Thanks to AI, we just got stunningly powerful tools to decode life itself.
In two recent back-to-back papers,
scientists at DeepMind and the University of Washington described deep
learning-based methods to solve protein folding—the last step of
executing the programming in our DNA.
Why does this matter?
Because proteins are the building
blocks of life. They form our bodies, fuel our metabolism, and are the
target of most of today’s medicine.
Proteins start out as a simple ribbon
of amino acids, translated from DNA, and subsequently folded into
intricate three-dimensional architectures. Many protein units then
further assemble into massive, moving complexes that change their
structure depending on their functional needs at a given time.
And misfolded proteins can be devastating—causing health problems from sickle cell anemia and cancer, to Alzheimer’s disease.
In
today’s blog, we’ll discuss the details of this AI-driven advance and
what it means for the future of biology and medicine. As ourA360 community
has often discussed, the biotech field is accelerating, and the decade
ahead will bring untold breakthroughs and multi-$100-billion-dollar
startups.
Let’s dive in…
(This article originally appeared onSingularityHub by Shelly Fan, adopted by Peter Diamandis for his Abundance Community.)
“A ONCE IN A GENERATION ADVANCE”
One of biology’s grandest challenges
for the past 50 years has been deciphering how a simple one-dimensional
ribbon-like structure turns into 3D shapes, equipped with canyons,
ridges, valleys, and caves.
It’s as if an alien is reading the
coordinates of hundreds of locations on a map of the Grand Canyon on a
notebook, and reconstructing it into a 3D hologram of the actual
thing—without ever laying eyes on it or knowing what it should look
like.
Yes, it’s hard. “Lots of people have broken their head on it,” said Dr. John Moult at the University of Maryland.
It’s not just an academic exercise. Solving the human genome paved the way for gene therapy, CAR-T cancer breakthroughs, and the infamous CRISPR gene editing tool.
Deciphering protein folding is bound to
illuminate an entire new landscape of biology we haven’t been able to
study or manipulate. The fast and furious development of Covid-19
vaccines relied on scientists parsing multiple protein targets on the
virus, including the spike proteins that vaccines target. Many proteins
that lead to cancer have so far been out of the reach of drugs because
their structure is hard to pin down.
With these new AI tools, scientists
could solve haunting medical mysteries while preparing to tackle those
yet unknown. It sets the stage for better understanding our biology,
informing new medicines, and even inspiring synthetic biology down the
line.
“What the DeepMind team has managed to
achieve is fantastic and will change the future of structural biology
and protein research,” said Dr. Janet Thornton, director emeritus of the
European Bioinformatics Institute.
“I never thought I’d see this in my lifetime,” added Moult.
BIRTH OF A PROTEIN
Picture life as a video game. If DNA is
the background base code, then proteins are its execution—the actual
game that you play. Any bugs in DNA could trigger a crash in the
program, but they could also be benign and allow the game to run as
usual. In other words, most modern medicine, like gamers, cares only
about the final gameplay—the proteins—rather than the source code that
leads to it, unless something goes wrong. From diabetes medication to
anti-depressants and potentially life-extending senolytics, these drugs all work by grabbing onto proteins rather than DNA.
It’s why deciphering protein structure
is so important: like a key to a lock, a drug can only dock onto a
protein at specific spots. Similarly, proteins often tag-team by binding
together into a complex to run your body’s functions—say, forming a memory or triggering an immune attack against a virus.
Proteins are made of building blocks
called amino acids, which are in turn programmed by DNA. Similar to the
Rosetta stone, our cells can easily translate DNA code into protein
building blocks inside a clam-shell-like structure, which spits out a
string of one-dimensional amino acids. These ribbons are then shuffled
through a whole cellular infrastructure that allows the protein to fold
into its final structure.
Back in the 1970s, the Nobel Prize
winner Dr. Christian Anfinsen famously asserted that the one-dimensional
sequence itself can computationally predict a protein’s 3D structure.
The problem is time and power: like trying to hack a password with
hundreds of characters suspended in 3D space, the potential solutions
are astronomical. But we now have a tool that beats humans at finding
patterns: machine learning.
ENTER AI
In 2020, DeepMind shocked the entire field with
its entry into a legacy biennial competition. Dubbed CASP (Critical
Assessment of Protein Structure Prediction), the decades-long test uses
traditional lab methods for determining protein structure as its
baseline to judge prediction algorithms.
The baseline’s hard to get. It relies
on laborious experimental techniques that can take months or even years.
These methods often “freeze” a protein and map its internal structure
down to the atomic level using X-rays. Many proteins can’t be treated
this way without losing their natural structure, but the method is the
best we currently have. Predictions are then compared to this gold
standard to judge the underlying algorithm.
Last year DeepMind stunned everyone
with their AI, blowing other competition out of the water. At the time,
they were a tease, revealing little detail about their “incredibly exciting”
method that matched experimental results in accuracy. But the 30-minute
presentation inspired Dr. Minkyung Baek at the University of Washington
to develop her own approach.
Baek used a similar deep learning strategy, outlined in a paper in Science this
week. The tool, RoseTTAFold, simultaneously considers three levels of
patterns. The first looks at the amino acid building blocks of a protein
and compares them to all the other sequences in a protein database.
The tool next examines how one
protein’s amino acids interact with another within the same protein, for
example, by examining the distance between two distant building blocks.
It’s like looking at your hands and feet fully stretched out versus in a
backbend, and measuring the distance between those extremities as you
“fold” into a yoga pose.
Finally, the third track looks at the
3D coordinates of each atom that makes up a protein building block—kind
of like mapping the studs on a Lego block—to compile the final 3D
structure. The network then bounces back and forth between these tracks,
so that one output can update another track.
The end results came close to those of
DeepMind’s tool, AlphaFold2, which matched the gold standard of
structures obtained from experiments. Although RoseTTAFold wasn’t as
accurate as AlphaFold2, it seemingly required much less time and energy.
