Where did Prozac (fluoxetine) come from?

The following summary of the history of Prozac and similar drugs (the SSRIs or Selective Serotonin Reuptake Inhibitors) is adapted from my master’s thesis.[i] I’m biased of course, but I reckon it’s a pretty interesting tale.

      Back in the 1960s, Scottish psychiatrist George Ashcroft found lowered levels of serotonin[ii] in the spinal fluid of depressed patients and cadavers of suicides and hypothesized that depression might be caused by low levels of the neurotransmitter serotonin in the nervous system. Following further investigation, he found this was not a causal relationship and he rescinded the theory.[iii]  In spite of this, the “chemical imbalance theory” of depression, and the suggestion that depression results from a deficiency of serotonin in the brain, continues to be a widely accepted belief in spite of the lack of any supporting scientific evidence.[iv] For more on serotonin, see my next post.

       The serotonin-deficiency hypothesis--supportable or not--was a boon to the pharmaceutical industry because it suggested that depression could be approached as a medical condition or illness with a biological cause, rather than as a result of one’s responses to the ups and downs of everyday life, and therefore medication could be developed to treat it. If consumers could be convinced to buy into a belief that low serotonin levels cause depression, and new antidepressants could be shown to target this low level, the potential for marketing the new drugs would be enormous.

In his book Let Them Eat Prozac, David Healy tells the story of the development of the first “blockbuster” SSRI drug, Prozac (fluoxetine)—an extraordinary case study of successful marketing. Adapted from the antihistamine diphenhydramine (trade name Benadryl) by researchers in the Eli Lilly laboratories, the new product was found to stimulate aggression in rats, which suggested it had some “activating” properties. Lilly was keen to develop a new antidepressant to replace their best-selling (but soon to lose patent rights) tricyclic antidepressant nortriptyline, marketed under the trade name Pamelor, but the new drug did not show efficacy for use with severe depression, causing distress and agitation in patients, nor did it work for schizophrenia, pain relief, hypertension or obesity. Finally, adjuncted with benzodiazepines[v] to quell subjects’ ensuing agitation, it was trialled with a group of five mildly depressed individuals[vi] All five responded positively (although it seems likely that they were also responding to the benzo). It was a small success, but enough to initiate the launch of the next blockbuster drug.

Prozac underwent numerous clinical trials over the next few years, enough of which yielded results adequate (but just barely) for FDA approval[vii] in 1987 (Read footnote vii if you haven't--the implications are interesting.) The marketing team launched the drug with much fanfare onto the American market in 1988 under a one-pill-a-day-fits-everyone banner in an attempt to expand beyond psychiatric prescribing market into the much larger sales arena of general practitioners. Promoted as “a breakthrough drug in the treatment of depression”, Prozac made the cover of Newsweek in 1990.

Ironically, it took six more years for the drug to pass German regulators for use there, one regulator noting “Considering the benefit and the risk, we think this preparation totally unsuitable for the treatment of depression.” (internal Eli Lilly communication reported in Healy, Let Them Eat Prozac, p. 39). Nevertheless, Prozac proved enormously popular, with sales for that one drug alone accounting for 30% of Eli Lilly’s company profits.[viii] Although the patent for the drug expired in 2001, generic fluoxetine remains a popular antidepressant drug choice for many today.

For more information on psychiatric drugs like Prozac and alternative non-drug ways to understand and resolve depression and other psychological "dis-eases", see my new book Reframing Mental Illness. 

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[i] Thrasher, S. (2010). Collateral Damage: A Mixed Methods Study to Investigate the Use and Withdrawal of AntidepressantsWithin a Naturalistic Population (pp. 14-18).

[ii] Serotonin functions as both a hormone and as a chemical neurotransmitter. Contrary to popular belief, most of the body’s serotonin is found in the digestive tract.

[iii] Ashcroft, G. & Healy, D. (2000). The receptor enters psychiatry. In The Psychopharmachologists III: Interviews by David Healy (pp. 189-2000).

[iv] Leventhal, A. M. & Antonuccio, D.O. (2009). On chemical imbalances, antidepressants, and the diagnosis of depression. Ethical Human Psychology and Psychiatry, 11, 199-214.

[v] tranquilzers

[vi] Breggin, P. (2008) Medication madness: The role of psychiatric drugs in cases of violence, suicide and crime (pp. 247-248).

[vii] The US FDA requires lodgement of two trials demonstrating superiority to placebo; data from unsuccessful trials need not be lodged (Medawar, Hardon, & Herzheimer, 2004). Of Lilly’s three submitted placebo-controlled trials for fluoxetine, one showed no effect, one showed a very small superiority over placebo but inferiority to the TCA imipramine, and the third showed efficacy but had only 11 completers of the 4-week trial (Healy, Let Them Eat Prozac, p. 35). Furthermore, Lilly trial subjects who experienced drug-induced agitation were co-prescribed benzodiazapines during the trials, although this was not reported in published results (Breggin, Medication Madness, pp. 247-248).

[viii] See McLean