A potted history of fluoxetine, Prozac and SSRI antidepressants

There is something a lot of people do not know about me. Every morning, I take two pills – mint green and dull yellow in colour – to help manage my depression. Each pill contains 20 milligrams (mg) of fluoxetine, an antidepressant more popularly known as Prozac.

Shrouded in hyperbole and hearsay, Prozac has a complicated history. To tell its true story, we must travel back to the very birth of antidepressants. We must wade through slurry and scandal, hype and hysteria, publicity and panic. After all, few drugs have been more divisive than Prozac – a wonder drug to some; a dangerous fad to others. 

In sharing this story, I do not wish to rule in favour of either viewpoint, but simply to present the facts of a compelling and momentous medication. Much ink has been spilled extolling and excoriating Prozac over the past four decades, and I hope to summarise that canon here, with one succinct portrayal. So let us explore the pill that changed mental health forever.

Joseph J Schildkraut and the chemical imbalance theory of depression

People have long sought to improve their mood by taking experimental drugs – from soldiers and beatniks inhaling amphetamine to popstars and artists popping Miltown pills. Indeed, as far back as the 1950s, scientists stumbled upon nascent antidepressants like iproniazid (brand name: Marsilid) and imipramine (Tofranil), but their discoveries were drenched in serendipity and stifled by ignorance. Potent side effects dampened early patient uptake, and for generations antidepressants were typically viewed as last-ditch alternatives for the seriously mentally ill.

However, the ascendency of modern antidepressants – and, indeed, of ‘depression’ as a diagnosable condition – began with the work of American psychiatrist Joseph J Schildkraut, whose efforts revolutionised the field. Before Schildkraut, people generally believed there were two types of depression: endogenous and neurotic. The former was broadly analogous with major depressive disorder as we know it today, while the latter was considered more circumstantial, pointing to emotional instability and temporary confusion rather than inherent genetic glitches. Schildkraut’s work smoothed those edges, honed those definitions and created a more holistic view of mental health disorders. In short, his titanic contribution saved countless lives.

Published in 1965, Schildkraut’s depression hypotheses changed the perception of mental health beyond comprehension. Schildkraut’s work popularised the notion of depression as an illness of the brain rather than as an ancillary and uncontrollable mood. That had never happened before. Moreover, Schildkraut was the first scientist to argue that depression was caused by a chemical imbalance in the brain. According to Schildkraut, the early antidepressants worked by inadvertently raising levels of biogenic amines, a class of compounds including neurotransmitters, which send chemical signals through the brain and body. Schildkraut advocated the biogenic-amine theory of depression – namely, that a deficiency of amines, or neurotransmitters, caused low mood.

As such, throughout the 1960s, a wave of new antidepressants hit the market, often leaning on Schildkraut’s theorem for support and legitimacy. Known as tricyclic antidepressants, these drugs – such as Nardil, Pamelor and Elavil – proved popular. A raft of negative side effects were reported by users, but many tolerated the risks – drowsiness, dizziness, nausea, mania – to access the intermittent rewards – reduced depressive symptoms and a generally calmer outlook. In sum, tricyclic antidepressants nudged the needle of psychological treatment, but such medication was still largely impractical for vast swathes of society.

From Valium to Prozac – How benzodiazepines paved the way for antidepressants

Indeed, while the chemical imbalance theory began to decode depression, it remained easier to treat anxiety – to mask general agitation and unease with stimulants, tranquilisers, experimental supplements, lifestyle changes and recreational highs. For better or worse, anything that provides a transient rush or an escapist pep can be – and has been – used to manage anxiety, albeit temporarily. Therefore, compared with trying to shift depression, aiming to forget about one’s anxiety is relatively straightforward. Alcohol, nicotine, sugar, caffeine or even moderate exercise can do the trick, and that realisation led to a boom in hedonistic self-denial among Baby Boomers.