For a simple protein, the algorithm was able to solve the structure
using a gaming computer in about 10 minutes.
RoseTTAFold was also able to tackle the
“protein assemble” problem, in that it could predict the structure of
proteins, made up of multiple units, by simply looking at the amino acid
sequence alone. For example, they were able to predict how the
structure of an immune molecule locks onto its target. Many biological
functions rely on these handshakes between proteins. Being able to
predict them using an algorithm opens the door to manipulating
biological processes—immune system, stroke, cancer, brain function—that
we previously couldn’t access.
HACKING THE BODY
Since RoseTTAFold’s public release in
July, it’s been downloaded hundreds of times, allowing other researchers
to answer their baffling protein sequence questions, potentially saving
years of work while collectively improving on the algorithm.
“When there’s a breakthrough like this, two years later, everyone is doing it as well if not better than before,” said Moult.
Meanwhile, DeepMind is also releasing (for open and free use) their AlphaFold2 code—the one that inspired Baek.
In a new paper in Nature, the DeepMind team described their approach to
the 50-year mystery. The crux was to integrate multiple sources of
information—the evolution of a protein and its physical and geometric
constraints—to build a two-step system that maps out a given protein
with stunningly high accuracy.
First presented at the CASP meeting,
Dr. Demis Hassabis, founder and CEO of DeepMind, is ready to share the
code with the world. “We pledged to share our methods and provide broad,
free access to the scientific community. Today we take the first step
towards delivering on that commitment by sharing AlphaFold’s open-source
code and publishing the system’s full methodology,” he wrote, adding
that “we’re excited to see what other new avenues of research this will
enable for the community.”
With the two studies, we’re entering a
new world of predicting—and subsequently engineering or changing—the
building blocks of life. Dr. Andrei Lupas, an evolutionary biologist at
the Max Planck Institute for Developmental Biology, and a CASP judge, agrees: “This will change medicine. It will change research,” he said. “It will change bioengineering. It will change everything.”
FINAL THOUGHTS
This breakthrough demonstrates the impact AI can have on scientific discovery.
And if we couple AI’s solution to the
protein folding problem with the anticipated breakthroughs in quantum
computing—another technology poised to disrupt medicine and
healthcare—we’re not far from a world where individually customized,
precision medicine will move from science fiction to the standard of
care.
Nowhere is the convergence of exponential tech bringing greater breakthroughs than in healthcare.
Common side effects include indigestion, trouble sleeping, sexual
dysfunction, loss of appetite, dry mouth, and rash. Serious side
effects include serotonin syndrome, mania, seizures, an increased risk of suicidal behavior in people under 25 years old, and an increased risk of bleeding.
Discontinuation syndrome is less likely to occur with fluoxetine than
with other antidepressants, but it still happens in many cases.
Fluoxetine taken during pregnancy is associated with significant
increase in congenital heart defects in the newborns. It has been suggested that fluoxetine therapy may be continued during breastfeeding if it was used during pregnancy or if other antidepressants were ineffective. Its mechanism of action is unknown, but some hypothesize that it is related to serotonin activity in the brain.
Efficacy
of fluoxetine for acute and maintenance treatment of major depressive
disorder in adults as well as children and adolescents (8 to 18 years)
was established in multiple clinical trials.
In addition to being effective for depression in 6-week long
double-blind controlled trials, fluoxetine was better than placebo for
the prevention of depression recurrence, when the patients, who
originally responded to fluoxetine, were treated for a further 38 weeks.
Efficacy of fluoxetine for geriatric as well as pediatric depression
was also demonstrated in placebo-controlled trials.
Fluoxetine is as effective as tricyclic antidepressants but is better tolerated. It is less effective than sertraline, mirtazapine, and venlafaxine. According to a network analysis
of clinical trials, fluoxetine may belong to the group of less
effective antidepressants; however, its acceptability is higher than any
other antidepressant, except agomelatine.
Obsessive–compulsive disorder
The efficacy of fluoxetine in the treatment of obsessive–compulsive disorder (OCD) was demonstrated in two randomized multicenter phase III clinical trials.
The pooled results of these trials demonstrated that 47% of completers
treated with the highest dose were "much improved" or "very much
improved" after 13 weeks of treatment, compared to 11% in the placebo arm of the trial. The American Academy of Child and Adolescent Psychiatry state that SSRIs, including fluoxetine, should be used as first-line therapy in children, along with cognitive behavioral therapy (CBT), for the treatment of moderate to severe OCD.
Panic disorder
The efficacy of fluoxetine in the treatment of panic disorder was demonstrated in two 12-week randomized multicenter phase III clinical trials that enrolled patients diagnosed with panic disorder, with or without agoraphobia.
In the first trial, 42% of subjects in the fluoxetine-treated arm were
free of panic attacks at the end of the study, vs. 28% in the placebo
arm. In the second trial, 62% of fluoxetine treated patients were free
of panic attacks at the end of the study, vs. 44% in the placebo arm.
Bulimia nervosa
A 2011 systematic review discussed seven trials which compared fluoxetine to a placebo in the treatment of bulimia nervosa, six of which found a statistically significant reduction in symptoms such as vomiting and binge eating. However, no difference was observed between treatment arms when fluoxetine and psychotherapy were compared to psychotherapy alone.
Premenstrual dysphoric disorder
Fluoxetine is used to treat premenstrual dysphoric disorder, a condition where individuals have affective and somatic symptoms monthly during the luteal phase of menstruation. Taking fluoxetine 20 mg/d can be effective in treating PMDD, though doses of 10mg/d have also been prescribed effectively.
Impulsive aggression
Fluoxetine is considered a first-line medication for the treatment of impulsive aggression of low intensity. Fluoxetine reduced low intensity aggressive behavior in patients in intermittent aggressive disorder and borderline personality disorder. Fluoxetine also reduced acts of domestic violence in alcoholics with a history of such behavior.
