Every year around the world, we take $13bn (?‚??6.6bn)-worth of antidepressants, and more than 80 percent of those is an SSRI (serotonin selective reuptake inhibitors) such as Prozac, Paxil and Zoloft.
SSRIs are among the best-selling drugs in medicine, and their enor-mous success is based on the 'chemical imbalance theory', which proposes that people are depressed because they are low in serotonin, a brain chemical and neurotransmitter that acts on the nervous system.
An SSRI redresses such a chemical imbalance by helping to promote serotonin, 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 signalled a revolution in mental care. Suddenly, clinical and severe depression wasn't something that the sufferer just had to endure or learn to get over. Instead, here's a simple remedy to hand: a chemical to treat a chemical. As a result, we've become a 'Prozac Nation', as Eliza-beth Wurtzel's best-selling book says.
The pharmaceutical industry has been the major promoter of the depression-serotonin theory-for obvious reasons. Yet, astonishingly, the concept has never been actually proven since it was first postulated in 1967-and not because there haven't been many attempts to do so.
Given that the theory remains unproven, it's not surprising that the SSRI antidepressant is far less effective than the drug companies are claiming. In a meta-analysis of both published and unpublished trials so far, researchers found that the trials, usually funded by the drug manufacturer itself, either put an unwarranted positive spin on the results or were suppressed if the results were not positive (N Engl J Med, 2008; 358: 252-60).
What's the idea?
It's generally accepted by doctors-as well as the general public-that severe depression is the result of a chemical imbalance and, especially, low levels of the neurotransmitter serotonin in particular. 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 prob-lem could be corrected by drugs, he believed. Two years later, researchers zoned in on serotonin as the neuro-transmitter responsible (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 evi-dence to support the theory.
Researchers who analyzed the cerebrospinal fluid of clinically depressed and suicidal patients couldn't find any differences in their serotonin levels compared with healthy controls. Even participants in medical trials whose levels of serotonin were deliberately lowered failed to become depressed (Pharmaco-psychiatry, 1996; 29: 2-11). Similarly, depressed people who were given huge increases of serotonin failed to witness any improvements in 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 substantiating evi-dence isn't helped by the fact that no one 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, a PhD candidate from Florida State University and co-author (with neuroanatomy professor Dr Jonathan Leo of Lake Erie College of Osteopathic Medicine) of the essay 'Serotonin and Depression: A Disconnect Between the Advertise-ments and the Scientific Literature' (PLoS Med, 2005; 12: 1211-6).
The psychiatric 'bible', The Diag-nostic and Statistical Manual of Mental Disorders (DSM-IV; published by the American Psychiatric Associa-tion), lists the definitions of all psy-chiatric diagnoses, and does not list serotonin as a cause of any mental disorder. However, the Textbook of Clinical Psychiatry, 4th edn (Hales RE, Yudofsky SC, eds. Washington, DC: American Psychiatric Publish-ing, 2003) does describe serotonin deficiency as "an unconfirmed hypothesis", adding: "Additional experience has not confirmed the monoamine depletion hypothesis."
The SSRI explosion
Nevertheless, and despite the lack of evidence, SSRI drug sales increased by 353 percent between 1981 and 2000 (Ann Pharmacother, 2002; 36: 1375- 9). Indeed, it's even 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 over the next couple of years, with sales there anticipated to increase by 52 percent (Datamonitor; at www.marketresearch. com/search/results.asp?sid=92042647-406931770-490552493&query=ssri+future+ use+Japan&vendorid=72&publisher=Datamonitor&cmdSubmitLt=Go).
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, only 100 people per one million population were diagnosed as being depressed; today, this figure now stands at 100,000 people per million population (Healy D. Let Them Eat Prozac. New York: NYU Press, 2006).
The depression-serotonin hypoth-esis has been actively promoted by drug companies in advertisements to both doctors and the general public, and in seminars to health professionals-and so successfully that it has been widely accepted as
a physiological 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 the support literature for its SSRI, Pfizer states that "scientists believe that it (depress-ion) could be linked with an im-balance of a chemical in the brain called serotonin".
SmithKline Beecham, the manu-facturer in the US of the SSRI Paxil (paroxetine), has this to say on its website: "Scientific evidence sug-gests that depression and certain anxiety disorders may be caused by a chemical imbalance in the brain. Paxil helps balance your brain's chemistry."
The idea is repeated constantly by SSRI manufacturers, even though the US drugs regulatory body, the Food and Drug Administration (FDA), has sent out 10 warning letters to them since 1997. In fact, the Irish Medical Board has banned GlaxoSmithKline
The SSRIs don't work
Not surprisingly for drugs based on a false hypothesis, they aren't effective. In a recent meta-analysis of 74 trials involving 12 antidepressants that had been logged with the FDA, researchers from the Oregon Health and Science University discovered that the manufacturers either tried to hide the fact or put a positive spin on any results that suggested that their drug was not helpful.
