The dangers of microscopic vision in science: The example of anti-depressants

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.

Melancholy by Jacob van Loo
Melancholy by Jacob van Loo. Source.
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.:

I must say, I found this piece incredibly disappointing. The whole point of it was to stress the importance of considering the 'macroscopic' view, i.e. the entire body of relevant scientific evidence. And yet, the only evidence the author provides for the statement, "Anti-depressants are highly effective treatments when appropriately used", is a reference to a single study. Ignoring the meta-analyses - e.g. [HTML_REMOVED]Kirch's[HTML_REMOVED] - that concluded SSRIs have no clinically significant benefits over placebo. (But see also [HTML_REMOVED]this[HTML_REMOVED]). Now, I'm not saying SSRIs are ineffective (or not) - since I don't know the literature, I don't have an opinion. But a post that commits the very error it laments - "microscopic vision" - is rather silly. As you well know, a systematic review of the evidence is higher on the hierarchy than a single study.

If there are good reasons for dismissing the negative meta-analyses then the author should have provided them. The impression not mentioning them at all leaves is that the author hasn't even heard of them - which would be worrying, to say the least.

Michael Meadon wrote on 21 August 2011 at 9:48 a.m.:

Why isn't HTML allowed?

Anyway, the links:

Marcus wrote on 22 August 2011 at 3:17 p.m.:

Michael. I’m sure the author has a very good understanding of the available evidence and simply didn’t think it necessary to cite a variety of studies to re-substantiate the efficacy of antidepressants. Citing only one study as an example might not be ideal, but since the relevant claim is in no way controversial I certainly wouldn’t call it microscopic vision.

Incidentally, even the JAMA study you cite suggests that antidepressants are effective for severe depression. I’m not that familiar with the literature in this field, but from some quick research it seems that efficacy in severe cases is well-established, but that efficacy in moderate cases is doubtful. This seems in line with the authors statement that, “Anti-depressants are highly effective treatments when appropriately used”.

Brent Murphy wrote on 24 August 2011 at 10:36 a.m.:

I must disagree with Dr Joska and Marcus regarding the effectiveness and risks of anti-depressants:

ANTIDEPRESSANTS AND CANCER: Antidepressants and Breast and Ovarian Cancer Risk: A Review of the Literature and Researchers' Financial Associations with Industry "Both the pre-clinical and clinical data are mixed in terms of showing an association between AD use and breast and ovarian cancer."

...and financial ties bias A new meta-analysis of 61 trials identified a connection in nearly 33 percent of the epidemiological and pre-clinical studies conducted between 1965 and 2010 found an association between cancer and antidepressants. And the link was stronger among women using selective serotonin reuptake inhibitors, or SSRIs. Moreover, the study found researchers with industry ties were significantly less likely than researchers without those affiliations to conclude antidepressants increase the risk of breast or ovarian cancer ”

ANTIDEPRESSANTS INCREASE DEATH AND STROKE: "Postmenopausal women taking either a tricyclic antidepressant (TCA) or a selective serotonin-reuptake inhibitor (SSRI) appear to be at increased risk for all-cause mortality, and SSRI users seem to be at increased risk for hemorrhagic and fatal stroke”

ANTIDEPRESSANTS: NO EVIDENCE OF EFFECTIVENESS: Do Antidepressants Cure or Create Abnormal Brain States? PLoS Med 3(7): e240. "Drug-induced effects of antidepressants vary widely according to their chemical class—from sedation and cognitive impairment to mild stimulation and occasionally frank agitation" "No evidence shows that antidepressants or any other drugs produce long-term elevation of mood or other effects that are particularly useful in treating depression."

Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration "Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance."

ANTIDEPRESSANTS AND WEIGHT GAIN/DIABETES Taking moderate to high daily doses of antidepressants for more than 2 years is associated with an 84% increased risk for diabetes, according to a large observational study. Weight gain might explain much of the relation between antidepressant use and diabetes, according to the study authors.

All the best

Brent Murphy - B.Pharm (Rhodes), MPS Pharmacist

Nathan Geffen wrote on 24 August 2011 at 12:26 p.m.:

There is indeed controversy about the effectiveness and safety of SSRIs.

However, Brent Murphy is with Solal Technologies, who are the company that published the Solal Technologies magazine containing the article that John Joska has criticised.

Whatever the controversies about SSRIs, the two key points about Joska's article are:

  1. The arguments put forward against them in Solal's magazine were hyperbolic at best and misrepresented the evidence.

  2. Alternative health products for depression such as those sold by Solal, are untested. They are best avoided.

Marcus wrote on 24 August 2011 at 1:09 p.m.:

Please note that there is a new post on the evidence for antidepressants on this site. That post was in part because of the concerns that Michael raised here. I recommend reading it for a more sober/relevant assessment of the evidence than that presented in Brent’s comment above.

Also see Roy Jobson’s somewhat related post on Camcheck. Jobson’s post excellently exposes the very dodgy science behind the scaremongering article published in Solal’s magazine. Brent, please do consider that some severely depressed people might stop taking antidepressants because of the dramatic over-extrapolation in that article.

Brent Murphy wrote on 26 August 2011 at 3:51 p.m.:

Dear Nathan and Marcus

1. With regards Health Intelligence's (edition 10) article Sad Facts on Happy Pills, the article was reviewed by a pharmacist (not myself). I have spoken to a few members of our board, who (myself included) agree with your points that the research should not have been reported as "FACTS", but rather possibilities. Marcus, I understand your concern. I agree that the article should not discourage the use of antidepressants in severely depressed patients. In future we will have more than one member of our board review articles. I will also become more actively involved in review myself.
Therefore we will be publishing the following statement in edition 12 (edition 11 is already in circulation so it can't appear in that):

In an article Sad Facts about Happy Pills featured in Health Intelligence 10, it was reported as “FACTS” that antidepressants cause death, brain damage and cancer. Whilst we believe it is correct that the research referred to in the article raises concerns that antidepressants may be associated with cardiac-related mortality, brain nerve damage, and ovarian and breast cancer, this research is preliminary, mostly performed on animals, and needs confirmation with larger human based data. Therefore these effects should not have been reported as “FACTS” implying certainty, but rather “CONCERNS” implying possibility. The writer also suggested that people who suffer from mood disturbances should consider stopping accepting prescriptions for antidepressants based on this evidence. The editorial board of Health Intelligence does not believe that people who are taking antidepressants should discontinue their therapy based on the possibilities mentioned in this article. Furthermore, should antidepressant therapy be discontinued or changed it should be done so under medical supervision and over a gradual weaning-off time period. It is also the opinion of our board, based on current evidence, that the risk vs. benefit ratio favours treatment of people who suffer from severe depression (as opposed to mild/moderate depression), with antidepressant medication."

2. With regards the "hyperbolic" :) claims by posters on this and CAMcheck blogs that there is NO evidence of effectiveness for the generic CAMS recommended in the antidepressant protocol listed in Health Intelligence, and that they are untested: I disagree. There is evidence. Using the amino acid S-adenosyl methionine (SAMe) mentioned in the protocol, by way of example (continued in part 2):

Brent Murphy wrote on 26 August 2011 at 3:52 p.m.:


SAMe (Natural amino acid) effectiveness for depression: S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies; Acta Neurol Scand Suppl. 1994;154:7-14.

"S-adenosyl-l-methionine (SAMe) is a naturally-occurring substance which is a major source of methyl groups in the brain. The efficacy of SAMe in treating depressive syndromes and disorders is superior with that of placebo and comparable to that of standard tricyclic antidepressants. Since SAMe is a naturally occurring compound with relatively few side-effects, it is a potentially important treatment for depression." S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl. 1994;154:15-8.

"The significant correlation between plasma SAMe levels and the degree of clinical improvement in depressed patients regardless of the type of treatment suggests that SAMe may play an important role in regulating mood."
Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women. Psychother Psychosom. 1993;59(1):34-40.

"There was a significantly greater improvement in depressive symptoms in the group treated with SAMe compared to the placebo group from day 10 of the study. Side effects were mild and transient." Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 1990 May;147(5):591-5.

"The results suggest that oral S-adenosylmethionine is a safe, effective antidepressant with few side effects and a rapid onset of action. S-Adenosylmethionine induced mania in a patient with no history of mania. S-Adenosylmethionine may be useful for patients who cannot tolerate tricyclic anti-depressants. These findings support a role for methylation in the pathophysiology of depression." Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr. 2002 Nov;76(5):1172S-6S.

"In both studies, the results of SAMe and imipramine treatment did not differ significantly for any efficacy measure. However, significantly fewer adverse events were observed in the patients treated with SAMe."

All the best

Brent Murphy – B.Pharm (Rhodes), MPs Pharmacist

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