How the SSRIs were derived from Benadryl, how a forgotten antidepressant almost brought the serotonergic industry to a halt in the 1980’s, and how this all culminated in a Nobel prize and a new theory of dopamine.
Few people remember Pete Best, the fifth Beatle who was replaced by Ringo Star. And few recall zimelidine, the first SSRI that almost brought the serotonergic antidepressant industry to a halt.
KELLIE NEWSOME: On March 14, 2012 Lexapro became the last SSRI to lose its patent, closing the book on a quarter century of science and marketing that changed and sometimes confused the way we think about antidepressants. Now that the unpublished studies have come to light and the incentives to favor one drug over another have dried up, we thought it was a time to take a sober look at what ─ if anything ─ really sets the six SSRIs apart. You’ll find that review in our Nov-Dec double issue, but we left one of them out. There was a seventh SSRI, but it was quickly forgotten after its inauspicious release in 1982. It was called zimelidine, and it was born out of discoveries that would lead its inventor to receive the Nobel prize, and today we tell its story.
CHRIS AIKEN: In 1955 a young pharmacologist Arvid Carlsson went on sabbatical from his post at the University of Lund in Sweden. He took up a position at the National Institutes of Health in Bethesda Maryland. Up to this time, the brain was thought to be an electrical organ, and its functions were explained by electrical transmissions through the neurons. But Dr. Carlsson felt a shift – “for the first time people really started to think of the brain in terms of chemistry.” He set out to search for the neurotransmitters that might explain this burgeoning science of brain chemistry using reserpine.
Reserpine had just been approved by the FDA as an antihypertensive, but it had psychological effects that were pivotal in the discovery of psychopharmacology. The drug had been isolated a few years before from an Indian milkweed flower known as Indian snakeroot. This plant had been used for centuries to treat mental illness in India, and the pharmaceutical version – reserpine – was effective at treating psychosis in patients with schizophrenia. Reserpine almost became the first antipsychotic, but two things held it back. First, it caused hypotension, and second it had a nasty tendency to induce depression.
But to Dr. Carlsson’s eyes, a drug with so many psychological effects might lead the way to the neurotransmitters that governed the chemical structure of the brain. Using the new science of fluorescence microscopy, he was able to show that reserpine caused three chemicals in the brain to disappear: dopamine, noradrenaline, and serotonin. It depleted them by blocking their reuptake into the neuron.
Dr. Carlsson returned to his native Sweden and spent the next 5 years trying to prove his ideas about the three big monoamines: dopamine, norepinephrine, and serotonin. They were met with skepticism at first, but by the mid 1960’s they had moved into the main stream and were influencing discoveries in psychiatry and neurology. In Vienna the neurologist Walther Birkmayer observed that reserpine induced a kind of muscle stiffness similar to what he was seeing in his Parkinson’s patients. Working from that clue, Dr. Birkmayer looked at dopamine levels in his Parkinson patients and found they were depleted, and when he gave them L-dopa to restore their dopamine their symptoms improved.
Dr. Carlson went on to receive the Nobel prize in medicine in 2000 for his role in the discovery of dopamine, along with Paul Greengard and the psychiatrist Eric Kandel. But dopamine was just the beginning of his journey. Reserpine had opened up three doors: Dopamine, serotonin, and norepinephrine, and he was about to turn the knob on the second.
From Dopamine to Serotonin
KELLIE NEWSOME: By the late 1960’s L-dopa became the standard of care of Parkinson’s disease, and Dr. Carlsson turned his eye toward another monoamine that reserpine depleted: Serotonin. The tricyclic antidepressants had been in use for a decade at this point, and it was widely thought that they acted through norepinephrine. But Dr. Carlsson demonstrated in 1968 that the tricyclics also blocked the reuptake of serotonin. Over the next 4 years he worked tirelessly at Astra – the Swedish pharmaceutical firm we now know as AstraZeneca – to develop a compound that selectively blocked serotonin reuptake. The search brought him to pheniramine, an antihistamine similar to Benadryl that’s still used today for allergies, not to be confused with weight loss drug phentermine to which it has no relation.
The early antihistamines were dirty drugs, and they did a lot more than just block histamine. They were anticholinergic, and two of them – pheniramine and diphenhydramine/Benadryl – blocked serotonin reuptake. Dr. Carlsson modified pheniramine to create zimelidine, the first SSRI. Meanwhile, in Indianapolis, IN, a neuroscientist at Eli Lily, David Wong, was tinkering with the other serotonergic antihistamine – diphenhydramine/Benadryl – in hopes to improve on its antidepressant properties. Yes, you heard that right, diphenhydramine has antidepressant properties, but they were meek and easily overcast by the drowsiness imparted by the drug.