As for 22 studies that had negative results, the researchers found that none of them had been published, while a further 11 reported positive conclusions that were not backed up by the research findings. Of the published trials, 94 percent were positive, suggesting that the drug was considerably better than a placebo in treating depression. Yet, the FDA's analyses of the same trials concluded that only 51 percent presented positive findings (N Engl J Med, 2008; 358: 252-60).
In a separate analysis of clinical trials involving SSRIs submitted to the FDA, researchers discovered that a placebo, or sugar pill, replicated up to 80 percent of the benefits of the so-called active agent, and that 57 per cent of all trials, published and unpublished, failed to demonstrate any statis-tically significant differences between the drug and a placebo (Prev Treat, 2002; 5: article 23; online at http://content.apa.org/journals/pre/5/1/23).
Other drugs and remedies for depression appear to work just as well as-if not better than-an SSRI drug, which serves to further challenge the depression-serotonin hypothesis. A Cochrane review of various antidepressants found that there was no major difference in effectiveness between SSRIs and tricyclics, an older class of anti-depressants that was developed in the 1950s (Cochrane Database Syst Rev, 2000; 3: CD002791).
In randomized trials, bupropion (Wellbutrin; Zyban), an antidep-ressant that is more commonly used today as a stop-smoking drug, and reboxetine (Edronax; Norebox) were found to be equally as effective as SSRIs for treating depression and, yet, neither interferes with serotonin levels (J Clin Psychiatry, 1997; 58: 532-7; J Clin Psychiatry, 2000; 61 [Suppl 10]: 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 SSRI sertraline was even bested by a placebo in another trial involving patients who were severely depressed (JAMA, 2002; 287: 1807-14).
Indeed, exercise was just as effective a remedy against depression when pitted against Zoloft in a randomized trial of older patients with severe depression (Arch Intern Med, 1999; 159: 2349-56).
The FDA has issued more public warnings and black-box notices-prominent announcements in the drug's literature and patient infor-mation sheets-regarding the dangers of SSRIs than for almost any other family of drugs. Although the drugs come with a vast array of adverse reactions, drugs regulators are especially concerned over the SSRI potential to increase the risk of suicide.
The risk was thought to be greatest among adolescents and teenagers, but the FDA has admitted that anyone 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 approv-ing 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 cor-porate 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 of age 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 kill himself than one not taking such a drug (Arch Gen Psychiatry, 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 genitourinary tract. In one review of drug reactions, it was found that "during a 10-year period, Prozac was associated with more hospital-izations, 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 seen 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 active lawsuits pending. Forest Lab-oratories, which makes Lexapro (escitalopram oxalate) and Celexa (citalopram), has been involved in at least 25 lawsuits recently, says US law firm Pogust & Braslow, and most of these involve cases of unexplained suicide or attempted suicide.
One major cause of the enormous success of the SSRIs has been off-label prescribing by doctors-where they prescribe drugs either to people, such as the very young or very old, for whom no safety trials have ever been undertaken, or for problems for which the drug has never been intended.
Although the SSRIs are labelled as antidepressants, the FDA has allowed their use as remedies for eight other psychiatric disorders, including 'social anxiety disorder', obsessive- compulsive disorder (OCD) and pre-menstrual dysphoric disorder (a severe form of PMS).
Despite such a loose definition of an antidepressant, one study found that 75 per cent of all prescriptions for SSRIs were off-label, as treat-ments for conditions for which the drugs have not been approved (J Clin Psychiatry, 2006; 67: 972-82). Lead author Dr Hua Chen, from the University of Houston, said that the findings reveal a "significant gap" in the US drugs-safety system.
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 even to preg-nant women, despite evidence that these drugs are harmful to an expectant mother as well as to her fetus (N Engl J Med, 1996; 335: 1010-5).
While it's not illegal for a doctor to prescribe a drug off-label, it is not allowed for drug companies to promote a drug for such unapproved uses, although it is known to be a widespread practice and one that has been the subject of a US House Committee hearing.
Mind over matter
The SSRIs are some of the most dangerous drugs ever developed and, yet, they are probably the least effective. Based on an hypothesis that stubbornly remains unproven, these agents usually fare little better than placebo, which suggests that any benefit while taking them is very likely being generated by the patient himself.
Depression can be debilitating, but it can be resolved without the use of these powerful, yet ineffect-ive, drugs. It may be that the most important contribution of SSRIs has been to our understanding of the power and importance of our own minds in bringing about health.
The WDDTY book Depression: Treating it Naturally is a comprehensive review of depression, including the many ways in which it can be treated without the use of SSRIs or other antidepressant drugs. The book costs ?‚??15.94, including post and packing, and is available from:
Unit 10, Woodman Works
204 Durnsford Road
London SW19 8DR.
Credit card orders can be made by telephoning 0870 444 9886. An e-book version is available from the WDDTY shop at www.wddty.com/shop/e-books .
What can cause depression?