Piggybacking on this new thirst for amenable, mind-altering experiences, a whole new drug family was spawned in the 1960s – the benzodiazepines, essentially sedative tranquilisers that slowed the world and allowed users to get more done. Diazepam (Valium) became a signature tool in the benzodiazepine arsenal, and within a generation, more than 2.3 billion of its tablets were sold annually in America alone. This notion of mass medicinal support – in the form of tranquilisers and antidepressants – was parodied, or perhaps mourned, by the Rolling Stones in their 1966 song Mother’s Little Helper. The lyrics illuminate a zeitgeist of chemical commodification:

How serotonin became the focus of depression treatment

Citing the negative side effects of tricyclics, and inspired by a commercial zest for more convenient medication, scientists sought a way of keeping the positive effects of powerful antidepressants while reducing their notorious downsides. Focusing on one neurotransmitter, rather than several, became a popular heuristic, and when experts identified a trend of low serotonin levels in post-suicide corpses, a credible mandate was established. 

“The new grail, pursued throughout the 1960s and 1970s and well into the 1980s, was a drug that would be like imipramine but that would selectively influence serotonin,” explained psychiatrist Peter Kramer in Listening to Prozac, his seminal book. And, just like that, serotonin became the dubious superstar of psychiatry.

One epochal metaphor likened the human brain to a bathtub, with serotonin akin to water flowing from the tap. Bygone scientists explained that, in a depressed brain – or bathtub – there was no plug, meaning that serotonin – or water – gushed down the drain faster than it left the faucet. By the late-1970s, a new family of trial antidepressants, known as selective serotonin reuptake inhibitors (SSRIs), provided that plug by blocking the channels in which neurotransmitters recycled and morphed into different iterations. SSRIs kept serotonin penned in, people learned, gradually redressing the supposed imbalances causing chronic low moods.

“Psychoanalysis was out, and psychopharmacology was in,” wrote Katherine Sharpe in Coming of Age on Zoloft. “Psychiatrists and ordinary people alike learned to think of a wide variety of mental problems as chemical imbalances, and came to see chemical-balancing medications as the most sensible response. The shift transformed the practice of psychiatry, with analytic methods giving way to a focus on the pharmaceutical management of symptoms that was, indeed, more reminiscent of general medicine than of traditional psychiatry.”

Eli Lilly, the discovery of fluoxetine, and the creation of Prozac

As SSRIs achieved mass appeal in the early-1980s, mainstream psychologists diverged from classic Freudian dogma to pursue data-driven solutions. At the confluence of an increased – albeit incomplete – understanding of serotonin and a rampant consumer culture centred on Hollywood, the antidepressant market was ripe for exploitation. One big pharma company, Eli Lilly, capitalised on that milieu unlike any other, discovering and distributing fluoxetine, a wonder drug that changed the face of global mental health treatment forever.

A staid old warhorse of pharmaceuticals, Eli Lilly possessed a fine heritage, of course. Based in Indianapolis, the firm played a pioneering role in the proliferation of polio vaccines and insulin availability. Yet in the age of technological innovation, Eli Lilly became synonymous with one product: Prozac, its patented SSRI, which captured the American imagination like few drugs before or since.

Eli Lilly actually began developing fluoxetine in 1970, spurred by the aforementioned zenith of Valium and Xanax. Bryan Molloy and Robert Rathbun, two Eli Lilly scientists, collaborated on the initial fluoxetine project after meeting at a Johns Hopkins University lecture by neuroscientist Solomon Snyder. The project was later developed by colleague David Wong, who published the first article about fluoxetine in 1974, showing how it selectively inhibited the reuptake of serotonin in rat brains. Then Louis Lemberger, another Eli Lilly expert, administered the first doses of fluoxetine to humans in 1976, with positive results found up to a 90mg dosage.