Special populations
In
children and adolescents, fluoxetine is the antidepressant of choice
due to tentative evidence favoring its efficacy and tolerability. In pregnancy, fluoxetine is considered a category C drug by the US Food and Drug Administration
(FDA). Evidence supporting an increased risk of major fetal
malformations resulting from fluoxetine exposure is limited, although
the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK
has warned prescribers and patients of the potential for fluoxetine
exposure in the first trimester (during organogenesis, formation of the
fetal organs) to cause a slight increase in the risk of congenital cardiac malformations in the newborn.
Furthermore, an association between fluoxetine use during the first
trimester and an increased risk of minor fetal malformations was
observed in one study.
However, a systematic review and meta-analysis of 21 studies – published in the Journal of Obstetrics and Gynaecology Canada
– concluded, "the apparent increased risk of fetal cardiac
malformations associated with maternal use of fluoxetine has recently
been shown also in depressed women who deferred SSRI therapy in
pregnancy, and therefore most probably reflects an ascertainment bias.
Overall, women who are treated with fluoxetine during the first
trimester of pregnancy do not appear to have an increased risk of major
fetal malformations."
Per the FDA, infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn.
Limited data support this risk, but the FDA recommends physicians
consider tapering SSRIs such as fluoxetine during the third trimester.
A 2009 review recommended against fluoxetine as a first-line SSRI
during lactation, stating, "Fluoxetine should be viewed as a
less-preferred SSRI for breastfeeding mothers, particularly with newborn
infants, and in those mothers who consumed fluoxetine during
gestation." Sertraline
is often the preferred SSRI during pregnancy due to the relatively
minimal fetal exposure observed and its safety profile while
breastfeeding.
Adverse effects
Side
effects observed in fluoxetine-treated persons in clinical trials with
an incidence >5% and at least twice as common in fluoxetine-treated
persons compared to those who received a placebo pill include abnormal
dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, decreased libido, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilation, and yawning. Fluoxetine is considered the most stimulating of the SSRIs (that is, it is most prone to causing insomnia and agitation). It also appears to be the most prone of the SSRIs for producing dermatologic reactions (e.g. urticaria (hives), rash, itchiness, etc.).
Sexual dysfunction, including loss of libido, anorgasmia, lack of vaginal lubrication, and erectile dysfunction,
are some of the most commonly encountered adverse effects of treatment
with fluoxetine and other SSRIs. While early clinical trials suggested a
relatively low rate of sexual dysfunction, more recent studies in which
the investigator actively inquires about sexual problems suggest that
the incidence is >70%. On the 11th of June 2019 the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency
concluded that there is a possible causal association between SSRI use
and long-lasting sexual dysfunction that persists despite
discontinuation of SSRI, including fluoxetine, and that the labels of
these drugs should be updated to include a warning.
Discontinuation syndrome
Fluoxetine's longer half-life
makes it less common to develop discontinuation syndrome following
cessation of therapy, especially when compared to antidepressants with
shorter half-lives such as paroxetine. Although gradual dose reductions are recommended with antidepressants with shorter half-lives, tapering may not be necessary with fluoxetine.
Pregnancy
Antidepressant
exposure (including fluoxetine) is associated with shorter average
duration of pregnancy (by three days), increased risk of preterm
delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). There is 30–36% increase in congenital heart defects among children whose mothers were prescribed fluoxetine during pregnancy,with fluoxetine use in the first trimester associated with 38–65% increase in septal heart defects.
Suicide
In 2007 the FDA required all antidepressants to carry a black box warning stating that antidepressants increase the risk of suicide in people younger than 25.
This warning is based on statistical analyses conducted by two
independent groups of FDA experts that found a 2-fold increase of the suicidal ideation
and behavior in children and adolescents, and 1.5-fold increase of
suicidality in the 18–24 age group. The suicidality was slightly
decreased for those older than 24, and statistically significantly lower
in the 65 and older group. This analysis was criticized by Donald Klein,
who noted that suicidality, that is suicidal ideation and behavior, is
not necessarily a good surrogate marker for completed suicide, and it is
still possible, while unproven, that antidepressants may prevent actual
suicide while increasing suicidality.
There is less data on fluoxetine than on antidepressants as a
whole. For the above analysis on the antidepressant level, the FDA had
to combine the results of 295 trials of 11 antidepressants for
psychiatric indications to obtain statistically significant results. Considered separately, fluoxetine use in children increased the odds of suicidality by 50% and in adults decreased the odds of suicidality by approximately 30%.Similarly, the analysis conducted by the UK MHRA
found a 50% increase of odds of suicide-related events, not reaching
statistical significance, in the children and adolescents on fluoxetine
as compared to the ones on placebo. According to the MHRA data, for
adults fluoxetine did not change the rate of self-harm and statistically significantly decreased suicidal ideation by 50%.[
QT prolongation
Fluoxetine can affect the electrical currents that heart muscle cells use to coordinate their contraction, specifically the potassium currents Ito and IKs that repolarise the cardiac action potential. Under certain circumstances, this can lead to prolongation of the QT interval, a measurement made on an electrocardiogram
reflecting how long it takes for the heart to electrically recharge
after each heartbeat. When fluoxetine is taken alongside other drugs
that prolong the QT interval, or by those with a susceptibility to long QT syndrome, there is a small risk of potentially lethal abnormal heart rhythms such as Torsades de Pointes. As of 2019, the drug reference site CredibleMeds lists Fluoxetine as leading to a conditional risk of arrhythmias.
Contraindications include prior treatment (within the past 5–6 weeks, depending on the dose) with MAOIs such as phenelzine and tranylcypromine, due to the potential for serotonin syndrome.
Its use should also be avoided in those with known hypersensitivities
to fluoxetine or any of the other ingredients in the formulation used. Its use in those concurrently receiving pimozide or thioridazine is also advised against.