Depression is a chronic and debilitating condition that goes far beyond feeling down or 'having the blues'. While doctors recognize that it can take various forms-such as moderate or severe, or clinical-they don't know precisely why some people become depressed, other than accepting that it can be due to a complex mix of causes. However, the one thing that is known with certainty is that the oft-repeated theory of a chemical imbalance is simplistic and not supported by any scientific evidence.
While patients' help groups often point to obvious causes of depression such as death in the family, job loss or chronic illness, WDDTY's scouring through the literature has uncovered many other, often unsuspected, causes.
- Hypothyroidism. Around one in five cases of chronic depression are believed to be due to the body producing too little thyroid hormone. One study found that women with even just mildly decreased thyroid function had three times the rate of depression compared with the average (Ann Rev Med, 1995; 30: 37-46). To check if your thyroid gland is underperforming, place a thermometer under your armpit for 10 minutes immediately upon waking in the morning. Any temperature below the normal range of 97.8-98.2 degrees F (36.6-37 degrees C) may be indicative of an underactive thyroid.
- Low blood sugar. This condition-which has the medical name of 'reactive hypoglycaemia'-is a recognized cause of depression. It can occur after compulsive snacking on sweet or starchy foods and, once these foods and carbohydrates are removed from your diet, the depression may well lift.
- Irritable bowel disease. Gastrointestinal problems are a major cause of irritability and depression. One-third of all sufferers of Crohn's disease complain of headache, eye problems and depression (South Med J, 1997; 90: 606-10).
- Coeliac disease. Depression is associated with this gastrointestinal condition, where the inner lining of the small intestine is damaged by eating wheat, rye, oats and barley.
- Allergies. One study found that a third of all depressed people also suffer from some sort of allergy such as to certain foods, or hayfever or bronchial asthma (J Affect Disord, 1981; 3: 291-6).
Do you have depression?
When considering whether or not you have depression, it's important to remember that the following symptoms should persist over time. We all feel inadequate on occasions, for example, but that doesn't necessarily indicate depression unless you feel it all the time. Having five of the symptoms from either category below could suggest moderate or severe depression.
Symptoms of mild depression
- Being bothered by things that aren't usually a problem
- Poor appetite
- Feelings of inadequacy
- Inability to concentrate
- Finding that doing things is an effort
- Fearful of the future
- Restless sleep
- Feeling people are unfriendly
- Increased irritability
- Persistently feeling 'blue'.
Symptoms of severe depression
- Getting no pleasure at all from life
- Persistent fatigue and exhaustion
- Unreasonably low self-esteem
- High anxiety levels
- Lack of interest in sex
- Poor concentration, memory loss
- Lack of motivation
- Feeling a burden to others
- Early-morning waking
- Persistent sleeping
- Fear of being alone/extreme
- Unexplained aches and pains
- Suicidal thoughts.
Treating depression without drugs
There is a range of strategies that can be adopted to help to overcome depression, depending on its severity, and they don't involve the use of toxic-or dubious-drugs such as the SSRIs.
- St John's wort (Hypericum perforatum). This herb, dubbed 'Nature's Prozac', is a proven remedy for mild-to-moderate depression, although it has also proved effective in more severe cases. In Germany, it has become the standard treatment for depression, and is even preferred over antidepressant drugs. Numerous studies have shown that the herb works. One found that 300 mg three times a day cured 75 per cent of depressed people (J Geriat Psychol Neurol, 1994; 71: 12-4). Doctors in the UK and Ireland have been opposed to the herb only because it can interfere with prescription drugs.
- Diet. Oily fish can ease depression. Tryptophan-rich foods, such as turkey, salmon and dairy, may also help, as may foods rich in vitamin B6, including soy-beans, lentils, meat, poultry, fish, fruit and brown rice. Make sure that you consume plenty of mono- or poly-unsaturated fats, and cut out caffeine and refined sugar, and eat only dark chocolate.
- Nutrition. The B-complex vitamins, including B12 and folic acid, can help with depression, as can calcium, zinc and the omega-3 essential fatty acids.
- Thought Field Therapy. The TFT technique involves finger tapping on specific acupuncture points around the body at the same time that the patient is generating a negative thought or emotion. The tapping is supposed to release the 'trapped' emotion. However dubious it may sound, the therapy has been tested in several trials, and the early results are promising.
- Cognitive behavioural therapy. This form of 'talking therapy', which is based on the idea that how we think, act and feel all interact with each other, is one of the most successful ways to treat mild-to-moderate depression. It's as effective as SSRI drugs, but without the dangerous side-effects (BMJ, 2006; 332: 1030-2).
- Exercise. Exercise can be surprisingly effective in combating depression. Even moderate exercise, which involves just walking briskly or jogging for 40 minutes, three or four times a week, can help. Those who already exercise regularly are less likely to become depressed. One study found that moderate exercise was as effective as the powerful SSRI sertraline (Zoloft) (Arch Intern Med, 1999; 159: 2349-56).