At that point, Eli Lilly got serious about fluoxetine, which held the potential to transform psychopharmacology by treating moderate to severe depression, obsessive-compulsive disorder, bulimia and panic disorder. Interbrand, a marketing agency retained by Microsoft, Nintendo, Sony and Nikon, was then tasked with developing a snazzy name for the drug. They settled on Prozac as a portmanteau of professional and activity. As such, right from the start, fluoxetine’s target audience was clear: young, ambitious, hardworking professionals jaded by office work and corporate pressure. In the waning shadows of late capitalism, Eli Lilly caught lightning in a bottle.

The wonder drug – How Prozac gripped America

Prozac first became available in 1987, following successful trials. In 1988, it flooded the US market, backed by 8 million brochures and 200,000 posters funded by Eli Lilly, declaring it a succinct cure for depression. Prozac’s advertising was instrumental in popularising the chemical imbalance theory of depression, with engaging visual graphics helping people understand neurotransmitters and their role in emotions. Even the US government was impressed, making Prozac the first SSRI it approved for widespread use.

Prozac quickly became a celebrity in its own right, fuelled by inexorable media coverage. It was profiled by The New Yorker, and Rolling Stone described it as a ‘hot yuppie upper.’ One urban myth held that 1990s burglars left VCRs and personal computers untouched while raiding homes, but emptied the medicine cupboard of Prozac. Furthermore, a broad array of icons brushed with Prozac – occasionally lauding it, often deriding it and always satirising the pill as a microcosm of the vain, commodified culture sweeping our globe. Homer Simpson cooked up a batch of ‘homemade’ Prozac in his kitchen, mixing it with ice cream. Tony Soprano took Prozac in his eponymous drama. Even New York magazine jumped on the bandwagon, splashing Prozac across its cover. A wonder drug was duly born, and people could not get enough.

“How extraordinary it was to see a green and off-white capsule on the cover of Newsweek, where we expect the falsely sincere phiz of a head of state, the curves of a starlet,” wrote Kramer. “Prozac enjoyed the career of a true celebrity – renown, followed by rumours, then notoriety and lawsuits, and finally a quiet rehabilitation. Prozac was on Nightline when you went to sleep and on the Today show when you woke up. How could a medicine preoccupy us, stimulate us so?”

To that end, Kramer’s Listening to Prozac became the cornerstone of an entire literary canon devoted to the drug and its interpretations. Drawing on his own empirical experience, Kramer contended that Prozac not only alleviated depressive symptoms, but also held the potential to change whole personalities. His book explored the moral, ethical and legal implications of widespread Prozac use, and it lingered on the New York Times’ bestseller list for months, a sociological bellwether.

Kramer coined the phrase ‘cosmetic psychopharmacology’ and foresaw the increased commodification of mental health treatment. In one passage, Kramer observed how Prozac could make perfectly fine, healthy individuals feel even better, smoothing the edges of life and enhancing performance. This resonated with an evolving technocratic class yearning for immortality, fuelling a revolution. Rarely have a drug and its cultural moment meshed so powerfully.

“I found it astonishing that a pill could do in a matter of days what psychiatrists hope, and often fail, to accomplish by other means over a course of years: to restore a person robbed of it in childhood the capacity to play,” wrote Kramer. “Prozac seemed to give social confidence to the habitually timid, to make the sensitive brash, to lend the introvert the social skills of a salesman. Prozac was transformative for patients in the way an inspirational minister or high-pressure group therapy can be – it made them want to talk about their experience.”

Across the US, around 2.4 million prescriptions were written for Prozac in its debut year. By 2002, that number soared to 33.3 million, a 13-fold increase. A line of cultural demarcation was crossed, and fluoxetine became the acceptable face of antidepressant medication. Dogs, cats and other household pets were even prescribed Prozac to deal with obsessiveness as the drug spawned an entirely new genre of mental health treatment – cosmetic psychopharmacology, which suggested superficial happiness and success were available for purchase.

“Enter Prozac, and suddenly I have a diagnosis,” wrote Elizabeth Wurtzel in Prozac Nation, her landmark book. “It seems oddly illogical: rather than defining my disease as a way to lead us to fluoxetine, the invention of the drug brought us to my disease. Which seems backward, but much less so later on, when we find that this is a typical course of events in psychiatry, that the discovery of a drug to treat, say, schizophrenia, will tend to result in many more patients being diagnosed as schizophrenics. This is strictly Marxian psychopharmacology, where the material – or rather, pharmaceutical – means determine the way an individual’s case history is interpreted.”

