SSRI drugs sell on false 'chemical imbalance' theory

Every year around the world we take $13bn (lb6.6bn)-worth of antidepressants, and more than 80 per cent of those prescriptions are for an SSRI (serotonin selective reuptake inhibitors) such as Prozac, Paxil and Zoloft.

The SSRI is one of the best selling drugs in medicine, and its enormous success is based on the 'chemical imbalance theory': people become depressed because they are low in serotonin, a neurotransmitter, or chemical transmitter, which acts on the peripheral and central nervous system.

An SSRI redresses this chemical imbalance by helping to promote serotonin levels, and can treat not only depression, the manufacturers claim, but also other psychiatric problems such as social anxiety disorder and obsessive-compulsive disorder.

The SSRI has signalled a revolution in mental care. Suddenly, clinical and severe depression is something that the sufferer doesn't just have to endure, or learn to get over. Instead, there's a simple remedy to hand: a chemical to treat a chemical. As a result, we've become a 'Prozac Nation', as Elizabeth Wurtzel's best-selling book has classified all of us to be.

The drug industry has been the major promoter of the depression-serotonin theory - for obvious reasons - but, astonishingly, it has never been proven since it was postulated in 1967, despite many attempts to do so.

As the theory is unproven, it's not surprising that the SSRI is far less effective than drug companies are claiming. In a meta-analysis of published and unpublished trials, researchers found that the trials, usually funded by the manufacturer, either put an unwarranted positive spin on the results, or were suppressed if the results were not positive (NEJM, 2008; 358: 252-60).

The chemical imbalance theory

It's generally accepted by doctors - and the public - that severe depression in particular is the result of a chemical imbalance, and especially low levels of serotonin, a neurotransmitter. Joseph Schildkraut was one of the pioneers of the general theory that chemical imbalances cause depression, and, in 1965, he postulated that depression was associated with low levels of a neurotransmitter. These imbalances caused mood swings, and the problem could be corrected by drugs, he said. Two years later, researchers zoned in on serotonin as the responsible neurotransmitter (Br J Psychiatry, 1967; 13: 1237-64).

But this acceptance has far more to do with aggressive marketing by the drug companies, who sell their SSRIs on the basis of the theory, than research from neuroscientists who have tried, unsuccessfully, for 40 years to come up with conclusive evidence to prove the theory.

Researchers who analysed the cerebrospinal fluid of clinically depressed and suicidal patients couldn't find any difference in their serotonin levels compared with healthy controls. Even participants in medical trials whose levels of serotonin were deliberately lowered didn't become depressed (Pharmacopsychiatry, 1996; 29: 2-11), while depressed people who were given huge increases of serotonin didn't witness any improvement to their condition (Arch Gen Psychiatry, 1975; 32: 22-30).

Not only has neuroscience been unable to prove the theory in independent studies, it has found plenty of evidence to suggest that depression and other mental disorders are the result of far more complex factors than a simple neurotransmitter deficiency.

The lack of supportive evidence isn't helped by the fact that nobody knows what an ideal serotonin level is supposed to look like, let alone the profile of a pathological imbalance.

"There is not a single peer-reviewed article that can be accurately cited to directly support claims of serotonin deficiency in any mental disorder," says Jeffrey Lacasse, from Florida State University, and co-author of the essay 'Serotonin and Depression: A Disconnect Between the Advertisements and the Scientific Literature' (PLoS Med, 2005; 12: 1211-6).

The psychiatric bible, The Diagnostic and Statistical Manual of Mental Disorders, which lists the definitions of all psychiatric diagnoses, does not list serotonin as a cause of any mental disorder, while the American Psychiatric Press Textbook of Clinical Psychiatry (4th ed, Washington DC, American Psychiatric Press) describes serotonin deficiency as "an unconfirmed hypothesis", adding: "Additional experience has not confirmed the monoamine depletion hypothesis."