In some cases, use of dextromethorphan-containing
cold and cough medications with fluoxetine is advised against, due to
fluoxetine increasing serotonin levels, as well as the fact that
fluoxetine is a cytochrome P450 2D6
inhibitor, which causes dextromethorphan to not be metabolized at a
normal rate, thus increasing the risk of serotonin syndrome and other
potential side effects of dextromethorphan.
Patients who are taking anticoagulants or NSAIDS
must be careful when taking fluoxetine or other SSRIs, as they can
sometimes increase the blood-thinning effects of these medications.
Fluoxetine and norfluoxetineinhibit many isozymes of the cytochrome P450 system that are involved in drug metabolism. Both are potent inhibitors of CYP2D6 (which is also the chief enzyme responsible for their metabolism) and CYP2C19, and mild to moderate inhibitors of CYP2B6 and CYP2C9. In vivo, fluoxetine and norfluoxetine do not significantly affect the activity of CYP1A2 and CYP3A4. They also inhibit the activity of P-glycoprotein, a type of membrane transport protein that plays an important role in drug transport and metabolism and hence P-glycoprotein substrates such as loperamide may have their central effects potentiated. This extensive effect on the body's pathways for drug metabolism creates the potential for interactions with many commonly used drugs.
There is also the potential for interaction with highly
protein-bound drugs due to the potential for fluoxetine to displace said
drugs from the plasma or vice versa hence increasing serum
concentrations of either fluoxetine or the offending agent.
Pharmacology
Pharmacodynamics
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and does not appreciably inhibit norepinephrine and dopamine
reuptake at therapeutic doses. It does, however, delay the reuptake of
serotonin, resulting in serotonin persisting longer when it is released.
Large doses in rats have been shown to induce a significant increase in
synaptic norepinephrine and dopamine.
Thus, dopamine and norepinephrine may contribute to the antidepressant
action of fluoxetine in humans at supratherapeutic doses (60–80 mg). This effect may be mediated by 5HT2C receptors, which are inhibited by higher concentrations of fluoxetine.
Fluoxetine increases the concentration of circulating allopregnanolone, a potent GABAA receptor positive allosteric modulator, in the brain Norfluoxetine, a primary active metabolite of fluoxetine, produces a similar effect on allopregnanolone levels in the brains of mice. Additionally, both fluoxetine and norfluoxetine are such modulators themselves, actions which may be clinically-relevant.
Fluoxetine
elicits antidepressant effect by inhibiting serotonin re-uptake in the
synapse by binding to the re-uptake pump on the neuronal membrane to increase serotonin availability and enhance neurotransmission.
Norfluoxetine and desmethylfluoxetine are metabolites of fluoxetine and
also act as serotonin re-uptake inhibitors, increasing the duration of
action of the drug.
The bioavailability of fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6–8 hours. It is highly bound to plasma proteins, mostly albumin and α1-glycoprotein. Fluoxetine is metabolized in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6. The role of CYP2D6 in the metabolism of fluoxetine may be clinically important, as there is great genetic variability in the function of this enzyme among people. CYP2D6 is responsible for converting fluoxetine to its only active metabolite, norfluoxetine. Both drugs are also potent inhibitors of CYP2D6.
The extremely slow elimination of fluoxetine and its active
metabolite norfluoxetine from the body distinguishes it from other
antidepressants. With time, fluoxetine and norfluoxetine inhibit their
own metabolism, so fluoxetine elimination half-life increases from 1 to 3 days, after a single dose, to 4 to 6 days, after long-term use. Similarly, the half-life of norfluoxetine is longer (16 days) after long-term use.
Therefore, the concentration of the drug and its active metabolite in
the blood continues to grow through the first few weeks of treatment,
and their steady concentration in the blood is achieved only after four
weeks.
Moreover, the brain concentration of fluoxetine and its metabolites
keeps increasing through at least the first five weeks of treatment.
The full benefit of the current dose a patient receives is not realized
for at least a month following ingestion. For example, in one 6-week
study, the median time to achieving consistent response was 29 days.
Likewise, complete excretion of the drug may take several weeks. During
the first week after treatment discontinuation, the brain concentration
of fluoxetine decreases by only 50%,
The blood level of norfluoxetine four weeks after treatment
discontinuation is about 80% of the level registered by the end of the
first treatment week, and, seven weeks after discontinuation,
norfluoxetine is still detectable in the blood.
Measurement in body fluids
Fluoxetine
and norfluoxetine may be quantitated in blood, plasma or serum to
monitor therapy, confirm a diagnosis of poisoning in hospitalized person
or assist in a medicolegal death investigation. Blood or plasma
fluoxetine concentrations are usually in a range of 50–500 μg/L in
persons taking the drug for its antidepressant effects, 900–3000 μg/L in
survivors of acute overdosage and 1000–7000 μg/L in victims of fatal
overdosage. Norfluoxetine concentrations are approximately equal to
those of the parent drug during chronic therapy, but may be
substantially less following acute overdosage, since it requires at
least 1–2 weeks for the metabolite to achieve equilibrium.
Usage
In 2010, over 24.4 million prescriptions for generic fluoxetine were filled in the United States, making it the third-most prescribed antidepressant after sertraline and citalopram. In 2011, 6 million prescriptions for fluoxetine were filled in the United Kingdom.
History
The work which eventually led to the discovery of fluoxetine began at Eli Lilly and Company in 1970 as a collaboration between Bryan Molloy and Robert Rathbun. It was known at that time that the antihistaminediphenhydramine
shows some antidepressant-like properties.
3-Phenoxy-3-phenylpropylamine, a compound structurally similar to
diphenhydramine, was taken as a starting point, and Molloy synthesized a
series of dozens of its derivatives. Hoping to find a derivative inhibiting only serotonin reuptake, an Eli Lilly scientist, David T. Wong, proposed to retest the series for the in vitro reuptake of serotonin, norepinephrine and dopamine. This test, carried out by Jong-Sir Horng in May 1972, showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series. Wong published the first article about fluoxetine in 1974.
