PureInsight | April 22, 2002
Recent studies indicate that moderate-level major depression is lifted in about the same 25-30% of patients whether they are given nothing at all, a placebo, an herbal treatment (St. John’s wort) or the most commonly used drug, Zoloft (Sertaline). This is notwithstanding imaging studies that show clearly visible abnormalities in the brains of patients who suffer from this illness. Maybe the most fruitful line of inquiry would be into how the patients who lifted themselves without pharmacologic intervention did so.
In a study published in the April 10, 2002, issue of the Journal of the American Medical Association, members of the Hypericum Depression Trial Study Group, coordinated from Duke University, reported that an extract of an herb widely held by Western supporters of herbal remedies to be effective against depression was no more effective than a placebo in a double-blind study in patients with moderately severe major depression (1). The extract came from a plant called St. John’s Wort (Hypericum perforatum), which is widely available over-the-counter as the dried plant and in extracts and is frequently taken without medical consultation. On the two primary outcome measures used in the study, there were no significant differences in improvement of the patients whether they were given the plant extract, a placebo, or Zoloft (Pfizer Inc. brand name of sertaline), a standard treatment for this level of depression, used in this study as an “active” or positive control. The average statistical estimate of the change in score (and 95% confidence limits) on the Hamilton Depression scale was -9.2 (-10.5 to -7.9) for patients who were given a placebo, -8.7 (-10.0 to -7.4) for patients given the hypericum extract, and -10.5 (-11.9 to -9.1) for patients who took Zoloft. The more negative the number, the greater the improvement. The confidence limits for these three groups overlap so there is no significant difference. The percentage of patients whose depression was completely lifted over the eight weeks of the study was 23.9% among those given the extract from St. John’s Wort, 24.8% among those given Zoloft, and 31.9% among those given the placebo. Again, statistical analysis shows that the three groups are not significantly different from each other. Patients who got Zoloft had more side effects than those who took hypericum extract, compared to the placebo-administered group.
But this is not so surprising, since the previous studies that reported an effect of hypericum extract on depression were concerned with mild, not moderate, depression [for an example, see (2)] and also showed fewer side effects from the plant extract than from conventional drugs. Of interest, though, is that the placebo effect, from just administering pills that look like the ones with the test agents, in this study in which neither patient nor the person who gave the patient the pill knew what was in it, was comparable to the effects of both “active” agents in the study. The magnitude of the placebo effect in this study is comparable to the average value, 29.7% (standard deviation of 8.3%), reported in an analysis of 75 published trials of medications for major depressive disorder (MDD) that were published between January 1981 and December 2000 (3). These investigators, from the College of Physicians and Surgeons of Columbia University, conclude that the response to placebo in these studies is highly variable and often substantial, and has increased significantly in recent years. One wonders how this can be. One wonders if MDD is a real clinical entity if a sugar pill can make it go away in roughly 30 % of cases, and, in a statistic that is often overlooked, it is totally relieved in about the same percentage of cases where there was no intervention at all, not even a placebo (4).
The people who suffer from MDD and the mental health professionals who try to help them certainly think it is a very real clinical entity. Furthermore, there are definite physical changes in brain structures during and after episodes of major depression that can be visualized with magnetic resonance imaging and positron emission tomography techniques (5). There seems to be increased activity in the region of the brain that is correlated with strong emotion and autonomic responses to it, such as perspiration or tachycardia, as well as dysfunction in the areas that are normally correlated with regulating emotion. So it does appear that that there are physical changes associated with the subjective and behavioral symptoms seen in MDD. What is not clear from the imaging studies is any sense of causation. Does the patient find he is losing control of his spirit and then the physical changes follow, or do the physical changes precede and bring about the psychological symptoms? Further, when the depressive episode is lifted, do the physical abnormalities disappear? Does, for example, serotonin receptor binding in regions associated with emotional stability return to normal? Are there any differences in the imaging patterns in patients who are released from depression after pharmacologic intervention versus those who recover spontaneously or after placebo treatment? In the case of the patients who completely lift themselves out of their depression without pharmacologic intervention, do they still have physiological abnormalities despite which they can now function normally? Or are they also able to reverse those as well? How is it that they are able to lift themselves out of their previous depressed state without reliance on exogenous agents? Perhaps even some of those are found to improve after administration of a pharmacologic agent do so, not because of the effects of the agent, but from the same mechanism that allows recovery in placebo or no treatment groups. Perhaps it would be wise to pay more attention to the internal states of those who are able to take responsibility for their own well-being rather than search about for more drugs to give to an already highly medicated population.
(1) Davidson Jonathan R.T. for the Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John’s Wort) in major depressive disorder, a randomized controlled trial. JAMA. 2002; 287:1807-1814.
(2) Linde K, Ramirez G, Mulrow C D, Pauls A, Weidenhammer W, Melchart D. T. Johns wort for depression—an overview and met-analysis of randomized clinical trials. BMJ. 1996; 313:253-258.
(3) Walsh B T, Seidman S N, Sysko R, Gould M. Placebo response in studies of major depression—variable, substantial, and growing. JAMA. 2002; 287:1840-1847.
(4) Hrobjartsson A, Gotzshe P C. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001; 344:1594-1602.
(5) Vastag, B. Medical news and perspectives: Decade of work shows depression is physical. JAMA. 2002; 287:1787-1788.