The issues of timing in antidepressant treatment are of great theoretical and practical relevance, even more so since recent meta-analyses yielded no evidence for a specific mode of action of antidepressants, which, according to the theory of delayed onset of action, is expected to emerge after 2 weeks of therapy. To address the issues of timing on a methodologically sound basis, future trials should adapt a ‘longitudinal’ rather than ‘cross-sectional’ design, standardized with respect to a washout period, baseline and first 2 week assessments. With this in mind, special attention should be paid to parameters which potentially enable the identification of placebo responders, true drug responders and patients at risk of non-improvement. Results and methods of the Zurich meta-analyses may serve as a starting point for further steps in this direction.

The onset of action of antidepressant drugs was investigated on the basis of two independent multicenter, double-blind efficacy studies comparing amitriptyline (n = 120), oxaprotiline (n = 120), imipramine (n = 506) and moclobemide (n = 580) with placebo (n = 189 + 191). The samples consisted of in- and outpatients diagnosed, according to Diagnostic and Statistical Manual (DSM)-III criteria, as suffering from major depressive disorder. Measures of efficacy criteria were the Hamilton Rating Scale for Depression (HAM-D), the Hamilton Rating Scale for Anxiety (HAM-A) and the Zung Self-Rating Depression scale. By using the Sustained Relative Improvement (SRI) criterion, onset of action was determined in each individual patient as that time point in the 30 day observation period at which a 20% baseline score reduction was achieved without subsequent deterioration. Analogously, a response to treatment was defined as a 50% baseline score reduction. As expected, highly significant differences between active drugs and placebo were found with respect to the total number of improvers and responders. Significant differences between treatment modalities surfaced in the percentage rate as well as the time distribution of premature withdrawals. Yet, unexpectedly, among improvers, the time spans to onset of improvement were found to be independent of treatment modality as indicated by virtually identical cumulative percentages of improvers throughout the whole observation period. The picture was essentially the same for the HAM-A and Zung assessments, except for a significant time lag between observer- and self-ratings. In particular, our analyses revealed no evidence for a delayed onset of action under various antidepressants with large biochemical and pharmacological differences in comparison to placebo. Moreover, the early onset of improvement was highly predictive of later outcome: on average, 70% of the patients showing improvement within the first 14 days became responders. Applying survival-analytical methods, we found that differences between active treatments and placebo emerged within the first 5 days and reached a point of maximum distinction around day 14. After this time point, differences between treatment modalities remained constant until the end of the observation period. According to our data, 20–25% of the patients were, on average, ‘true’ drug responders, thus suggesting that the therapeutic qualities of antidepressants do not lie in the suppression of symptoms, but rather are related to their ability to elicit and maintain certain conditions which allow recovery in a subgroup of patients who would otherwise remain non-responders.

Is the onset of efficacy of antidepressants always delayed and which early clinical signs predict final outcome of therapy ? Our analyses show that strict response criteria produce necessarily later onset estimations rather than less strict ones. In two large-scale clinical samples we compared different estimation methods of the day of onset. Patients' direct ratings produced the earliest onset estimations. Because of the strong dependency of onset estimations on measurement methods, we argue that it is still open to debate, in which degree drug response is delayed. Concerning early clinical signs of final outcome we compared early changes of the Hamilton Rating Scale for Depression (HAM-D) items with several measures of final outcome. From the data we analyzed, there are no sufficiently precise signs of final outcome within the first 2 weeks of therapy.

Dysthymia clinical trials raise several methodological issues. The validity of the concept remains a matter of concern, as does the need for specific instruments, the difficulties in assessment of change and long-term assessments. Diagnostic criteria for inclusion should be used in a polydiagnostic approach. This paper summarises the main assessment tools and diagnostic criteria used in clinical trials on dysthymia. Severity criterion for inclusion could be a Hamilton Depression Rating Scale score (HAMD-17) between 13 and 17. The main response criteria should be a decrease of at least 50% of the total score on this scale and a final score under a predetermined limit. However, other response criteria may be useful: depression self-ratings, global assessments, general psychopathology assessments, personality and defense mechanisms, quality of life, psychosocial and functional impairment, diagnostic criteria (presence or absence) and side-effect assessment.