At Eli Lilly, Dr. Wong’s team lined up 12 derivatives of diphenhydramine and tested there effects on the big three monoamines: serotonin, norepinephrine and dopamine. One of them – fluoxetine – stood out as the most selective for serotonin, and he filed for the drugs patent in 1974 – two years after zimelidine’s patent, and zimelidine came to market 6 years before Prozac’s release.
CHRIS AIKEN: Zimelidine was released in the European market in 1982. It looked like a major advance. It worked as well against the tricyclics in head-to-head trials (it was tested against four of them), but it lacked their sedative, anticholinergic, and cardiotoxic properties, and it appeared safe in overdose. There was no mention of sexual side effects on the drug, but some authors were concerned about a different risk on the drug – weight loss.
KELLIE NEWSOME: Weight loss? That sounds like a positive effect
CHRIS AIKEN: Yes, those were different times. Body mass index did not start its steady and unending rise in the U.S. until the early 1980’s. And back in those days weight loss was often viewed as a problematic symptom of depression. Medications were reserved for the more severe cases of depression back then, and most of the severe cases had melancholic features, and appetite loss was one of the cardinal symptoms of melancholia. The others were:
- Early morning awakening
- Mood worse in morning
- Mood that doesn’t react much to positive or negative events
- Profound agitation or slowing in the muscles
When the SSRIs came out, it opened the door for milder cases of depression to be treated with medications, and these milder cases tended to have high appetite and weight gain – these were called “atypical” features because they were in many ways the opposite of the melancholic features that psychiatrists were used to seeing in the hospital and treating with medications:
- Oversleeping and fatigue
- Mood worse as the day went on
- Mood is highly reactive to positive and negative events, including high sensitivity to rejection
- Arms and legs feel heavy as if weighed down by lead weights (leaden paralysis)
But zimelidine’s story was one of great promise and great disappointment. Within a year of its release, there were reports of Guillain–Barré syndrome soon after starting the drug. The problem was rare but serious – zimelidine was causing the body’s immune system to attack its nerves, causing paralysis and even death. Merk pharmaceuticals planned to launch the drug in the U.S. through a licensing agreement with Astra, but those plans never took shape as the association with Guillain–Barré caused the drug to be withdrawn from the market in 1983. The scare slowed down research on serotonin medications
Prozac Presses On
KELLIE NEWSOME: But back in Indiana Eli Lilly had invested over a decade of work in their candidate SSRI, fluoxetine/Prozac. They submitted data on fluoxetine to the FDA in 1985, but the FDA was slow to approve the drug. And so they waited.
Dr. Wong and his team at Eli Lilly waited anxiously for the FDA’s decision on their new antidepressant, but it took 2 and half years to come. The Guillain–Barré scare had caused the agency to be extra cautious. The news came over the Christmas season of 1987 and, because Eli Lilly was closed during Christmas, Dr. Wong heard about it while watching the local television news on December 29th, after 16 years of clinical and laboratory work the drug would finally be brought to market. “It was the ultimate vindication,” he wrote, “as we had carried the burden of the project, and had been ridiculed for many years as the ones who discovered and developed a molecule looking for a disease.”
But perhaps the ones who awaited the arrival of fluoxetine most anxiously were the patients who had recovered on zimelidine but could no longer take it. Some of them had had toxic side effects to the drug, and psychiatrists were hesitant to restart fluoxetine for fear of a repeat reaction. But they did, and no nerve damage or toxicity occurred. The same thing happened with each new SSRI that was released in the early 1990’s. Soon after their release reassuring papers appeared showing no cross-sensitivity in patients who had experienced toxicity on zimelidine.
Prozac would soon capture the imagination of the public in a way that zimelidine never did. Dr. Wong attributes this to the unique qualities of the drug, “The sustained effectiveness of fluoxetine, low side-effect profile, overdose safety, once-a-day dosing, lack of a requirement for dose titration and improved risk–benefit ratio have led to widespread use by physicians.” But zimelidine enjoyed those same qualities, at least before the link with Guillain–Barré was discovered. But zimelidine was primarily released in countries that don’t allow pharmaceutical advertising. These are countries with a socialized system of medicine, and the government knows that advertising to doctors or patients mainly serves to drive up the cost of health care. Eli Lilly had one of the best ad agencies in the business, and they got an extra boost from a young psychiatrist in Rhode Island, Peter Kramer.
