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Severity at Baseline Determines Drug Effect

Placebo-Drug Differences

Placebo-drug differences are generally modest for all classes of pychotropic drugs, although their onset of action is immediate [e.g., Angst and Stassen 2001; Agid et al 2003]. Differences between active compounds and placebo evolve from the very beginning of treatment, achieving over 65% of the maximal difference within the first two weeks, while differences among active compounds remain marginal throughout a typical drug trial of six weeks. There is no distinct increase in the number of patients benefitting from treatment after 3-4 weeks as postulated by the "delayed onset-of-action hypothesis". For the "average patient", response rates under active compounds are in the range of 55% while those under placebo lie around 30%.

The "Average Patient"

However, the "average patient" is rarely encountered in the treatment of psychiatric disorders and single case analyses reveal that there is a lot of between-patient variation. For example, the efficacy of antidepressants in the treatment of MDD depends essentially on the severity of depression at baseline [Figure 3], with drug-placebo differences hardly ever reaching significance in mild MDD cases. For this reason, clinical drug trials typically require a minimum baseline score of at least 15 points on the 17-item HAM-D scale at entry into study (after washout), whereas Figure 3 suggests a minimum baseline score > 18 as inclusion criterion.

⇒ For mild depression the patients' benefits from antidepressant drug treatment are marginal and rarely outweigh the burden of the drugs' side effects.

Alternative Treatments in Mild Depression

Seeing a doctor should always be the patient's first step in dealing with depression, but there are some ways patients can deal with depression on a daily basis. Though it may seem impossible, exercise is one of the best ways to deal with mild depression. In fact, several studies have reported more depressive symptoms in physically inactive individuals. Regular exercise has also been shown to protect against relapse to previous levels of depression and a 16-week exercise intervention found exercise to be as effective as antidepressants in treating older patients with depression.

References

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Severity at baseline
Fig. 3: Response to treatment under imipramine (circles, n=506), moclobemide (triangles, n=580) and placebo (squares, n=191) as a function of HAM-D17 baseline score after placebo washout. The 4-week response rates (50% baseline score reduction) are plotted along the y-axis for baseline scores 15 (HAM-D17 ≤ 15), 18 (15 < HAM-D17 ≤ 18), 21 (18 < HAM-D17 ≤ 21),… 33 (30 < HAM-D17), indicating that placebo-drug differences reach 30% for HAM-D17 baseline scores >27.
Please note: (1) placebo-drug differences rarely ever reach statistical statistical significance in mild cases (HAM-D17 ≤ 18); (2) placebo-drug differences are highly significant and largely independent of baseline scores for moderately to severely ill patients (HAM-D17 > 18).
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