In Listening to Prozac, Kramer explained how contemporary psychiatrists relied on available medications to signpost diagnoses. “The embarrassing truth about clinical work with antidepressants was that it was all art and no science,” he wrote. “Various combinations of symptoms were said to be more serotonin- or norepinephrine-related, and various strategies were advanced for trying medications in logical order for particular sorts of patients. But these strategies varied from year to year, and even from one part of the country to another. It was true that a given patient might respond to one antidepressant after having failed to respond to another, but the doctor would have to manufacture a reason to explain why.”

One US town – Wenatchee, Washington – became synonymous with fluoxetine when local psychologist Jim Goodwin put the majority of his patients on Prozac after experiencing its benefits firsthand. Around 700 of the town’s 21,000 residents were prescribed Prozac, per a 1994 Journal Times investigation. Once renowned for producing fine apples, Wenatchee became known as Happy Town, Prozacville and The Prozac Capital of the World. Nicknamed The Pied Piper of Prozac, Goodwin even appeared on Oprah to trumpet the drug’s potential, branding it ‘less toxic than salt.’ According to The New Republic, Goodwin ‘singlehandedly raised the serotonin level in the small town.’ That he was later brought in himself for psychiatric evaluation and had his license revoked buttressed early scepticism, and Wenatchee became a microcosm of the gathering Prozac storm. 

Reading Balzac, Knocking Back Prozac – How fluoxetine fuelled the Britpop zeitgeist

America was not alone in its Prozac infatuation, though. Britain was an early adopter, too, welcoming fluoxetine in 1989. Throughout the 1990s, the drug became a simulacrum of British liberation, which culminated in the election of Tony Blair, a centrist figurehead who promised good times and small fortunes. Britpop became the defining soundtrack of this spartan age, with stylish casuals setting the cultural agenda. “In the sixties, people took acid to make the world weird,” said Damon Albarn, lead singer of Blur, an era-defining band. “Now, the world is so weird, people take Prozac to make it normal.”

Blur were considered somehow softer than Oasis, their great musical rivals – more melodic, poetic and introspective. That Albarn suffered with various mental health problems seemed to enhance his charisma, somewhat strangely, and Blur’s back catalogue is littered with references to antidepressants and their mellowing effects. Take this vignette from Country House, Blur’s 1995 blockbuster, as an example:

In a somewhat perverse way, Prozac was cool, hip and edgy. It was romanticised by a quirky commentariat yearning for emancipation. In some quarters, Prozac was even considered a fulcrum of creative ideation. A rainbow of writers, musicians, poets, artists, politicians and socialites became embroiled in the Prozac mise en scène, lending it a transient veneer steeped in stigma. Naturally, perhaps, it was not long before controversy engulfed the drug, which became a lightning rod of political and societal polarisation. The ineffable volatility of its users became a blessing and a curse as Prozac was probed from all sides.

The dark side of Prozac

In 1989, Prozac was linked to the deadliest mass shooting in Kentucky state history, when Joseph T Wesbecker, a 47-year-old printing press operative, killed eight people and wounded 12 more with an AK-47 before committing suicide. Wesbecker began taking Prozac two weeks before his rampage, and the victims’ families filed a lawsuit against Eli Lilly, claiming the drug contributed to his actions. An 11-week trial captivated America, and Eli Lilly paid $20 million to settle with Wesbecker’s victims – a gesture many conflated with an admission of guilt pertaining to Prozac’s dark side.

A further Kentucky shooting – in which patient Rebecca McStoots killed her doctor following a minor disagreement – was also blamed on Prozac. Meanwhile, Macy’s department store infamously barred 44-year old Mark Woodley from posing as Santa Claus because he took Prozac. Store management deemed Woodley too unhinged to work with children, and he eventually filed a lawsuit against the corporation.

Finally, in 1990, Prozac was implicated in the suicide of rockstar Del Shannon, who took the drug for two weeks before shooting himself with a .22 calibre rifle. Shannon suffered with depression in the years preceding his death, but Prozac exacerbated those issues, according to his widow, Leanne Westover, who sued Eli Lilly alleging ‘improper testing.’ The lawsuit was eventually dropped, but Westover became a vocal critic of Prozac, which developed a base of detractors almost evangelical in their zeal.

In the early-1990s, professors Martin Teicher and Jonathan Cole suggested 3.5% of Prozac users attempted or committed suicide, largely due to akathisia, an unquenchable restlessness. David Healy, a leading British critic, subsequently concluded that ‘50,000 people have committed suicide on Prozac since its launch, over and above the number who would have done so if left untreated.’ Such findings, from such distinguished doctors, substantiated the pall of uncertainty that plagued Prozac even during its pomp. Some swore off the drug forever.

Indeed, as a critical subculture coalesced around leading Prozac sceptics, more than 200 lawsuits were filed against Eli Lilly in the 1990s. Plaintiffs cited fluoxetine as a catalyst for a broad range of disorders, phobias, actions and impulses. Most of the cases were settled out of court, with terms kept confidential, adding to the susurrus of discontent among naysayers. Meanwhile, Eli Lilly did little to quell the dystopian narratives, which threatened to spiral out of control.

To some, Prozac was just another chemical fad imbibed by raucous subcultures. But to others, it was a far more sinister proposition – a commodity driven by a profit-hungry corporation sustained by unproven hypotheses. Cynics viewed Prozac as a triumph of corporate America and its unparalleled marketing ability – Gen X consumers weighing the symbolic optics and practical utility of SSRIs as with gourmet coffee, DVDs, MP3 players and the internet. Rampant capitalism made it harder to separate existential needs from shiny vicarious desires, though, and a cost-benefit analysis was required before leaping into Prozac. Some made the jump, but others stood firm. Few remained agnostic, and polarised rhetoric marred the debate.

The demise of Prozac – How Eli Lilly lost its patent protection

Despite the tsunami of bad publicity, Prozac prescriptions held steady throughout the 1990s, and it did not take long for big pharma to synthesise generic fluoxetine doppelgangers, hoping to earn a slice of the antidepressant pie. In 2001, due partly to the spike in lawsuits, Eli Lilly lost its patent protection for Prozac, allowing those generic fluoxetine alternatives to enter the market. Where once a patented 20mg Prozac tablet retailed for $2.50, generic fluoxetine capsules submerged the market, dropping the price to 25 cents. The news wiped $36 billion from Eli Lilly’s market cap in one day, and the firm lost $2.4 billion in US sales overnight. 

More worryingly, during the doomed patent renewal process, journalists unearthed major issues within Eli Lilly stretching back many decades. Citing internal documents, the Boston Globe argued that Eli Lilly knew for years that Prozac cause suicidal reactions in small but significant portions of its userbase. According to the Globe, Eli Lilly memos detailed corporate executives pressuring company scientists to obfuscate mentions of suicide attempts in Prozac trials. The Globe also obtained official Eli Lilly statistics showing that 1 in 100 previously non-suicidal patients who took Prozac in early trials developed akathisia, causing them to attempt or commit suicide. Extrapolated to a global scale befitting Prozac’s early uptake, instances of medication-triggered akathisia could therefore be in the hundreds of thousands, if not millions.

Moreover, as the patent renewal process became strained, Eli Lilly licensed a different version of Prozac, named R-fluoxetine, as a contingency. Needing to show material differences between Prozac and R-fluoxetine to obtain patent protection for the backup, Eli Lilly’s own application claimed R-fluoxetine was less likely to cause ‘akathisia, suicidal thoughts and self-mutilation’ than Prozac. Way to shoot yourself in the foot.