A year later, it was given the official chemical name fluoxetine and
the Eli Lilly and Company gave it the trade name Prozac. In February
1977, Dista Products Company, a division of Eli Lilly & Company,
filed an Investigational New Drug application to the U.S. Food and Drug Administration (FDA) for fluoxetine.
Fluoxetine appeared on the Belgian market in 1986. In the U.S., the FDA gave its final approval in December 1987, and a month later Eli Lilly began marketing Prozac; annual sales in the U.S. reached $350 million within a year. Worldwide sales eventually reached a peak of $2.6 billion a year.
Lilly tried several product line extension
strategies, including extended release formulations and paying for
clinical trials to test the efficacy and safety of fluoxetine in premenstrual dysphoric disorder
and rebranding fluoxetine for that indication as "Sarafem" after it was
approved by the FDA in 2000, following the recommendation of an
advisory committee in 1999. The invention of using fluoxetine to treat PMDD was made by Richard Wurtman at MIT; the patent was licensed to his startup, Interneuron, which in turn sold it to Lilly.
To defend its Prozac revenue from generic competition, Lilly also
fought a five-year, multimillion-dollar battle in court with the
generic company Barr Pharmaceuticals
to protect its patents on fluoxetine, and lost the cases for its
line-extension patents, other than those for Sarafem, opening fluoxetine
to generic manufacturers starting in 2001. When Lilly's patent expired in August 2001, generic drug competition decreased Lilly's sales of fluoxetine by 70% within two months.
In 2000 an investment bank had projected that annual sales of Sarafem could reach $250M/year.
Sales of Sarafem reached about $85M/year in 2002, and in that year
Lilly sold its assets connected with the drug for $295M to Galen
Holdings, a small Irish pharmaceutical company specializing in
dermatology and women's health that had a sales force tasked to
gynecologists' offices; analysts found the deal sensible since the
annual sales of Sarafem made a material financial difference to Galen,
but not to Lilly.
Bringing Sarafem to market harmed Lilly's reputation in some quarters. The diagnostic category of PMDD was controversial since it was first proposed in 1987, and Lilly's role in retaining it in the appendix of the DSM-IV-TR, the discussions for which got under way in 1998, has been criticized. Lilly was criticized for inventing a disease in order to make money, and for not innovating but rather just seeking ways to continue making money from existing drugs.
It was also criticized by the FDA and groups concerned with women's
health for marketing Sarafem too aggressively when it was first
launched; the campaign included a television commercial featuring a
harried woman at the grocery store who asks herself if she has PMDD.
Society and culture
American aircraft pilots
Beginning 5 April 2010, fluoxetine became one of four antidepressant drugs that the FAA permitted for pilots with authorization from an aviation medical examiner. The other permitted antidepressants are sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro). These four remain the only antidepressants permitted by FAA as of 2 December 2016.
Sertraline, citalopram and escitalopram are the only antidepressants permitted for EASA medical certification, as of January 2019.
Environmental effects
Fluoxetine has been detected in aquatic ecosystems, especially in North America.
There is a growing body of research addressing the effects of
fluoxetine (among other SSRIs) exposure on non-target aquatic species.
In 2003, one of the first studies addressed in detail the
potential effects of fluoxetine on aquatic wildlife; this research
concluded that exposure at environmental concentrations was of little
risk to aquatic systems if a hazard quotient approach was applied to risk assessment.
However, they also stated the need for further research addressing
sub-lethal consequences of fluoxetine, specifically focusing on study
species' sensitivity, behavioural responses, and endpoints modulated by
the serotonin system.
Since 2003, a number of studies have reported fluoxetine-induced
impacts on a number of behavioural and physiological endpoints, inducing
antipredator behaviour, reproduction, and foraging at or below field-detected concentrations. However, a 2014 review on the ecotoxicology
of fluoxetine concluded that, at that time, a consensus on the ability
of environmentally realistic dosages to affect the behaviour of wildlife
could not be reached.
Politics
During the 1990 campaign for Governor of Florida, it was disclosed that one of the candidates, Lawton Chiles,
had depression and had resumed taking fluoxetine, leading his political
opponents to question his fitness to serve as Governor.
Sertraline shares the common side effects and contraindications
of other SSRIs, with high rates of nausea, diarrhea, insomnia, and
sexual side effects, but it appears not to lead to much weight gain, and
its effects on cognitive performance are mild. Similar to other
antidepressants, the use of sertraline for depression may be associated
with a higher rate of suicidal thoughts and behavior in people under the
age of 25. It should not be used together with MAO inhibitor medication: this combination causes serotonin syndrome. Sertraline taken during pregnancy is associated with a significant increase in congenital heart defects in newborns.
Sertraline was invented and developed by scientists at Pfizer and approved for medical use in the United States in 1991. It is available as a generic medication. In 2016, sertraline was the most commonly prescribed psychiatric medication in the United States
and in 2018, it was the fourteenth most commonly prescribed medication
in the United States, with over 38 million prescriptions.
Multiple
controlled clinical trials established efficacy of sertraline for the
treatment of depression. Sertraline is also an effective antidepressant
in the routine clinical practice. Continued treatment with sertraline
prevents both a relapse of the current depressive episode and future
episodes (recurrence of depression).
In several double-blind studies, sertraline was consistently more effective than placebo for dysthymia, a more chronic variety of depression, and comparable to imipramine in that respect. Sertraline also improves the depression of dysthymic patients to a greater degree than psychotherapy.
Sertraline provides no benefit to children and adolescents with depression.
