Unfortunately, although we continue to diagnose and medicate people for depression, there is little science and certainly no evidence to continue to prescribe antidepressants to most individuals. There are more myths in this area than there are facts and, as a result, many people are led astray by an industry that makes huge amounts of money from people's suffering.
It is important to understand that most of what we know about the biochemistry and physiology of depression is theory and not fact. It is an hypothesis but is often presented by professionals as truth, with the connotation that these professionals know the full truth about depression. No, in fact, they do not. What we do know is that serotonin is located in the pineal gland, blood platelets, the digestive tract and the brain. Serotonin acts as a chemical messenger that transmits nerve signals between nerve cells and also causes blood vessels to narrow (3). We know that there are many other chemical messengers in the body that can have an impact on our mood and state of wellbeing.
Traditionally, it has been thought that drugs most commonly used to treat depression - the selective serotonin reuptake inhibitors (SSRIs) such as Prozac® and Zoloft® - act according to the serotonin hypothesis. This hypothesis purports that levels of serotonin in the brain determine how we feel: high levels of serotonin cause heightened happiness, while decreased levels lead to sadness. Clinical depression has been attributed to low levels of serotonin transmission in the brain (4). The serotonin transporter 5-HT is a reuptake molecule that removes serotonin, so it is thought that the SSRIs act to interfere with the action of 5-HT and therefore allow serotonin to accumulate and levels to increase (4). This theory is still strongly supported by the pharmaceutical industry (5), which even uses it to encourage people to "correct" their serotonin levels in advertising for the drugs(6).
More recently, this theory has received much criticism as neuroscience research has failed to confirm "any serotonergic lesion in any mental disorder" (6). That is, the theory is just not supported by evidence. A growing body of research disagrees with the serotonin hypothesis (6,7,8). In support of this, a Cochrane review found that tricyclic antidepressants are of the same efficacy as SSRIs (8). Since tricyclics do not impact serotonin levels, this would suggest that the serotonin hypothesis has been disproved. But someone forgot to tell the drug companies and professionals who continue to aggressively dish out these drugs.
Despite the blind acceptance of the serotonin theory, the GlaxoSmithKline website has posted: "There is no clear cut reason for depression, and a number of factors may be at play, including altered levels of chemical messengers (neurotransmitters) in the brain, such as serotonin and noradrenaline" (9). If antidepressants were a cure for depression, there would be a definite illness, with definitive symptoms and causes that the drugs are targeting. GlaxoSmithKline's statement does not support this case.
Antidepressants describe the broad range of medications prescribed to alleviate the symptoms of certain depression - and anxiety-related mood disorders and include a number of different groups of medications. These include monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and the current standard treatment group: selective serotonin reuptake inhibitors (SSRIs), which became immensely popular in the 1990s (10).
The first antidepressant that came along with a huge fanfare was Prozac®. Prozac® appeared on the market in 1988 and is still being prescribed today. It has become one of the most prescribed drugs to date (11). Prozac® is part of a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs).
The prescription of antidepressants has skyrocketed over recent decades (10). From 1996 to 2005, individuals treated with antidepressants became more likely to also receive treatment with antipsychotic medications and less likely to undergo psychotherapy - the net result is more drugs and less treatment. The percentage of the United States population using at least one psychotropic medication increased from 5.9% in 1996 to 8.1% in 2001("http://archpsyc.jamanetwork.com/article.aspx?articleid=483159" l "ref-yoa90007-5") (12).
Among the psychotropic drugs, antidepressants are the most frequently prescribed medications. The US CDC found that antidepressant use in the United States jumped nearly 400% by the 2005-2008 survey period, compared with the 1988-1994 period, with 11% of those over age 12 taking the drugs (US CDC and Prevention's National Center for Health Statistics), up from six percent in 1996 (13).
Antidepressants are now used by more than 27 million Americans, most of whom are women (14). Women are twice as likely as men to be diagnosed with major depressive disorder and up to three times more likely to be diagnosed with dysthymic disorder (15). However, despite the absence of any scientific evidence, antidepressants are increasingly being prescribed for other conditions such as hot flashes, headache, back pain, neuropathy, sleep-related conditions, anxiety spectrum disorders, eating disorders and fibromyalgia (16). Once prescribed, many people continue taking antidepressants, with more than 60% of Americans who use the drugs reporting being on them for two years or more. And about 14% of Americans taking antidepressant medication have done so for 10 years or longer. Patients who take the drugs often get them from their regular doctor rather than a so-called mental health professional.
Last year in Australia, there were 29 million prescriptions written for medications related to mental health issues. Antidepressant medications accounted for nearly 60% of these scripts, followed by anti-anxiety and antipsychotic drugs (17). This suggests that around 2.4 million Australians are using medication to deal with mental health issues.
