-release in 1990 included a mandatory monitoring system.

The rediscovery of clozapine was the turning point for the development of a new class of drugs, the “atypical” antipsychotic agents. These new antipsychotic agents are being developed to target specific areas and chemicals in the brain. Some of these more targeted medications are currently undergoing clinical trials.

From TB to antidepressants

The first antidepressant agent, iproniazid, was developed in the 1950s as a possible treatment for tuberculosis. Patients with tuberculosis who were treated with iproniazid showed higher mood and increased activity. This observation led to research on iproniazid’s effect on depression. By 1957, promising studies resulted in widespread prescribing of iproniazid—to 400,000 patients within the first year.

Iproniazid belongs to a class of antidepressants called monoamine oxidase inhibitors (MAOIs) . Although isproniazid is no longer used because of toxic side effects, other MAOI antidepressants are available.

The next class of antidepressants was also discovered in the 1950s, while searching for treatments for schizophrenia. The first agent in this class was imipramine, a tricyclic antidepressant (TCA) . Although imipramine was not effective as an antipsychotic for treating schizophrenia, it did improve mood and energy in depressed patients.

By the time MAOIs and TCAs had became popular, it was no longer believed that people with depression were morally weak or possessed by demons. Rather, depression was seen to be accompanied by an imbalance in chemical messengers in the brain. Antidepressant agents compensated for this chemical imbalance. All medications that help with depression increase, directly or indirectly, the levels of three neurotransmitters (norepinephrine, serotonin and dopamine).
In 1987, a third class of antidepressant medications was designed specifically to address this chemical imbalance in the brain. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that was created to produce the same effect as the MAOI and TCA antidepressants, but with fewer side effects.

Since then each new medication has been designed to optimize the antidepressant effect and minimize or avoid side effects.

Back to nature

Lithium is a simple molecule found in nature. Many mineral springs contain lithium, and as early as the 2nd century, mineral springs were used for their mood elevating properties—the waters were used for both drinking and bathing.

Lithium’s mood stabilizing properties were discovered by accident. In the 1940s, Dr. John F.J. Cade, an Australian psychiatrist, speculated that a toxin in the blood was responsible for bipolar disorder and was providing patients with a mixture that he believed would counteract the effect of the toxin. That mixture, containing lithium, produced a calming effect.

Later studies found that lithium alone was responsible for the positive effects and, when taken continuously, decreased depression and mania. Despite this evidence, lithium did not receive widespread acceptance as a treatment for bipolar disorder until the 1970s, after more studies supported its effectiveness. Many patients prefer lithium because of its natural origins.

Chance has played a huge role in the development of medications of all kinds. Each discovery, however, leads the way for more research to find better treatments. Thankfully, we’ve moved from an era of discovering medications, to one of designing them.

Debbie is the Clinical Pharmacy Consultant in Psychiatry for Fraser Health, Mental Health and Addictions. She provides support and service to clients, families and staff from Burnaby to Boston Bar. Debbie is also a classroom and clinical instructor for the University of British Columbia Faculty of Pharmacy undergraduate program.

About the author
Anthony graduated from Pharmaceutical Sciences at UBC in 2006. He worked as a community pharmacist for London Drugs following graduation, and is now a Pharmacy Resident for the Fraser Health Authority.
  1. “The Bethlem Royal Hospital of London, which has been variously known as St. Mary Bethlehem, Bethlem Hospital, Bethlehem Hospital and Bedlam, is the world’s oldest psychiatric hospital. The word Bedlam has long been used for lunatic asylums in general.”

  • Kaplan, H. & Sadock, B. (2003). Kaplan and Sadock’s synopsis of psychiatry: Behavioral sciences, clinical psychiatry (9th ed.). New York: Lippincott Williams & Wilkins.

  • Trujillo, K. & Chinn, A. ( 1996). Classifications of psychoactive drugs. Drugs and the Brain (online tutorial). San Marcos, CA: California State University.


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