Perhaps unsurprisingly, Prozac lost much of its sparkle by the mid-2000s, but use of generic fluoxetine – cheaper and more readily available outside the Eli Lilly monopoly – continued to grow. Correspondingly, in 2004, traces of fluoxetine were found in British drinking water, according to the Environment Agency – a fitting descriptor of the drug’s mounting ubiquity. Fluoxetine prescriptions have plateaued since, and SSRIs remain the first line of defence for many doctors working with depressives.

Eli Lilly does still produce Prozac, but generic fluoxetine has flooded the market. For instance, the capsules currently sitting in my bedside drawer were manufactured by Brown & Burk in Middlesex rather than by Eli Lilly in Indianapolis. Debating the virtues and drawbacks of such medicinal genericism is a task for another day, but the legacy of Prozac in shaping our psychological outlook – literally and figuratively – cannot be disputed.

“In short, the story of the Prozac revolution wasn’t a tale of crisp scientific breakthrough,” concludes Sharpe in Coming of Age on Zoloft. “Instead, it was a case of science and culture pulling each other along together, our concept of a complicated illness shifting to correspond to our most promising means of treating it. The story of modern antidepressants and the story of the invention of depression as we know it go hand in hand.”

Final thoughts

Indeed, almost 40 years down the road, stigma still swirls around Prozac, perhaps more than any other antidepressant. Satirists gravitate to fluoxetine, using it as a reliable avatar through which to lampoon modern society and its vainglorious, consumptive mores. Celebrities admonish fluoxetine, seemingly frustrated by its refusal to become cocaine, and journalists misconstrue fluoxetine, projecting phantom properties onto it in search of bold copy. Most of these assessments miss the mark, and the inexperienced should refrain from adding their hyperbolic voices to the chorus.

Yes, people on Prozac commit violent crimes, but so do people on nicotine, alcohol, caffeine and Coca-Cola. What distinguishes driving cause from coincidental tchotchke in this regard? How do we measure the actual impact – good or bad – of SSRIs when we cannot even measure the baseline quantity of serotonin itself? As yet, there is no way of achieving this, save for idealistic reasoning and semantic jostling, so all attempts at quantitative analysis are fatally flawed.

As such, very intelligent people have bickered about the pros and cons of Prozac for a very long time – and we still do not have clear answers. When you have Harvard professors refuting one another, and when you have esteemed experts relying on fanciful data decades into their research, there becomes a point where you have to draw your own conclusions, do what works for you, and move on.

Ultimately, everybody’s experience of fluoxetine – and antidepressants more generally – is different. You should not become convinced to try, nor reject, a specific medication based on Britpop arcana, YouTube vlogs or snarky influencer blog posts. All drugs have unique side effects on each individual, owing to our diverse psychological makeup. Therefore, we cannot rely on the experiences of other people to make our own decisions easier.

At this stage, I’m relatively agnostic about the chemical imbalance theory of depression. I’m not entirely convinced by some of the purported evidence, and the near-exclusive focus on serotonin in mental health treatment strikes me as myopic. However, fluoxetine does help me, and much of my personal growth would have been stunted without it. I will likely mine the positive and negatives of Prozac in another article, on another occasion, because the debate is so wide-ranging. For now, though, I just want to present the Prozac story, so unendingly fascinating in its impact. There may never be another drug like it, for better or worse, and we should all take a moment to reflect on its legacy.

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Sources

• Wikipedia
• Listening to Prozac by Peter Kramer
• Prozac Nation by Elizabeth Wurtzel
• Coming of Age on Zoloft by Katherine Sharpe
• The Catecholamine Hypothesis of Affective Disorders by Joseph Schildkraut
• Guardian
• UPI
• Dovetail
• The Discovery of Fluoxetine Hydrochloride (Prozac) by David Wong, Kenneth Perry and Frank Bymaster
• Welcome to Happy Valley, PBS Frontline documentary
• Freedom Magazine
• NME
• USA Today
• CNN Money
• Boston Globe