Zoloft (sertraline) is the world's most commonly prescribed antidepressant, with more than 37 million prescriptions written every year in the US alone—and it doesn't work.
Researchers who carried out the trial, one of the first independent studies that wasn't funded by the drug's manufacturer, say they were left "shocked and surprised" by the results, which revealed the drug was only slightly more effective than a placebo, or sugar pill.
The discovery puts a big question mark over the whole family of SSRI (selective serotonin reuptake inhibitor) antidepressants, which were developed based on the controversial theory that depression is the result of an imbalance in serotonin, a chemical that acts as a neurotransmitter in the peripheral and central nervous system.
The SSRIs were launched more than 30 years ago and are now generating annual global sales of around $15 billion—but there were always concerns about the theory and, from that, the effectiveness of the drugs.
Critics were silenced in 2018 when a major reanalysis of 522 trials, involving more than 116,000 people, concluded that some SSRIs were around twice as effective as a placebo, although one of the least effective of the 21 drugs that researchers from Oxford University reviewed was Prozac, the best known of the antidepressants.1
But researchers from University College London weren't so sure, because around 80 percent of the papers the Oxford researchers had reviewed were biased or were poorly put together. In other words, the drug manufacturer that paid for the research got the result it wanted.
The handful of independent studies had discovered a much smaller positive effect, if any at all, they noted.So the London researchers decided to find out for themselves, and without industry funding, by focusing on sertraline (Zoloft), which accounts for around 54 percent of all antidepressant prescriptions.
They recruited 655 people who had suffered depression over the previous two years, half of whom were given sertraline while the rest were instead given a placebo, although they all thought they were being given the drug.2
By the end of the six-week test, there was almost no difference in levels of depression between the two groups; those on sertraline scored just 5 percent better on a standard measurement gauge for depressive symptoms, which includes poor sleep, lack of concentration and an inability to enjoy life.
"We were shocked and surprised. We definitely need better treatments for depression, and we need more research in this area," said lead researcher Glyn Lewis.
Sertraline did have some positive impact, but not on depression. Those taking the drug said they felt less anxious, with the standard symptoms of anxiety, including worry, nervousness, irritability and restlessness reducing by 21 percent over the six weeks.
This explains why people taking sertraline often report feeling better, even though the depression hasn't improved. It's an unexpected benefit, but it seems to have little to do with serotonin. And because all SSRIs grew from the serotonin theory, Professor Lewis expects to see similar results for other drugs in the family.
This means the standard treatment for depression isn't working and has never worked, even though the SSRI class of antidepressants has been the focus of more research than almost any other drug.
From the few to the many
John Ioannidis, a researcher at Stanford University, investigated this phenomenon in a seminal paper in which he discovered that Prozac (fluoxetine) won approval from the US drug regulator, the Food and Drug Administration (FDA), on the basis of just five trials that involved a total of just 817 patients. 3
At the time, in 2008, more than 40 million people had been treated with Prozac. "A simple calculation shows that for each randomized patient receiving fluoxetine in the FDA application package, approximately 50,000 patients have been treated subsequently in everyday practice," he writes.
Prozac went on to become the first SSRI blockbuster, with an explosion in sales that made it "the most widely prescribed antidepressant in medical history," its manufacturer, Eli Lilly, announced. Others SSRIs, including Zoloft and Paxil, quickly followed, and from 1981 to 2000, SSRI drug sales rose by 353 percent. Revenues are anticipated to exceed $15 billion by 2023.
Subsequent SSRI trials were either biased or suppressed by the manufacturer. In fact, around a third of all SSRI studies have never been published.
Researchers from Oregon Health and Science University gained access to some of the suppressed papers under the US Freedom of Information Act, and when the results of the suppressed papers were factored back in, average SSRI effectiveness dropped to just 11 percent.
In many of the suppressed studies, SSRIs performed worse than the placebos. The average beneficial effect was 32 percent—far lower than the 94 percent the drug industry promotes.4
Many antidepressant trials are conducted over a six-week period, but even for such short-term studies, the attrition rate is high, says Professor Ioannidis. A high rate of participants leave the trials prematurely, usually because they cannot tolerate the drugs' side-effects.
Side-effects as serious as suicide have been reported, especially among teenagers taking Prozac, but the real extent of the problem is unknown. As psychiatrist Dr David Healy told an FDA advisory committee meeting: "The idea that you would have a risk in one age group but not in another is just wrong."
Another psychiatrist, Dr Peter Breggin, told the same panel: "The primary data on suicidality has been generated in short-term controlled clinical trials planned by drug companies, carried out by drug company hacks and evaluated by drug company employees at corporate headquarters. If that kind of carefully cultivated evaluation bears such bad fruit, imagine what the real data must show."
All the SSRIs come with a range of side-effects. Prozac alone lists 242 different side-effects; the most common include gut problems, such as stomach pain, diarrhea, constipation and indigestion, affecting up to 22 percent of patients. The drugs also have anticoagulant qualities to prevent blood from clotting, which can cause serious bleeds and increase the risk for strokes.
If these effects are real, and any ability to counter depression is illusory, then the major way that medicine treats depression is not only useless, it's dangerous, too.
What can help?
If SSRIs can't help lift depression, what can? Depression is being seen as a multifactorial problem—and inflammation, environmental causes, trauma and nutritional deficiencies have all been cited as possible causes.
This suggests that many different therapies could be used to relieve symptoms, and even reverse the problem. Lifestyle changes, including an improved diet, adopting a positive attitude, exercise and social activity, have all been used successfully.
If depression isn't a chemical imbalance, what is it? One theory gaining traction is that it has to do with inflammation—and it could be an inflammatory response to something in your environment or to a traumatic experience from childhood, such as parental rejection.
Researchers at the University of Notre Dame in Indiana tested the theory when they assessed early childhood experiences and depression among 177 young offenders at a juvenile detention center in Russia. Many were suffering from depression, and the researchers discovered a correlation between the severity of their condition and the extent of childhood trauma, such as punishment, hostility, parents' unjustified criticism and lack of respect.1
Before SSRI antidepressants were developed, just 100 people per million were diagnosed with depression—but this exploded to 100,000 people per million, 10 percent of the population, when the drugs were launched on the back of the chemical imbalance theory of depression.
In 1965, Harvard psychiatrist Joseph Schildkraut put forward the theory that depression was caused by low levels of a neurotransmitter, and two years later, other researchers singled out serotonin.
If a chemical is linked to depression, then the drug industry could produce another chemical to adjust the balance, and so research into SSRIs began.
But neuroscientists were doing their research, too, and they were unable to find evidence that supported the theory. Clinical researchers didn't fare any better. Studies of depressed people found that their serotonin levels were the same as in healthy controls, and even when serotonin levels were deliberately lowered, the participants didn't become depressed.1
Conversely, depressed people given very high doses of serotonin didn't see any improvement in their symptoms.2
Even the psychiatric profession quietly agrees. Its "bible," the Diagnostic and Statistical Manual of Mental Disorders, doesn't list serotonin as a cause of depression, while the American Psychiatric Press Textbook of Clinical Psychiatry cites serotonin deficiency as "an unconfirmed hypothesis."