In the United States, "The number of visits by patients for depression was 24.5 million in 2001, a 70% increase since 1987" (18). The ambiguous nature of depression has provided leeway for significant misdiagnosis. The difficulty in identifying valid cases of depressive disorder lies within its tendency to share unclear boundaries with other mental disorders and normality (19). The distinction between major depression and sadness, for instance, has become completely obscure. Previously, depression was classed as either endogenous or reactive (19). Endogenous depression was regarded as a rare biological condition, whereas reactive depression was exogenous and triggered by stressful events outside our control, such as the loss of a loved one (19).
Under the Diagnostic and Statistical Manual (DSM-III), the diagnosis of clinical depression requires the presence of at least five of the possible nine symptoms for at least two weeks. Some of these symptoms include loss of interest in usual activities, depressed mood, fatigue, insomnia and lowered appetite. Yet many of these symptoms can be seen in natural responses to stress, loss (19), illness, fatigue and poor sleep. Unfortunately, this weak criterion translates into a "low threshold for diagnosing clinical depression" (20). This suggests that there are huge risks in misdiagnosing normal emotional states as clinical illnesses. As an example, chronic fatigue is also commonly mistaken for depression due to the large overlap in symptoms. In one study involving 3,200 individuals, patients who were depressed in the beginning of the study were found to be four times more likely to be fatigued, rather than "depressed" (21). Alas, due to the reinforcing nature of depression and fatigue, diagnosis becomes difficult.
Considering the major ambiguities surrounding the concept of depression, it is not surprising that the quantity of prescriptions for antidepressant medication is so high. What is of most concern is the number of people who are taking antidepressants and exposing themselves to unnecessary risk and, in too many cases, are not taking action to resolve underlying issues.
In 2002, a group of researchers studying the "placebo effect" compared studies on those taking sugar pills (placebo) and those taking antidepressants - a group of drugs the researchers expected to be effective - and found the opposite of what they expected. The meta analysis, written by Professor Irving Kirsch, was titled "The Emperor's New Drugs: An Analysis of Antidepressant Medication Data Submitted to the U.S. Food and Drug Administration." Kirsch obtained data from the FDA and reported that antidepressants were no more effective than a placebo. However, he did state that antidepressants might have a small effect and that in severe depression the placebo did not function as well as normal while the drug did show some efficacy (22). Professor Kirsch has also published a book of the same title The Emperor's New Drugs that is well worth reading.
In a later analysis of additional data, Kirsch supported his earlier findings and reported antidepressants may be more effective than a placebo only in severe depression (23). Now with more than a dozen major meta analyses, the research continues to show there is little supporting evidence that antidepressants work when placebos appear to be just as, and in some case more, effective. The research also shows the long term effects tend to be severe (22,23,24,25,26,27). In the majority of studies, antidepressants performed the same as inactive placebo pills.
A recent study found that a minority of antidepressant users actually fared worse than placebo users. In this study, researchers randomly assigned 156 depression patients to either take the antidepressant sertraline (Zoloft® and other brands) daily for 16 weeks or be in a placebo group given inactive pills. After 16 weeks, there were no overall differences in how the groups fared (28). Of the antidepressant patients, 31% were treatment "responders", meaning they had fallen below a certain score on a standard measure of depression symptoms, or had seen their score drop at least 50%. The same was true of about 28% of patients in the talk therapy group, and 24% in the placebo group. The differences among the three groups were so small as to likely be due to chance (28).
Two even bigger reviews in 2010 came to the same conclusions. A review of four meta analyses of efficacy trials submitted to the U.S. Food and Drug Administration (FDA) suggests that antidepressants are only "marginally efficacious" compared with placebo and "document profound publication bias that inflates their apparent efficacy". In addition, when the researchers analysed the largest antidepressant effectiveness trial ever conducted, they found that "the effectiveness of antidepressant therapies was probably even lower than the modest one reported... with an apparent progressively increasing dropout rate across each study phase" due to side effects (29). A review of nine studies involving 751 participants found that, from the results presented, antidepressants had only a small positive effect when compared to an active placebo (30). Other studies have also shown St John's Wort to be more effective than an SSRI (31) and exercise to be at least as effective in older patients (32).
Other irregularities were seen in the data. It was noted that published data consisted entirely of positive outcomes and that many of the negative trials' reports were not published or that negative data were displayed in a positive manner (25,26). Publication bias, where only the positive results are reported and published, is well known in the drug industry and just a part of the drug companies' everyday deception.
