The dangers of microscopic vision in science: The example of anti-depressants
Published: Aug. 19, 2011, 11:32 a.m., Last updated: Aug. 19, 2011, 1:23 p.m.
Depression is a common and disabling illness that may occur in about 10% of the population at any time. There are lots of conflicting opinions about anti-depressants on the web and in the media. Dr John Joska of the Department of Psychiatry and Mental Health at the University of Cape Town has written an article for Quackdown addressing some of the misconceptions about these medicines.
Treatment response to SSRI’s has become confused by two main issues: the placebo effect in clinical trials, and the reports of increased rates of suicide in patients starting treatment.
Clinical depression, or major depressive disorder as it is known, is a common and disabling condition that may occur in about 10% of people at any time.
Depression causes disability; it was estimated by a World Bank Study of 1997 to be the 4th leading cause of medical disabilities. It is a toxic brain disease that can result in death. More than half of patients with severe major depression are at risk of recurrent episodes.
A large research effort has shown that there are a variety of structural, chemical and hormonal changes that occur in the brains of people with depression. What causes depression in specific cases is less obvious. A combination of genetic, psychological and social stressors are likely involved. Our limited understanding of the brain in general, and specifically of depression have hampered progress in preventing first and subsequent episodes of the disease.
Serendipity led to the 'mono-amine' theory of depression, in which it was thought that depletion of the mono-amine neurotransmitters, serotonin and noradrenaline, caused depression. Success in clinical trials in humans with classes of medications like the tricyclics and selective-serotonin re-uptake inhibitors (SSRI’s- for example fluoxetine [more commonly known by one of it's brand names, Prozac -Editor]) has led to additional related medications finding their way into the market. Treatment response to SSRI’s has become confused by two main issues: the placebo effect in clinical trials, and the reports of increased rates of suicide in patients starting treatment.
In clinical trials, depressed people are randomly allocated to receive the active medication (for example fluoxetine) or placebo (an inactive sugar pill). By their nature, these trials involve extensive clinical interviewing and follow-up, which is thought to play a part in the 'placebo response'. Study participants receiving placebo still feel included, valued and supported. These human interactive effects may account for placebo response rates of up to 50% in some trials.
Despite these issues, most studies have shown that medications like the SSRI’s outstrip placebo in improving depressive symptoms by about 25% (see for example this study by Vanessa Snow and colleagues, published in May 2000 in the Annals of Internal Medicine). Anti-depressants are highly effective treatments when appropriately used.
The risk of suicide among people starting treatment (treatment initiators) has been hotly contested. The yardstick against which this adverse outcome needs to be measured is the rate at which depressed people might have attempted suicide had they not been treated at all. All things considered, the rates of SSRI induced suicide are low, and need to be balanced against depression induced suicide. If patients are properly monitored and supported, the benefits of treatment outweigh the risks.
Efforts to better understand depression and its treatment are ongoing. Research into brain mechanisms of signalling, gene expression and neuroplasticity has revealed many new findings. New treatments are slow in coming. The anti-depressant medications are not without their issues. Side-effects such as sexual dysfunction, bleeding problems and sleep disturbance may occur in up to a third of people. Evidence-based guidelines (such as those of the Maudesley Trust or American Psychiatric Association) are at pains to point out that anti-depressants are not indicated for mild depression, that they be initiated at the lowest possible doses and that side-effects be continuously monitored. When used this way, anti-depressants are not only effective but also safe.
Despite evidence for the overall effectiveness and relative safety of anti-depressants like the SSRI’s -what you might call a macroscopic view- nay-sayers of anti-depressants remain. The most ardent of anti-SSRI protestors will usually gather up individual studies and focus on a particular aspect of the finding to bolster support for their case. This is a blinkered, microscopic view.
An example of a study used for anti-SSRI rhetoric was recently published in the Proceedings of the National Academy of Sciences (May 2011). In this study, the authors investigated the hypothesis that patients with depression produce certain inflammatory chemicals in the brain; that SSRI’s reduce the amount of chemicals in the brain; but that using anti-inflammatory medication and SSRI's together may oppose this effect.
