The modern age of chemical medicine: a brief biography on fluoxetine

Author | Si Xia

Editor's note: This is the best time for the pharmaceutical industry

In October 2021, the University of Queensland in Australia published online research on the surge in major depression and anxiety around the world under the new crown pandemic on the Lancet

Studies have shown that before the outbreak, it is estimated that the number of patients with major depression worldwide will reach 193 million in 2020.

In fact, as early as 2600 BC, the term "depression" appeared in ancient Egyptian documents, and "depression" was also recorded in the "Huang Di Nei Jing"

The dawn of depression treatment

Before the 1950s, there was no real effective treatment for depression.

Until the discovery of imipramine (tricyclic antidepressants, TCAs) in 1959, it was of fundamental significance to the formation of the initial etiological theory of depression.

Based on the serotonergic hypothesis, by inhibiting the reuptake of 5-HT by nerve cells and increasing its concentration in the synaptic cleft, thereby improving the patient’s depression and reducing side effects, Eli Lily started a long serotonin reuptake The road to research and development of inhibitors (SSRIs)

At the beginning of discovery, there were many doubts

Initially, Eli Lilly established a "Serotonin-Depression" group led by researchers Fuller, WongMolloy and Rathbun

In addition, in a standard antidepressant test, diphenhydramine showed comparable effects to imipramine and amitriptyline in blocking ptosis induced by tetraphenylhydrazine in mice

On July 24, 1972, the team compiled the structure-activity relationships of these aryloxyamphetamines and found that fluoxetine was the most effective and selective 5-HT reuptake inhibitor

However, because fluoxetine did not have obvious activity in the depression animal models at the time, such as the forced swimming test and apomorphine-induced low temperature test, and it could not produce the TCA-like behavioral effects known to pharmacologists, fluoxetine Ting's antidepressant potential is frequently questioned

Figure 1.

regain confidence

Fortunately, Asberg and his colleagues published an article in time.

Figure 2.

Preclinical studies delayed by phospholipid disease

In 1973, after learning about the laboratory findings of fluoxetine, the Eli Lilly Central Nervous System Research Committee recommended that a project team be established to guide subsequent product development

After 9 months of thinking to no avail, the research team consulted with the FDA's Neuropharmacology Department and learned that cationic amphiphilic molecules can cause reversible accumulation of phospholipids in tissues

Clinical research: twists and turns

In 1976, Eli Lilly's clinical researcher Lemberger used fluoxetine for the first time in humans.
The subjects were well tolerated by fluoxetine, and the dosage was as high as 90 mg.
The platelet intake of 5-HT in subjects treated with fluoxetine Suppressed, the 5-HT content in platelets decreased after repeated administration
.
This study proved for the first time that fluoxetine can selectively and effectively inhibit the absorption of 5-HT by platelets in the human body, and has no obvious adrenergic effect on the cardiovascular system
.

With the successful completion of the phase I clinical study, the team is ready to advance fluoxetine to phase II clinical trials
.
However, Eli Lilly had other priority drug candidates at the time and lacked experienced psychiatric clinical researchers.
Therefore, the phase II trial of fluoxetine in patients with depression was almost stopped
.
There are only relatively small studies on the treatment of fluoxetine for patients with depression, and unfortunately the drug is ineffective
.
This undoubtedly disappointed the people who were closely involved in this project
.
However, the research team was subsequently told that the failure of the trial may be related to the types of patients involved, who are very difficult to respond even with other antidepressant treatments
.
After learning of this news, the research team decided to continue to develop fluoxetine and repeat the study in a group of patients with refractory depression
.

After a long search, Eli Lilly hired a young psychiatrist as a clinical researcher
.
He spent nearly two years searching for suitable institutions in the United States to conduct clinical trials of fluoxetine
.
However, he left Eli Lilly before the start of the clinical study
.
Eli Lilly had to search for suitable clinical researchers again, until the famous pharmacologist Slater, who is also a doctor with rich clinical research experience, agreed to assist in the project, and the phase II study of fluoxetine was carried out
.
Just before Dr.
Slater retired, the results of an open-label study in patients with depression lived up to expectations
.