The SSRI explosion

Despite this lack of evidence, SSRI drug sales increased by 353 per cent between 1981 and 2000 (Annals of Pharmacotherapy, 2002; 36: 1375-9). It's anticipated that SSRI sales will peak in 2010 with global revenues of $14.6bn, and Japan is expected to be a major market for growth in the next couple of years, with sales anticipated to increase 52 per cent (Datamonitor).

The first blockbuster SSRI, Prozac (fluoxetine hydrochloride), was launched in 1986, and is "the most widely prescribed antidepressant medication in history", according to its manufacturer, Eli Lilly. Another SSRI, Pfizer's Zoloft (sertraline), was the 10th best-selling drug in the world in 2003, with sales of $3.4bn.

Before the SSRIs were developed, just 100 people per million were diagnosed as being depressed; today, it apparently affects 100,000 people per million (Healy, D. Let Them Eat Prozac; New York, NYU Press 2006).

The depression-serotonin hypothesis has been actively promoted by the drug companies in advertisements to doctors and the general public, and in seminars to professionals, and so successfully that it has been widely accepted as a biological fact. In the US, where drug companies are permitted to market directly to consumers, Pfizer's TV advertising for Zoloft has claimed that depression may be due to a chemical imbalance, and that "Zoloft works to correct this imbalance". In supportive literature for its SSRI, Pfizer states that "scientists believe that it (depression) could be linked with an imbalance of a chemical in the brain called serotonin".

SmithKline Beecham, the manufacturer in the US of the SSRI Paxil (paroxetene), states on its website: "Scientific evidence suggests that depression and certain anxiety disorders may be caused by a chemical imbalance in the brain. Paxil helps balance your brain's chemistry."

The depression-serotonin hypothesis is repeated constantly by SSRI manufacturers even though the FDA has sent 10 warning letters to them since 1997, while the Irish Medical Board has banned GlaxoSmithKline from claiming in its patient information that Paxil corrects a chemical imbalance. Nonetheless, it continues to repeat the claim on its website and in other countries.

Despite these occasional slaps across the wrist, manufacturers are generally allowed to continue promoting the hypothesis.

The SSRIs don't work

Not surprisingly for drugs that are based on a false hypothesis, they don't work too well. In a recent meta-analysis of 74 trials on 12 antidepressants that had been logged with the FDA, researchers from Oregon Health and Science University discovered that the manufacturers either tried to hide the fact or put a positive spin on results that suggested the drug was not helpful.

The researchers found 22 studies that had negative results were not published, while a further 11 had positive conclusions that were not warranted by the research findings. Of the published trials, 94 per cent were positive - suggesting the drug was considerably better than a placebo in treating depression - but the FDA analysis of the same trials concluded that just 51 per cent were positive (NEJM, 2008; 358: 252-60).

In a separate analysis of clinical trials of SSRIs submitted to the FDA, researchers discovered that a placebo, or sugar pill, replicated up to 80 per cent of the benefits of the drug itself, and that 57 per cent of all trials, published and unpublished, failed to demonstrate a statistically-significant difference between the drug and a placebo (US FDA, 2002; Prev Treat 5: article 23).

Other drugs and remedies for depression seem to work just as well as - if not better than - an SSRI drug, which is a further challenge to the depression-serotonin hypothesis. A Cochrane review of various antidepressants found there was no major difference in effectiveness between SSRIs and tricyclics, an older class of antidepressants that were developed in the 1950s (Cochrane Database Syst Rev, 2000; CD002791).

In randomized trials, buproprion, marketed as Wellbutrin and Zyban, an antidepressant that is more commonly used today as a stop-smoking drug, and reboxetine, marketed as Edronax or Norebox, were just as effective in the treatment of depression, and yet neither interferes with serotonin levels (buproprion study: J Clin Psychiatry, 1997; 12: 532-7; reboxetine study: J Clin Psychiatry, 2000; 61: 31-8).

The herbal remedy St John's wort (Hypericum perforatum) was more effective than an SSRI in one trial involving patients with moderate to severe depression (BMJ, 2005; 330: 503), and the drug was even beaten by a placebo in another trial of patients with severe depression (JAMA, 2002; 287: 1807-14).