Comparison with other antidepressants
In general, sertraline efficacy is similar to that of other antidepressants. For example, a meta-analysis of 12 new-generation antidepressants showed that sertraline and escitalopram are the best in terms of efficacy and acceptability in the acute-phase treatment of adults with depression. Comparative clinical trials demonstrated that sertraline is similar in efficacy against depression to moclobemide, nefazodone, escitalopram, bupropion, citalopram, fluvoxamine, paroxetine, venlafaxine and mirtazapine. Sertraline may be more efficacious for the treatment of depression in the acute phase (first 4 weeks) than fluoxetine.
There are differences between sertraline and some other
antidepressants in their efficacy in the treatment of different subtypes
of depression and in their adverse effects. For severe depression,
sertraline is as good as clomipramine but is better tolerated. Sertraline appears to work better in melancholic depression than fluoxetine, paroxetine, and mianserin and is similar to the tricyclic antidepressants such as amitriptyline and clomipramine. In the treatment of depression accompanied by OCD, sertraline performs significantly better than desipramine on the measures of both OCD and depression.
Sertraline is equivalent to imipramine for the treatment of depression
with co-morbid panic disorder, but it is better tolerated. Compared with amitriptyline, sertraline offered a greater overall improvement in quality of life of depressed patients.
Depression in elderly
Sertraline
used for the treatment of depression in elderly (older than 60)
patients is superior to placebo and comparable to another SSRI
fluoxetine, and tricyclic antidepressants (TCAs) amitriptyline, nortriptyline and imipramine.
Sertraline has much lower rates of adverse effects than these TCAs,
with the exception of nausea, which occurs more frequently with
sertraline. In addition, sertraline appears to be more effective than
fluoxetine or nortriptyline in the older-than-70 subgroup. Accordingly, a meta-analysis of antidepressants in older adults found that sertraline, paroxetine and duloxetine were better than placebo. On the other hand, in a 2003 trial the effect size was modest, and there was no improvement in quality of life as compared to placebo. With depression in dementia, there is no benefit of sertraline treatment compared to either placebo or mirtazapine.
Obsessive–compulsive disorder
Sertraline is effective for the treatment of OCD in adults and children. It was better tolerated and, based on intention-to-treat analysis, performed better than the gold standard of OCD treatment clomipramine. Continuing sertraline treatment helps prevent relapses of OCD with long-term data supporting its use for up to 24 months.
It is generally accepted that the sertraline dosages necessary for the
effective treatment of OCD are higher than the usual dosage for
depression.
The onset of action is also slower for OCD than for depression. The
treatment recommendation is to start treatment with a half of maximal
recommended dose for at least two months. After that, the dose can be
raised to the maximal recommended in the cases of unsatisfactory
response.
Cognitive behavioral therapy
alone was superior to sertraline in both adults and children; however,
the best results were achieved using a combination of these treatments.
Panic disorder
Sertraline is superior to placebo for the treatment of panic disorder.
The response rate was independent of the dose. In addition to
decreasing the frequency of panic attacks by about 80% (vs. 45% for
placebo) and decreasing general anxiety, sertraline resulted in
improvement of quality of life on most parameters. The patients rated as
"improved" on sertraline reported better quality of life than the ones
who "improved" on placebo. The authors of the study argued that the
improvement achieved with sertraline is different and of a better
quality than the improvement achieved with placebo. Sertraline is equally effective for men and women, and for patients with or without agoraphobia. Previous unsuccessful treatment with benzodiazepines does not diminish its efficacy. However, the response rate was lower for the patients with more severe panic. Starting treatment simultaneously with sertraline and clonazepam, with subsequent gradual discontinuation of clonazepam, may accelerate the response.
Double-blind comparative studies found sertraline to have the same effect on panic disorder as paroxetine or imipramine. While imprecise, comparison of the results of trials of sertraline with separate trials of other anti-panic agents (clomipramine, imipramine, clonazepam, alprazolam, and fluvoxamine) indicates approximate equivalence of these medications.
Other anxiety disorders
Sertraline has been successfully used for the treatment of social anxiety disorder. All three major domains of the disorder (fear, avoidance, and physiological symptoms) respond to sertraline. Maintenance treatment, after the response is achieved, prevents the return of the symptoms. The improvement is greater among the patients with later, adult onset of the disorder. In a comparison trial, sertraline was superior to exposure therapy,
but patients treated with the psychological intervention continued to
improve during a year-long follow-up, while those treated with
sertraline deteriorated after treatment termination. The combination of sertraline and cognitive behavioral therapy appears to be more effective in children and young people than either treatment alone.
Sertraline has not been approved for the treatment of generalized anxiety disorder; however, several guidelines recommend it as a first-line medication referring to good quality controlled clinical trials.
Premenstrual dysphoric disorder
Sertraline is effective in alleviating the symptoms of premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome.
Significant improvement was observed in 50–60% of cases treated with
sertraline vs. 20–30% of cases on placebo. The improvement began during
the first week of treatment, and in addition to mood, irritability, and
anxiety, improvement was reflected in better family functioning, social
activity and general quality of life. Work functioning and physical
symptoms, such as swelling, bloating and breast tenderness, were less
responsive to sertraline. Taking sertraline only during the luteal phase, that is, the 12–14 days before menses, was shown to work as well as continuous treatment. Continuous treatment with sub-therapeutic doses of sertraline (25 mg vs. usual 50–100 mg) is also effective.
Other indications
Sertraline is approved for the treatment of post-traumatic stress disorder (PTSD). National Institute of Clinical Excellence recommends it for patients who prefer drug treatment to a psychological one. Other guidelines also suggest sertraline as a first-line option for pharmacological therapy. When necessary, long-term pharmacotherapy can be beneficial. There are both negative and positive clinical trial results for sertraline, which may be explained by the types of psychological traumas, symptoms, and comorbidities included in the various studies.
Positive results were obtained in trials that included predominantly
women (75%) with a majority (60%) having physical or sexual assault as
the traumatic event.