Participants in the study were 10-week old male mice. Most had been genetically modified to examine the specific hypothesis. The anti-depressant behaviours investigated were the “tail-suspension test” and the “forced swim test”. Mice that had been given anti-inflammatories seemed to display less of these anti-depressant behaviours.
The authors proceeded to analyse data from a separate human study -the large STAR*D trial- which seemed to lend support to this idea. The authors concluded that the concomitant use of anti-inflammatory medications (such as those used in arthritis) may reduce the effectiveness of SSRI’s.
A critic of SSRIs has used this study to suggest that SSRI’s increased levels of inflammatory cytokines. [The article appeared in Solal Technology's magazine, Health Intelligence - Editor] In fact the opposite is true.
The same critic of SSRIs suggested that there is a small increased risk of developing breast and ovarian cancer through use of anti-depressants. But a close inspection of the data appears to show that the pre-clinical and clinical data are mixed in terms of showing an association between anti-depressant use and these cancers. The possibility that anti-depressants may exhibit a bi-phasic effect, whereby short-term use and/or low dose antidepressants may increase the risk of breast and ovarian cancer, needs further investigation. In practice, if anti-depressants are appropriately used for moderate to severe cases of depression, then normal doses for longer periods would be the norm and these effects would be minimised or absent. This work has been brought into question by allegations of conflict of interest. Researchers with industry affiliations were significantly less likely than researchers without those ties to conclude that anti-depressants increase the risk of breast or ovarian cancer. These biases must be investigated and independent analyses performed. The findings have implications in light of the 2009 USPSTF guidelines for breast cancer screening and for the informed consent process.
Other negative reports concerning SSRI’s have revolved around their effect on coronary heart disease (CHD) and sudden cardiac death (SCD). In the study concerned, the cohort of women without baseline CHD, depressive symptoms were associated with fatal CHD. Also, the presence of clinical depression including antidepressant use was specifically associated with SCD. The authors concluded that antidepressants were not associated with risk of CHD. Tricyclic antidepressants and SSRIs may be associated with increased risk of mortality, and SSRIs with increased risk of hemorrhagic and fatal stroke, although absolute event risks are low. These findings must be weighed against quality of life and established risks of cardiovascular disease and mortality associated with untreated depression. The confounding effect of the presence of depression in these patients could not be ruled out.
In summary, anti-depressants are effective for people suffering from moderate to severe depression -a condition independently associated with significant distress, loss of function, and in some cases, death. No prescriber is blind to the presence of clinically relevant side-effects, and the small increased risk of severe adverse events. When balanced against the potential benefits, and through informing patients about the risks, medications like the SSRI’s improve the lives of patients.
A common response to the reports of the risks of medications such as SSRI’s, is to turn to the so-called safety of natural products. Proponents of natural products, such as tryptophan, tyrosine and SAMe, do not make clear that the case for these products in fatally flawed in two ways.
First, the assumption that “natural is safe”. This is a myth and simply not true. Many natural substances, including edible ones, are toxic in small or large doses (for example, foods infected with naturally occurring bacteria, or perhaps penicillin taken by an allergic person).
Second, the use of these natural products has not been subjected to any form of scientific evaluation. By “scientific”, read “clear, comparative, controlled and regulated”. In this way, the clinical effectiveness (or not) of a product is established. Furthermore, it is through these published and controlled studies that “adverse event” data comes to light. Which might be why the makers and suppliers of natural products prefer to attack tested products and keep theirs in the dark.
Comments in chronological order (8 comments)
Michael Meadon wrote on 21 August 2011 at 9:46 a.m.:
Michael Meadon wrote on 21 August 2011 at 9:48 a.m.:
Brent Murphy wrote on 24 August 2011 at 10:36 a.m.:
Brent Murphy wrote on 26 August 2011 at 3:51 p.m.:
Brent Murphy wrote on 26 August 2011 at 3:52 p.m.: