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Meta-analysis shows difference between antidepressants and placebo is only significant in severe depression

BMJ 2008; 336 doi: (Published 28 February 2008) Cite this as: BMJ 2008;336:466

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Is it time to come back to Hippocrates’ principles in the treatment of depression?

The results of the recent meta-analysis of clinical trials about antidepressants (Kirsch et al., 2008; Mayor, 2008) add to the never ending debate in the scientific and clinical community about the choice of the best treatment for depression. The importance of recognizing many factors (psychological variables, family and social context, living habits, etc…) in the etiology and treatment of many disorders could be historically represented in one of the best of Hippocrates’ pronouncement, translated in Latin as “Similia similibus curantur” or, in English, “Like is cured by like.” These Hippocrates’ considerations have been “forgotten” by part of modern medicine, especially in the mental health field.

Coming back to Hippocrates’ suggestions, we have to consider the pathology as the product of different factors and the relative treatments have to be built using the “Like is cured by like” principle. Remaining in the mental health field, if a problem is generated at a cultural, social, interpersonal, family, etc… level, perhaps the best treatment is to provide care at the same level. In fact there is a lot of possibilities to treat a psychological or psychopathological problem: working with the single patient, the couple, the family, the social context, the school, etc… but one of the leading trends of official medicine is an individual and biological (pharmacological) response.

If a problem is generated at biological, molecular, neurological level (such in a severe depression), perhaps the best choice for treatment is to consider this level, but if a person shows the problem only in some particular and selected situations and contexts (such as at work but not in the family, alone but not with people, etc…), is the bio-pharmacological approach the best treatment that respects the “Similia similibus curantur” principle? Is the bio-pharmacological reductionism (Ahn, Tewari, Poon, & Phillips, 2006; Longino, 1998) the best approach to solve psychopathological problems, such as in mild depression?

Moreover it is important to underline that bio-psychopharmacological reductionism could increase some negative effects (Hammad, Laughren, & Racoosin, 2006): in a recent study about children and adolescents, the risk of suicide attempts was 1.52 times higher after antidepressant drug treatment compared with no antidepressant drug treatment (Olfson, Marcus, & Shaffer, 2006). But the most worrying aspect of the use of drugs in mental health field is that from a longer-term perspective, the brains of teenagers are still developing, and the effects of drug use and abuse may be harmful in ways that are not yet understood (Friedman, 2006). Many criticisms about using and following to use pharmacological treatments have been expressed by the same psychiatrists (Moncrieff, 2006; Moncrieff & Cohen, 2006). For example antidepressants create, and not cure, abnormal brain states: “antidepressants are assumed to work on the specific neurobiology of depressive disorders according to a “disease-centered” model of drug action. However, little evidence supports this idea. An alternative, “drug-centered,” model suggests that psychotropic drugs create abnormal states that may coincidentally relieve symptoms.

Drug induced effects of antidepressants vary widely according to their chemical class—from sedation and cognitive impairment to mild stimulation and occasionally frank agitation. Results of clinical trials may be explained by drug-induced effects and placebo amplification. 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” (p. 961, Moncrieff & Cohen, 2006). Moreover the research on maintenance drug treatment is flawed: “If withdrawal induced adverse effects could be effectively managed, the success of drug discontinuation might be much greater than usually assumed and might outweigh the disadvantages of continued treatment” (p. 517, Moncrieff, 2006).

Is it time to come back to Hippocrates’ principles in the treatment of depression?


Ahn, A. C., Tewari, M., Poon, C. S., & Phillips, R. S. (2006). The limits of reductionism in medicine: could systems biology offer an alternative? PLoS Med, 3(6), e208.

Friedman, R. A. (2006). The changing face of teenage drug abuse-¬the trend toward prescription drugs. N Engl J Med, 354(14), 1448-1450.

Hammad, T. A., Laughren, T., & Racoosin, J. (2006). Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry, 63(3), 332-339.

Kirsch, I., Deacon, B. J., Huedo-Medina, T. B., Scoboria, A., Moore, T. J., & Johnson, B. T. (2008). Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med, 5(2), e45.

Longino, C. F., Jr. (1998). The limits of scientific medicine: paradigm strain and social policy. J Health Soc Policy, 9(4), 101-116.

Mayor, S. (2008). Meta-analysis shows difference between antidepressants and placebo is only significant in severe depression. BMJ, 336(7642), 466.

Moncrieff, J. (2006). Why is it so difficult to stop psychiatric drug treatment? It may be nothing to do with the original problem. Med Hypotheses, 67(3), 517-523.

Moncrieff, J., & Cohen, D. (2006). Do antidepressants cure or create abnormal brain states? PLoS Med, 3(7), e240.

Olfson, M., Marcus, S. C., & Shaffer, D. (2006). Antidepressant drug therapy and suicide in severely depressed children and adults: A case-control study. Arch Gen Psychiatry, 63(8), 865-872.

Competing interests: None declared

Competing interests: No competing interests

07 March 2008
Gianluca Castelnuovo
PhD, PsyD, Professor of Psychology and Researcher in Clinical Psychology
Elena Faccio, Gianpiero Turchi, Alessandro Salvini, Enrico Molinari
Istituto Auxologico Italiano IRCCS, Psychology Research Laboratory, 28824, Verbania