Contrary to the above suggestions, a meta-analysis of sertraline
clinical trials for PTSD found it to be not significantly better than
placebo. Another meta-analysis relegated sertraline to the second line, proposing trauma focused psychotherapy as a first-line intervention. The authors noted that Pfizer had declined to submit the results of a negative trial for the inclusion into the meta-analysis making the results unreliable.
Sertraline when taken daily can be useful for the treatment of premature ejaculation. A disadvantage of sertraline is that it requires continuous daily treatment to delay ejaculation significantly.
A 2019 systematic review suggested that sertraline may be a good way to control anger, irritability and hostility in depressed patients and patients with other comorbidities.
Contraindications
Sertraline is contraindicated in individuals taking monoamine oxidase inhibitors or the antipsychotic pimozide. Sertraline concentrate contains alcohol and is therefore contraindicated with disulfiram.
The prescribing information recommends that treatment of the elderly
and patients with liver impairment "must be approached with caution".
Due to the slower elimination of sertraline in these groups, their
exposure to sertraline may be as high as three times the average
exposure for the same dose.
Nausea, ejaculation failure, insomnia, diarrhea, dry mouth, somnolence, dizziness, tremor, and decreased libido are the common adverse effects associated with sertraline with the greatest difference from placebo. Those that most often resulted in interruption of the treatment are nausea, diarrhea and insomnia. The incidence of diarrhea is higher with sertraline—especially when prescribed at higher doses—in comparison with other SSRIs.
Over more than six months of sertraline therapy for depression, people showed a nonsignificant weight increase of 0.1%. Similarly, a 30-month-long treatment with sertraline for OCD resulted in a mean weight gain of 1.5% (1 kg). Although the difference did not reach statistical significance, the average weight gain was lower for fluoxetine (1%) but higher for citalopram, fluvoxamine and paroxetine
(2.5%). Of the sertraline group, 4.5% gained a large amount of weight
(defined as more than 7% gain). This result compares favorably with
placebo, where, according to the literature, 3–6% of patients gained
more than 7% of their initial weight. The large weight gain was observed
only among female members of the sertraline group; the significance of
this finding is unclear because of the small size of the group.
Over a two-week treatment of healthy volunteers, sertraline slightly improved verbal fluency but did not affect word learning, short-term memory, vigilance, flicker fusion time, choice reaction time, memory span, or psychomotor coordination.
In spite of lower subjective rating, that is, feeling that they
performed worse, no clinically relevant differences were observed in the
objective cognitive performance in a group of people treated for
depression with sertraline for 1.5 years as compared to healthy
controls.
In children and adolescents taking sertraline for six weeks for anxiety
disorders, 18 out of 20 measures of memory, attention and alertness
stayed unchanged. Divided attention was improved and verbal memory under interference conditions
decreased marginally. Because of the large number of measures taken, it
is possible that these changes were still due to chance. The unique effect of sertraline on dopaminergicneurotransmission may be related to these effects on cognition and vigilance.
Sertraline has a low level of exposure of an infant through the
breast milk and is recommended as the preferred option for the
antidepressant therapy of breast-feeding mothers. There is 29-42% increase in congenital heart defects among children whose mothers were prescribed sertraline during pregnancy, with sertraline use in the first trimester associated with 2.7-fold increase in septal heart defects.
Abrupt interruption of sertraline treatment may result in
withdrawal or discontinuation syndrome. Dizziness, insomnia, anxiety,
agitation, and irritability are its common symptoms. It typically occurs within a few days from drug discontinuation and lasts a few weeks. The withdrawal symptoms for sertraline are less severe and frequent than for paroxetine, and more frequent than for fluoxetine.
In most cases symptoms are mild, short-lived, and resolve without
treatment. More severe cases are often successfully treated by temporary
reintroduction of the drug with a slower tapering off rate.
Like other SSRIs, sertraline is associated with sexual side effects, including sexual arousal disorder, erectile dysfunction and difficulty achieving orgasm. While nefazodone and bupropion
do not have negative effects on sexual functioning, 67% of men on
sertraline experienced ejaculation difficulties versus 18% before the
treatment. Sexual arousal
disorder, defined as "inadequate lubrication and swelling for women and
erectile difficulties for men", occurred in 12% of people on sertraline
as compared with 1% of patients on placebo. The mood improvement
resulting from the treatment with sertraline sometimes counteracted
these side effects, so that sexual desire
and overall satisfaction with sex stayed the same as before the
sertraline treatment. However, under the action of placebo the desire
and satisfaction slightly improved. Some people continue experiencing sexual side effects after they stop taking SSRIs.
Suicide
The FDA requires all antidepressants, including sertraline, to carry a boxed warning
stating that antidepressants increase the risk of suicide in persons
younger than 25 years. This warning is based on statistical analyses
conducted by two independent groups of FDA experts that found a 100%
increase of suicidal thoughts and behavior in children and adolescents,
and a 50% increase - in the 18 – 24 age group.
Suicidal ideation
and behavior in clinical trials are rare. For the above analysis, the
FDA combined the results of 295 trials of 11 antidepressants for
psychiatric indications in order to obtain statistically significant
results. Considered separately, sertraline use in adults decreased the
odds of suicidal behavior with a marginal statistical significance by
37% or 50%
depending on the statistical technique used. The authors of the FDA
analysis note that "given the large number of comparisons made in this
review, chance is a very plausible explanation for this difference". The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidal behavior. Similarly, the analysis conducted by the UK MHRA
found a 50% increase of odds of suicide-related events, not reaching
statistical significance, in the patients on sertraline as compared to
the ones on placebo.
Overdose
Acute
overdosage is often manifested by emesis, lethargy, ataxia, tachycardia
and seizures. Plasma, serum or blood concentrations of sertraline and
norsertraline, its major active metabolite,
may be measured to confirm a diagnosis of poisoning in hospitalized
patients or to aid in the medicolegal investigation of fatalities. As with most other SSRIs its toxicity in overdose is considered relatively low.
