Our study has several unique features: a large number of subjects, reliable ratings, inclusion of patients with concomitant physical illness, no exclusion because of placebo response, low attrition rate, serum concentration measurements to control for compliance, duration of 6 months, a simple psychological treatment close to the reality of primary care, and clinical meaningful criterion for response.
Our findings challenge current guidelines2,12,13
that claim equality of effect between drug and psychological treatment in mild to moderate depression in primary care. Although the remission rate in patients given emotional support and counselling plus placebo (47%) was comparable with the intention to treat results in psychotherapy studies,2
the combination of active drug and psychological treatment yielded higher response rates.
The failure to show significant interaction between predictor and treatment variables, however, do not justify confirmative conclusions about preferred treatment. Future studies with a more equal sample size for assessing the prevalence of melancholia versus non-melancholia and first depression versus recurrent depression are needed to explore the predictive value of these variables in primary care.
Patients treated with sertraline continued to improve over the 24 week treatment period. In contrast, patients treated with mianserin showed a faster remission rate in the first 6 weeks, and in patients taking placebo a plateau of the recovery rate was seen after 12 weeks.Most guidelines are based on results from short term (for example, 6 weeks) trials despite the fact that studies on the natural course of depressive episodes suggest a duration of 12-20 weeks.14
Our findings support the recommendation of a 6 month treatment period for evaluation of treatment efficacy.
Do all drugs have equal efficacy?
The lack of superiority of mianserin over placebo in this study is of note and not easily explained. The frequency of side effects did not suggest underdosage of mianserin compared with sertraline; moreover, serum concentrations of mianserin were in the treatment range (mean 156-160 ng/ml after 8 and 24 weeks respectively). The initial difference between mianserin and sertraline was mainly explained by better initial improvement of sleep and appetite in the patients treated with mianserin. Sertraline had better effects on pessimistic thoughts and worrying, which appeared later in the course of treatment. This raises the issue of different response to treatment depending on the nature of depression. More studies are needed in primary care to clarify possible differences in response over time between drugs with different mechanisms of action and their overall significance for patients.
Sex and response to treatment
Women responded better to treatment than men, suggesting sex differences in response to treatment. More women than men seem to suffer from depression and seek treatment,15
and there are important sex differences in the phenomenology and neurobiology of psychiatric disorders and stress.13
Sex differences in the response to treatment have, however, largely been neglected in clinical trials. It may be that men seeking treatment for depression differ neurobiologically from women with depression, although this has not been assessed. The number of men in our study, however, was too small to answer this conclusively.
Methodological issues and limitations of the study
Our study was designed to be as close to real practice as possible. Accordingly, several cases of depression may have gone undetected. In retrospect, we have roughly estimated that about 0.5% of the patients seen by the participating general practitioners were enrolled. Studies based on selected general practices suggest that 4.8%-8.6% of patients seen by general practitioners have depression,3
with a detection rate about one third to one half.16
How many of those would have fitted into our inclusion and exclusion criteria is unknown. However, the mean age of our patients and the ratio of women to men and first depressive episode to recurrent depressive episode correspond to other studies of depression in primary care, suggesting that our sample is representative of the type of patients actually treated by highly qualified general practitioners.15,16
Eleven local psychiatrists were consulted by the general practitioners. We do not think this has influenced the results. Consultations occurred infrequently and were close to what is regular practice in Scandinavia (for example, uncertainty about likelihood of committing suicide, uncertainty about side effects). It is likely, however, that the possibility to consult when in doubt had increased the compliance rate of both patients and general practitioners.
We excluded patients who had been non-responsive to the study drugs in the past. From a clinical point of view this makes sense as general practitioners do not treat patients with drugs previously known not to benefit the patients. By doing so, however, we may to some degree enhance drug effects. This should, however, affect the two active drug arms equally.
None of the general practitioners was able to identify the patient-drug combinations correctly, probably owing to the few and rather insignificant side effects in this sample of patients. We therefore do not think that our findings can be explained by expectations of general practitioners of differences in effect.
Our forced titration regimen, rigorous response criteria, and the good tolerability of sertraline may have favoured the higher sertraline doses.17
The rapid upward titration is not in line with the current recommendations for sertraline, however, which claim that patients should remain on the starting dose of 50 mg for 2-4 weeks before escalation of dose is considered.17
Clinical implications and conclusions
Our results suggest that the criticism towards doubtful quality of treatment of depression in general practice is not justified, at least for trained and motivated general practitioners. The effectiveness of simple psychological treatment and active drug over 24 weeks was comparable with treatment results reported by psychiatrists and clinical psychologists, and thus offers a good alternative to the more complicated cognitive behavioural therapies in the treatment of mild to moderate depression in primary care.2
With regard to the drug of choice for general practitioners in the treatment of depression, current guidelines suggest that all drugs have equal efficacy. Our results raise several important questions for future research. Though a sedative drug with a dual mechanism of action, such as mianserin, may facilitate faster remission in some patients,18
this advantage may be transient and not sustainable over a 6 month period. This surprising finding, and the observation of sex differences in remission rates, opposite to those reported in studies conducted in specialised psychiatric settings,13
emphasise the need for more studies in general practice not only comparing simple psychological treatments with drug treatments but also drugs with different mechanism of action over an appropriate period of time.