Exercise was just as effective a remedy against depression when it was pitted against Zoloft in a randomized trial of older patients with severe depression (Arch Intern Med, 1999; 159: 2349-56).

SSRI dangers

The FDA has issued more public warnings and black box notices - prominent announcements on the drug's literature and patient information sheets - about the dangers of SSRIs than almost any other drug family. Although the drugs come with a vast array of adverse reactions, drug regulators are especially concerned by the SSRI's potential to increase the risk of suicide.

The risk was thought to be greatest among adolescents and teenagers, but the FDA has admitted that anybody who takes an SSRI is at greater risk of committing suicide.

At an FDA drugs advisory committee meeting held in December, 2006, psychiatrist Dr David Healy told the members: "The idea that you would have a risk in one age group but not in another is just wrong."

Another psychiatrist, Dr Peter Breggin, also testified, and said: "America's drug watchdog needs to come clean because it's been approving depressants as antidepressants. 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."

Despite these very real dangers, doctors continue to prescribe SSRIs to children. In one study, researchers discovered that children as young as six years were being prescribed an SSRI, and they were 52 per cent more likely to commit suicide within the following two months. Overall a child on an SSRI was 15 times more likely to commit suicide than one not taking the drug (Arch Gen Psych, 2006; 63: 865-72).

In addition to the suicide risk, SSRIs have been linked to a wide range of other adverse reactions. Prozac alone has 242 different side effects listed, including 34 problems of the genital and urinary tract. In one review of drug reactions, "during a 10-year period Prozac was associated with more hospitalizations, deaths or other serious adverse effects reported to the FDA than any other drug in America" (Moore, T: Prescription for Disaster. New York, Dell Publishing, 1998).

The most common problems associated with SSRIs are neurological (22 per cent), psychiatric (19.5 per cent), gastrointestinal (18 per cent) and dermatological (11.4 per cent) (Drug Safety, 1999; 20: 277-87).

Every SSRI manufacturer has lawsuits pending. Forest Laboratories, which makes Lexapro (escitalopram oxalate) and Celexa (citalopram) has been involved in at least 25 active lawsuits recently, says US law firm Pogust & Braslow, and most of these involve cases of unexplained suicide or attempted suicide.



Off-label prescribing

One major cause of the enormous success of the SSRIs has been off-label prescribing by doctors - where they either prescribe to people, such as the very young, for whom proper safety trials have never been undertaken, or for problems for which it was never intended.

Although the SSRIs are labelled as antidepressants, the FDA has allowed them to be used as remedies for eight psychiatric disorders, including 'social anxiety disorder', obsessive-compulsive disorder and premenstrual dysphoric disorder.

Despite this broad definition of an antidepressant, one study discovered that 75 per cent of all prescriptions for SSRIs were off-label for treatments for which the drugs had not been approved (J Clin Psych, 2006; 67: 972-82). Lead author Dr Hua Chen from the University of Houston said the findings reveal a "significant gap" in the US drug safety system as off-label prescribing regularly exposes patients to drugs that are untested for their condition or age.

Over the years SSRIs have been prescribed for pain, insomnia, shyness, menstrual discomfort, dementia, and restless leg syndrome, and to every age group, including young children and to pregnant women, even though there is evidence to suggest that the drugs are harmful to an expectant mother and her fetus (NEJM, 1996; 335: 1010-15).

While it is not illegal for a doctor to prescribe a drug for off-label use, drug companies are not allowed to promote a drug for unapproved use, although it is known to be a widespread practice and one that has been the subject of a US House Committee hearing.

Conclusion

The SSRIs are some of the most dangerous drugs ever developed, and yet they are probably the least effective. Based on an unproven theory, they usually fare little better than placebo, which suggests that any benefit is generated by the patient himself, rather than from any chemical inter-action.

Depression can be a debilitating problem, but it's one that can be successfully resolved without the use of SSRIs. Perhaps the most important contribution that SSRIs have made to our understanding of severe depression is the power and importance of our own minds.

Bryan Hubbard