Interactions
Sertraline is a moderate inhibitor of CYP2D6 and CYP2B6in vitro. Accordingly, in human trials it caused increased blood levels of CYP2D6 substrates such as metoprolol, dextromethorphan, desipramine, imipramine and nortriptyline, as well as the CYP3A4/CYP2D6 substrate haloperidol.
This effect is dose-dependent; for example, co-administration with
50 mg of sertraline resulted in 20% greater exposure to desipramine,
while 150 mg of sertraline led to a 70% increase. In a placebo-controlled study, the concomitant administration of sertraline and methadone caused a 40% increase in blood levels of the latter, which is primarily metabolized by CYP2B6.
Sertraline had no effect on the actions of digoxin and atenolol, which are not metabolized in the liver. Case reports suggest that taking sertraline with phenytoin or zolpidem may induce sertraline metabolism and decrease its efficacy, and that taking sertraline with lamotrigine may increase the blood level of lamotrigine, possibly by inhibition of glucuronidation.
CYP2C19 inhibitor esomeprazole increased sertraline concentrations in blood plasma by approximately 40%.
Clinical reports indicate that interaction between sertraline and the MAOIsisocarboxazid and tranylcypromine may cause serotonin syndrome. In a placebo-controlled study in which sertraline was co-administered with lithium, 35% of the subjects experienced tremors, while none of those taking placebo did.
Sertraline also shows relatively high activity as an inhibitor of the dopamine transporter (DAT) and antagonist of the sigmaσ1 receptor (but not the σ2 receptor). However, sertraline affinity for its main target (SERT) is much greater than its affinity for σ1 receptor and DAT. Although there could be a role for the σ1 receptor in the pharmacology of sertraline, the significance of this receptor in its actions is unclear. Similarly, the clinical relevance of sertraline's blockade of the dopamine transporter is uncertain.
Pharmacokinetics
Desmethylsertraline—sertraline's major metabolite
Sertraline is absorbed slowly when taken orally, achieving its
maximal concentration in the plasma 4 to 6 hours after ingestion. In the
blood, it is 98.5% bound to plasma proteins.
Its half-life in the body is 13–45 hours and, on average, is about 1.5
times longer in women (32 hours) than in men (22 hours), leading to a
1.5-times-higher exposure in women. According to in vitro studies, sertraline is metabolized by multiple cytochrome 450isoforms; however, it appears that in the human body CYP2C19 plays the most important role, followed by CYP2B6. Poor CYP2C19 metabolizers have 2.7-fold higher levels of sertraline, and intermediate metabolizers - 1.4-fold higher levels,
than normal (extensive) metabolizers. In contrast, poor CYP2B6
metabolizers have 1.6-fold higher levels of sertraline and intermediate
metabolizers - 1.2-fold higher levels.
The major metabolite of sertraline, desmethylsertraline, is about 50 times weaker as a serotonin transporter inhibitor than sertraline and its clinical effect is negligible. Sertraline can be deaminatedin vitro by monoamine oxidases; however, this metabolic pathway has never been studied in vivo.
History
Skeletal formulae
of thiothixene, lometraline and tametraline, from which sertraline was
derived. Commonalities to the structure of sertraline are highlighted in
green.
The history of sertraline dates back to the early 1970s, when Pfizer chemist Reinhard Sarges invented a novel series of psychoactive compounds, including lometraline, based on the structures of the neuroleptics thiothixene and pinoxepin. Further work on these compounds led to tametraline, a norepinephrine and weaker dopamine reuptake inhibitor. Development of tametraline was soon stopped because of undesired stimulant effects observed in animals. A few years later, in 1977, pharmacologist Kenneth Koe,
after comparing the structural features of a variety of reuptake
inhibitors, became interested in the tametraline series. He asked
another Pfizer chemist, Willard Welch, to synthesize some previously
unexplored tametraline derivatives. Welch generated a number of potent
norepinephrine and triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogs was a serotonin reuptake inhibitor. Welch then prepared stereoisomers of this compound, which were tested in vivo by animal behavioral scientist
Albert Weissman. The most potent and selective (+)-isomer was taken
into further development and eventually named sertraline. Weissman and
Koe recalled that the group did not set up to produce an antidepressant
of the SSRI type—in that sense their inquiry was not "very goal driven",
and the discovery of the sertraline molecule was serendipitous.
According to Welch, they worked outside the mainstream at Pfizer, and
even "did not have a formal project team". The group had to overcome
initial bureaucratic reluctance to pursue sertraline development, as
Pfizer was considering licensing an antidepressant candidate from
another company.
Sertraline was approved by the US Food and Drug Administration
(FDA) in 1991 based on the recommendation of the Psychopharmacological
Drugs Advisory Committee; it had already become available in the United Kingdom the previous year. The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of major depression.
During the discussion, Paul Leber, the director of the FDA Division of
Neuropharmacological Drug Products, noted that granting approval was a
"tough decision", since the treatment effect on outpatients
with depression had been "modest to minimal". Other experts emphasized
that the drug's effect on inpatients had not differed from placebo and criticized poor design of the clinical trials by Pfizer. For example, 40% of participants dropped out of the trials, significantly decreasing their validity.
Until 2002, sertraline was only approved for use in adults ages
18 and over; that year, it was approved by the FDA for use in treating
children aged 6 or older with severe OCD. In 2003, the UK Medicines and Healthcare products Regulatory Agency issued a guidance that, apart from fluoxetine (Prozac), SSRIs are not suitable for the treatment of depression in patients under 18. However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents. In 2005, the FDA added a boxed warning concerning pediatric suicidal behavior to all antidepressants,
including sertraline. In 2007, labeling was again changed to add a
warning regarding suicidal behavior in young adults ages 18 to 24.
Society and culture
Generic availability
The US patent for Zoloft expired in 2006, and sertraline is available in generic form and is marketed under many brand names worldwide.
In May 2020, the FDA placed Zoloft on the list of drugs currently facing a shortage.