The understanding and classification of persistently depressed mood has undergone many changes since the term ‘dysthymia’ was first used nearly 150 years ago. Originally it was applied to both melancholia and mania; later it was applied to depressive personality. The Diagnostic and Statistical Manual (DSM)-III in 1980 and in subsequent updates classified dysthymia as a mood disorder, characterized by a frequently insidious onset and a course that is chronic and unremitting. The assessment of clinical response in the pharmacologic treatment of dysthymia has been more difficult than that for major depression. The Hamilton Rating Scale for Depression, among others, is oriented towards episodic rather than chronic states of depression. A new rating scale, the Cornell Dysthymia Rating Scale, has been developed to better assess milder symptomatology in chronically depressed patients. Early studies suggest its utility, but further validation of the scale is needed in patients with dysthymia and without major depression.

Major depression is one of the medical disorders in which quality of life instruments have most often been applied. It is important to distinguish between disease-dependent scales (ie, scales measuring the symptoms of major depression, such as the Beck Depression Inventory) and generic scales (ie, scales measuring self-reported states without reference to a specific disorder, such as the WHO well-being scale). The empirical use of generic scales for quality of life major depression has indicated that they can predict relapse and compliance. In the future, more trials comparing the different treatments with cost-effectiveness vs quality of life in major depression are required.

The joint development of the Dutch and English versions of the Quality of Life in Depression Scale (QLDS) is described. The QLDS is based on the needs model of quality of life developed by Hunt and McKenna. The scale has good reliability and internal consistency. Test-retest correlation coefficients were 0.94 and 0.87 in the United Kingdom and the Netherlands, respectively. Internal consistency alpha-coefficients were 0.95 and 0.92, respectively. The validity of the scale is highly acceptable. The QLDS was shown to correlate relatively highly with established measures of well-being, and scores obtained with the measure were related to severity of depression as assessed by the Hamilton Rating Scale for Depression. The QLDS was shown to be responsive to change in an open study with fluoxetine in 540 patients with major depression. The scale has wide applicability and has been shown to be user-friendly, both for respondents and administrators. It has been, or is in the process of being, tested for reliability and validity in the following additional countries: Australia, Austria, Belgium, Canada, Denmark, France, Germany, Italy, Morocco, Spain and the United States.

The term ‘quality of life’ has only recently been introduced to psychiatric outcome assessment. Current approaches to such assessment include the development of disease-specific quality of life instruments for psychiatric patient populations as well as the examination of generic quality of life instruments for use in psychiatric outcome studies. The current paper describes the psychiatric work with one example for a generic instrument: the short-form health survey questionnaire (SF-36). The 36 item patient-based questionnaire was developed within the Medical Outcome Study in the United States, was translated, validated and standardized in several countries and has been used in psychiatric settings. Results of epidemiological studies suggest that the SF-36 is applicable to psychiatric patients, is a psychometrically sound instrument also in this indication and yields relevant information in showing the degree of impairment in quality of life domains as experienced by psychiatric patients. The use of generic instruments in psychiatric population, such as the SF-36, might contribute to a better understanding of patients' quality of life as assessed in epidemiological studies, clinical trials and quality of care evaluations.

Obtaining a level of consensus over the definition, construction and measurement of the concept of quality of life would allow for an improved degree of standardization in the assessment of clinical intervention for people with mental health problems. One of the many benefits of this standardization would be the ability to make valid and reliable comparisons between various interventions and across different groups or settings, which is of particular interest to economists. There are, however, a host of sociocultural issues that present fundamental obstacles to the satisfactory attainment of consensus over definitions and domains of quality of life. This paper considers the arguments pertinent to each of these two alternative perspectives, the economic and the sociocultural (or anthropological), and draws out the lessons that these perspectives — despite the apparent polarity that exists between them — can offer to the improved measurement of quality of life for those with mental health problems.