Despite the findings of researchers, the FDA in the U.S. reports that 94% of its studies have shown positive results, with antidepressants found to be effective in treating depression (33). However, publication of antidepressant studies by the FDA is highly selective: "The studies that the FDA judged as positive were approximately 12 times as likely to be published in a way that agreed with the FDA analysis as were studies with non-positive results according to the FDA" (Turner et al. 2008). Why have the FDA in the U.S. and Australian regulatory authorities continued to go against the scientific evidence?
The likely benefit of antidepressants is the placebo effect (23,25). In trials, the patients on placebos would see the doctor on a weekly basis for check-ups and to update the analysts for the report. In addition, the patients were within easy access to help 24 hours a day (26,34). Thus, the amount of human contact, attention and care skews the results (26). This could possibly reveal the reason the placebo had such a strong effect. Imagine the positive feeling from being closely cared for by your medical practitioner, including having his or her phone number, rather than just in and out of the office in 12 minutes. The amount of attention and care influenced the strength of the placebo. Under real-world conditions, the patient sees the doctor less frequently and is less likely to seek help (26,34).
The actual efficacy of SSRIs, therefore, remains in question and often subject to the merits and interests of those conducting a particular study. Many people drop out of drug trials because of the seriousness of side effects. The serotonin receptors are responsible for a variety of functions unrelated to mood, such as sleep, appetite and sexual function, as well as symptoms such as pain, nausea, depression, and anxiety (35). Common side effects of taking an SSRI include nausea, dizziness, gastrointestinal disturbances, anxiety, agitation, insomnia, sexual dysfunction and weight gain (35). Significant literature exists documenting the symptoms of SSRI discontinuation syndrome, which range from moderate to severe (36). There can also be more serious consequences: SSRI use has been linked to serotonin syndrome, birth defects and high risk of suicide. The link between antidepressants and suicide has been recognised for at least 20 years and the United States FDA requires that antidepressants carry a label warning of this increased risk on each box (37). In such cases it would seem antidepressants are not effective at all and, in fact, can have serious and even deadly side effects.
Despite these findings that have now been repeated many times, professionals working in the field still state that antidepressants work and continue to prescribe them to more and more people.
It is also worth pointing out that in the United States until 1990, tryptophan dietary supplements were being taken by approximately 15 million Americans. On March 22, 1990, the Food and Drug Administration (FDA) banned the sale of L-tryptophan in response to several deaths during the previous year from a deadly flu-like condition called EMS (38). This is despite L-tryptophan having been used as a supplement for decades prior to this, by a large number of people, without any adverse side effects. The problem was caused by a contaminated batch of tryptophan, not the tryptophan itself. One wonders why it was banned, as most drugs, including antidepressants, would be removed from the marketplace if this principle were applied across the board, including drugs that have been linked with hundreds of thousands of deaths.
However, on March 26, 1990, only four days after the banning of L-tryptophan, Prozac®, the wonder drug in the treatment of depression, was introduced with great fanfare after more than 10 years of development. What a coincidence. As mentioned earlier, Prozac® is an SSRI, while tryptophan actually increases the serotonin levels in the body.
Other interesting facts about this controversy:L-tryptophan was banned as a dietary supplement in the United States and Australia until 2005. It could, however, be imported from Japan and became available as a prescription-only drug. One hundred 500 mg capsules cost approximately $75.00. This is about five times more expensive than its previous cost as a dietary supplement.L-tryptophan is still used in baby food produced and sold in the United States.Farmers are still allowed to use it in stock feed for animals. I wonder if this is because happy animals are more likely to gain weight?
Dr Peter Dingle is a researcher, educator and public health advocate.
He has a PhD in the field of environmental toxicology and is not a medical doctor.
Individuals diagnosed with severe depression are urged to continue treatment as advised by their own doctor or other medical professional.
Mathers et al. 2000
Minas et al. 2007
Lacasse and Leo 2005
Geddes et al. 2005
Olfsen et al. 1998
Wrobel 2007 HYPERLINK "http://archpsyc.jamanetwork.com/article.aspx?articleid=483159" l "ref-yoa90007-5"
Olfson et al. 2009
Cosgrove et al.
American Psychiatric Association 2000
Australian Institute of Health and Welfare
Fergusson et al. 2006
Lucassen et al. 2007
Johnson and Kirsch 2008
Kirsch and Moncrieff 2005
Ioannidis et al 2008
Posternak and Zimmerman 2007
Crawford and Parker 2007
Pigott et al. 2010
Moncrieff et al. 2010
Szegedi et al. 2005
Blumenthal et al. 1999
Turner et al. 2008
Reeves and Ladner 2010
Dr Peter Dingle (PhD) has spent the past 30 years as a researcher, educator, author and advocate for a common sense approach to health and wellbeing. He has a PhD in the field of environmental toxicology and is not a medical doctor. He is Australia’s leading motivational health speaker and has 14 books in publication.