Stark is a pharmacologist.
After he took over the phase III clinical research project of fluoxetine, he quickly confirmed the trial and achieved success
.
Fluoxetine has been shown to be effective in the treatment of major depression, with fewer side effects than TCAs, including low levels of dry mouth, blurred vision, constipation, orthostatic hypotension, lethargy, and sedation
.
More importantly, fluoxetine does not have a direct effect on the electrical conductivity of the heart like taking high-dose TCA drugs
.

New drug application, waiting and turning point

When Eli Lilly submitted a New Drug Application (NDA) for fluoxetine to the FDA in 1983, Astra Pharmaceuticals, with the help of the Carlsson group, introduced the SSRI drug Zelmid to Europe in 1982 for the treatment of depression
.
Eli Lilly thought it had lost its first opportunity to go public, but zimeridine had to withdraw from the market due to serious side effects, namely Guillain-Barré syndrome, and Astra Pharmaceuticals terminated all research on SSRIs
.
Therefore, Eli Lilly rekindled confidence in fluoxetine
.

Approximately two years after the NDA of fluoxetine was submitted, the FDA advisory committee only considered whether it was worthy of approval in October 1985
.
Although some people questioned that fluoxetine may have side effects similar to zimeridine, Eli Lilly believes that the molecular structure of fluoxetine and zimeridine is significantly different, and this Guillain-Barré syndrome is likely to be zimeridine Set unique, and finally convinced the members of the advisory committee
.

It is a long process to wait for the final approval of the FDA.
As it was Christmas, the team learned about the FDA approval of fluoxetine as an antidepressant drug through local television news on December 29, 1987
.
In January 1988, fluoxetine was finally marketed under the trade name Prozac
.
From the first kinetic study of distinguishing 5-HT uptake and norepinephrine uptake in rat brain nerve terminals, to the first time that fluoxetine is an effective and selective inhibitor of 5-HT uptake in vitro The research and development of fluoxetine, until finally approved for marketing, fluoxetine's research and development process has exceeded 16 years
.

Figure 3.
Timeline of the key milestones that led to the development of Prozac and other SSRIs4

Clinical research

In the clinical selection of drugs for depression, both safety and effectiveness must be considered at the same time
.
A 5-week multicenter double-blind randomized controlled trial compared the efficacy of fluoxetine with the TCA drug amitriptyline in the treatment of major depression
.
The results showed that the overall efficacy of fluoxetine and amitriptyline in 136 outpatients was equivalent, and the response rates of the two after 4 weeks (the total score of HAM-D21 decreased by ≥50%) were 46.
7% and 66.
0%, respectively (p= 0.
039), the remission rate (HAM-D21 total score ≤ 7) was 18.
3% and 28.
3% (p=0.
209)
.
The fluoxetine (87.
7%) treatment group had a higher degree of completion than amitriptyline (66.
2%), with a very significant difference and higher safety.
The number of patients who discontinued treatment due to adverse reactions accounted for 6.
2%, while Amitriptyline It was as high as 22.
5% in the Mitriptyline group (p=0.
007)
.

Table 1.
Reasons for study discontinuation5

A 48-week double-blind trial involving 140 patients with recurrent unipolar major depression showed that fluoxetine 20 mg/day significantly improved the recurrence rate of depression, and the recurrence rate was 20% (placebo group : 40%, p=0.
010), the asymptomatic period was significantly longer (fluoxetine: 295 days, placebo: 192 days, p=0.
002), and the patients were well tolerated during the treatment
.

Table 2.
Treatment-emergent adverse events during the double-blind maintenance phasea 6

a: Adverse events occurring in ≥10% of patients.
Data are presented as N (%); b: Statistically significantly greater incidence between treatment groups (2, p=0.
013)

Look back

As a breakthrough drug in the treatment of depression, fluoxetine opened up a new era of drug treatment for depression, and it is still a classic drug used in the first-line
.
The drug entered the Chinese market in April 1995.
By 2002, the frequency of use of TCAs in China was 41.
9%, and the frequency of SSRIs was 44.
5%.
Among the 29 antidepressants in China, fluoxetine was used the most frequently
.
Looking back on its research and development process, only decades of persistence can win a world in the turbulent new drug market
.

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