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The Best SSRI – Part 1

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We search through the rubble of 1990’s marketing to find out what makes the SSRIs different, and encounter along the way our word of the day: Zimelidine.

Published On: 7/27/20

Duration: 10 minutes, 47 seconds


From the quest for the holy grail to the meaning of dreams, humankind has always had a thirst for unanswerable questions. And in the 1990’s, billions of dollars were poured into this one: Which is the best SSRI?

Kellie: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003.

Dr. Aiken: I’m Chris Aiken, the editor in chief of The Carlat Psychiatry Report.

Kellie: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue. Your patient is a 35 year old woman who has never taken an antidepressant and has been depressed for a year since moving to a new city. Which antidepressant should you start with? David Osser’s Psychopharmacology Algorithm Project took a stab at that question, and we covered that in our May issue. That article generated a lot more reader feedback than usual, including this one: Why was fluoxetine left off the list of first-line options for major depression?

Dr. Aiken: The first line options were, in alphabetical order, bupropion (Wellbutrin), escitalopram (Lexapro), and sertraline (Zoloft), unless there is an urgent need for ECT in which case they recommend going straight there.

Kellie: Who has an urgent need for ECT?

Dr. Aiken: Well, psychotic depression and melancholic depression have the best response to ECT, so if the patient has one of those depressive subtypes and is acutely suicidal, or gravely ill like so depressed that they aren’t eating, or even if they’re pregnant because ECT is safer in pregnancy than psychotropics than they would go straight to ECT.

Kellie: So back to the fluoxetine question. Fluoxetine was the first SSRI released in the U.S., and it quickly became the standard bearer for depression. So why didn’t it make the cut for first line options? We reached out to Dr. Osser and here’s what he had to say in an email:

“Fluoxetine did not do as well as others in the two comparative efficacy network meta-analyses by Andrea Cipriani and colleagues, the latest being in 2018. In fact it had one of the worst results compared with other SSRIs which might be because it takes longer to work due to the long time it takes for the active metabolite norfluoxetine to reach steady state, and most of the studies reviewed were short term and there wouldn’t be time for fluoxetine to reach its full effect.  Also it has more drug interactions than the preferred agents.”

Then Dr. Osser went on to share a story about practicing in the heyday of the SSRIs the 1990s:

“The huge effect of marketing can’t be better illustrated than by the market share of fluoxetine when it was competing with sertraline and paroxetine – when all three were brand products.  Prozac was #1 with market share no matter what the other products did.  Everyone thought it was the most effective SSRI.  So Lilly got away with charging almost twice as much for it than the others and would not cut the price with the Pharmacy Benefit Manager companies.  So those companies went nuts trying to get prescribers to prefer the others, even restricting access to Prozac in some cases.  But Prozac was the first SSRI and they were able to keep it positive in people’s thinking with their ad campaigns.  But when it became generic and cheap and they stopped advertising it, it rapidly dropped below the others – and it seemed everyone became convinced it didn’t work as well as the others or had more side effects.  Only with these network meta-analyses do we start to have some evidence on the question of what is best – not perfect by any means, though.” 

Dr. Aiken: There was a lot of misinformation about SSRIs in the 1990’s, and some of those myths still linger today. In this two-part episode we’re going to clear some of that smoke, and at the end of it we’ll find some solid ground to help you choose among the SSRIs at the end.  

First let’s go back to those early days. Fluoxetine came out in 1987, but it was really December 29, 1987 so nobody took it until 1988. America was just coming out of the Iran Contra affair, and the stepping into an election year that would pit Michael Dukakis against the eventual winner, George HW Bush. “Phantom of the Opera” premiered on Broadway, the Surgeon General came down on nicotine, and Jimmy the Greek was fired from CBS for making racist comments about black atheletes. And  based on the #1 song of the year people were looking at themselves in the mirror, and they were ready to make a change.

[Michael Dukakis Audio Clip]

Kellie: Wait a minute  Man in the mirror was the #1 song in America, but it wasn’t big in Australia it only charted at 39, and didn’t do so well in Europe. And I’ve got to say it’s a very American song “Make that change” in other countries we’re not so into self improvement in the way that Americans are. We don’t have Tony Robbins, Zig Ziglar, and Dale Carnegie prancing around the stage. 

Dr. Aiken: Sertraline was the next to come in 1991, followed by Paroxetine in 1992. That’s when I started my career at the National Institutes of Mental Health, so I witnessed some of the outsized effect that these medications had on our field.

Kellie: What was that like?

Dr. Aiken: The SSRIs were a topic of constant conversation. Psychiatrists who not long ago spend their time trying to understand what motivated people and all the intricacies of the human mind, were now just trying to scrambling to figure out which was the best SSRI. Demand for these medications was up, and reimbursement for psychotherapy was down, so much of what we did all day was help patients choose between Prozac, Zoloft, and Paxil. Doctors don’t like to admit ignorance, but here they were forced to make this decision every hour without any good data to guide that decision. And into that knowledge gap stepped the industry, or more specifically the speakers on their panels. 

I remember going to those talks, and it made me sad. The audience was hungry for knowledge – everyone was chattering about which SSRI worked the best. One doctor cornered me, asking which one I preferred “They all come out the same in the studies,” I said, “Ah, but no – I asking for what you see with your own eyes which do you get the best results with cause for me it’s Paxil!” So there was this palpable hunger, but with it an undercurrent of cynicism, because people knew that most of the answers they were being fed were served up by the pharmaceutical industry.

Kellie: And Dr. Osser’s sense was that Prozac won that marketing war. Eli Lilly, the manufacturer of Prozac, hired interbrand to market the drug, and here’s interbrand on how they came up with the name:


The goal of their marketing campaign, in their words, was to “intentionally distance the medication from everything typically associated with anti-depressants – strong chemicals, side effects, and mood swings. The easy and accessible language provided patients a platform to talk comfortably and openly about their condition. “

Dr. Aiken: And that’s what they did. They SSRI’s were safe in overdose and seemed to lack any serious medical risks. As long as you didn’t mind the sexual side effects, they were risk free, and doctors started prescribing them far outside their FDA indications. The main problem the drug companies had was how to distinguish their brand. And we’ll continue on that note tomorrow in part II of this episode, where we’ll weed through those marketing claims to see how well they’ve held up over time.

Kellie: And now, for the word of the day…. Zimelidine

Dr. Aiken:The first SSRI was actually not Prozac, it was zimelidine, a serotonergic antidepressant derived from a antihistamine, and when it first came out it had all the qualities that made fluoxetine famous: safe, effective, and well tolerated. Zimelidine had its start in Germany in 1981 as Normud. Other European countres soon followed, but by 1983 reports of Guillain–Barré syndrome on the drug emerged, and it was withdrawn from the worldwide market. 

Kellie: So fluoxetine was the second SSRI to be released?

Dr. Aiken: No, fluoxetine was the third. The second was fluvoxamine Luvox, which came out in Switzerland in 1983. It didn’t hit the American market until 1993, where it has only been approved for OCD, but in other countries it’s approved for depression.

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