Listening to Prozac
CHRIS AIKEN: Dr. Kramer had finished a stint at the Iowa Writer’s workshop, and he was ready to put the tools he’d learned to use. Like most outpatient psychiatrists in the 1980’s, he practiced psychodynamic psychotherapy and mixed in medications when appropriate. But those appropriate times were few. There were antipsychotics for schizophrenia, there was lithium for bipolar disorder, but only severe depressions received antidepressants, because the side effects were too much for most people with neurotic anxiety to tolerate. That left one class of medication for the millions of people with generalized anxiety and mild depressions – the benzodiazepines. And these were starting to get a bad rap.
When they first came out, the benzodiazepines were not thought to cause tolerance or abuse except in very rare cases. The original prescribing information listed those problems as possible but not proven. That started to change in the late 1970’s, and by the early 1980’s the psychiatric profession had reached a unanimous agreement that these drugs were addictive. The public was catching on too. 1 in 10 had taken a benzodiazepine in the past decade, and the problem of addiction and withdrawal was playing out in the movie theaters – in the film “I’m Running as Fast as I Can” – and in the testimony of celebrities like Stevie Nicks and Elizabeth Taylor.
Psychiatrists were eager to jump ship, and Prozac arrived at just the right time. They started prescribing them to people with mild depression, and then to people who didn’t even meet the criteria for depression at all but whose anxious-avoidant and neurotic personality traits tended to improve on the drug. And that’s when Peter Kramer took notice. Personality disturbances that would normally take years of psychotherapy to work through were relieved within weeks on the SSRI. He wrote these cases up in a book, Listening to Prozac, which interspersed these fascinating case histories with scientific pearls on serotonin from the benchside world of animal research. Dr. Kramer’s book took off as patients reached for something to help them understand this brave new world they were prescribed into, and soon became the second psychiatric book to reach #1 on the best seller list. The first? Sigmund Freud’s The Psychopathology of Everyday Life.
A Nobel Prize
KELLIE NEWSOME: Dr. Carlsson died in 2018 at the age of 95, but he stayed on the cutting edge of psychopharmacology to the end.
When he went to Stockholm in 2000 to receive the Nobel Prize, he suggested that psychopharmacology needed to move in a different direction than the path his early discoveries had taken it down. His early work helped uncover the three monoamines that were critical to psychiatric disorders – dopamine, norepinephrine and serotonin – and the pharmaceutical industry searched for drugs with the highest potency to block the reuptake or actions of these chemicals. Dr. Carlsson came to believe that was a mistake, and that instead of potent blockade what was needed was greater balance – drugs that stabilized these chemicals. He applied that to schizophrenia, developing partial agonists at dopamine D2 receptors and serotonin 5-HT2A receptors. He developed several compounds with those properties, and his research suggested they could improve both positive and negative symptoms of schizophrenia, with a low risk of parkinsonism and tardive dyskinesia.
The drugs that Dr. Carlsson worked on at the end of his life have not come to market, but the ideas lead to the novel antipsychotics pimavanserin (Nuplazid) and lumateperone (Caplyta). Over the past year, we’ve covered them both in our pages, first for their antipsychotic effects and later for their mood benefits which have recently come out in the trials.
KELLIE NEWSOME: You can read more about those new antipsychotics online at the Carlatreport.com along with this month’s feature “How to Select an SSRI,”
Word of the Day
KELLIE NEWSOME: And now for the word of the day…. The mote-beam mechanism
CHRIS AIKEN: The mote-beam mechanism is a type of cognitive bias where people see negative qualities in others that they are unable to see in themselves. The origin of the “mote and beam” comes from a parable of Jesus gave in the Sermon on the Mount: “Judge not, that ye be not judged…And why beholdest thou the mote that is in thy brother’s eye, but considerest not the beam that is in thine own eye?”
The term was originally used by Gustav Ichheiser, a social psychologist who wrote prejudices and social misperceptions, both on an individual level and between nations. Ichheiser’s ideas were similar to Freud’s concept of projection as a defense mechanism, except that Ichheiser was trying to move it more into the realm of cognitive psychology, where there was no concept of intrapsychic conflict in the unconscious depths. In Ichheiser’s model of mental life, the mind was a socio-cultural organ that could be understood through four fundamental questions: “i) what we actually are; ii) what we think we are; iii) what other people think we are; and iv) what we assume other people think we are.”
KELLIE NEWSOME: Join us next week for part II in our winter series on psychotherapy: Psychotherapy Side Effects: An Interview with Michael Linden. An if you like this podcast, share it with a friend – it’s easy you just hit that share button with an upward arrow and text it to your colleague – they’ll appreciate the thought in these disconnected times. And it will help us keep operating the way we always have – free of commercial support.