Summary of the Main Results
Antidepressants were found to be potentially useful with a high level of evidence for 15 conditions and potentially useful with a lower level of evidence for 5 others. Prescribing an AD was found to be potentially beneficial for patients with many pain conditions as well as urological, gastroenterological and gynaecological conditions. Nevertheless, while prescribing, the GP has to refer to on-label use for his own country, because unfortunately, proof of benefit is not related to "on label use". The evidence reviewed provided insufficient support for prescribing ADs for 24 other conditions. Restless legs syndrome, non-specific urinary incontinence and erectile dysfunction exposed in the "proof of no benefit" section were side effects of ADs. For rheumatologic conditions, (musculoskeletal symptoms and non-specific low back pain) the "proof of no benefit" should be interpreted with caution, due to the difficulty in assessing these patients in a primary care setting. Pain symptoms or somatoform complaints may be similar to those encountered in fibromyalgia, a clinical syndrome that lacks a clear definition and is still a subject of debate. For the other 15 conditions listed in the "No proof of benefit" section, this should be understood as "having no specific effect on the non-psychiatric condition mentioned". For example, no guidelines found ADs to have a specific effect in treating Parkinson's disease comparable to their effect in treating dementia-related agitation. Nevertheless, ADs should be prescribed in the event of a major depressive episode related to Parkinson. The same can be said for treating depression in physically ill people or those with cancer. Thus, an AD considered as having no specific benefit for a given condition may prove beneficial for certain specific PC patients. As a result, it is difficult for prescribing physicians to assess the potential benefit of using them in clinical practice in PC settings where several conditions are involved.
Strengths and Limitations of the Study
The first strength of the study was the meticulous methodology and careful step-by-step process used to extract the data. The analysis was not started from a theoretical framework, but from real daily practice in primary care, based on the qualitative material of our previous research. No previous study has assessed in that way the appropriateness of AD prescriptions for non-psychiatric conditions. This review gives a new insight on studies emphasizing misuse as an explanation for the increasing rate of AD prescription. A second strength was that it provided all GPs a clear overview of information on ADs not limited to the information and guidelines available in their own country. Finally, a third strength of the study was that it updated the guidelines with recent reviews, in order not to miss relevant information. This study, being an analysis of guidelines and systematic reviews did not focus on a single condition, population or intervention, but on a family of drug (ADs) and their indications. Thus, the nature of this analysis made it impossible to perform a systematic review fulfilling the "Prisma" statements. Another limitation of this study was the consistency of the available data. First of all, levels of evidence were not always available. When available, levels of evidence were not always consistent between the different guidelines, as was the case with diabetic painful neuropathy. Additionally, either a given AD, only certain ADs or an entire class of ADs could be considered as having a potential benefit in treating a specific condition. For example, among the SSRIs, only citalopram and sertraline were assessed in treating dementia-related agitation. Also, the optimum dosage to be used in treating a condition was not always determined, as in the case of using amitryptiline to treat migraine or neuropathic pain. Finally a limitation of our study could be that some guidelines in other languages than French and English were not selected in the search. However we used the big databases such as Medline and NGC, which already include guidelines, sometimes translated in English, from many guideline developers worldwide.
Performing a strict assessment and comparison of several conditions appeared arduous: although the subjects of the recommendations were similar, the guidelines did not refer to strictly comparable conditions. For example difficulties were encountered with fibromyalgia, chronic fatigue syndrome and rheumatologic pain, which were difficult to distinguish from one another. This lack of precision can lead to difficulties in assessing and summarizing information, and consequently in correctly understanding the potential benefit of ADs for patients. As well, the randomised trials were designed for well-defined conditions and homogeneous populations, which is rarely the case for PC patients. The inclusion criteria for the studies often involved secondary care and did not reflect primary care situations.
The limitations of available data and the wide variety of conditions made it difficult to formulate clear recommendations. In any case, the results of the study provide new insight to enable clinicians to prescribe ADs with more accuracy, and could potentially serve as a point of reference for health policy organizations in specifying prescription rules.
Consistency of GPs' Prescriptions With the Evidence
Comparing the 24 non-psychiatric health conditions for which the GPs claimed to prescribe ADs  with the results of this review study, 12 conditions were found to be based on evidence. Of the 12 other conditions for which GPs claimed a prescription of an AD, there was no scientific evidence. In our qualitative study, the GPs correctly assessed the benefit of ADs in treating pain conditions. This seems contradictory with observational studies finding that pain management could be improved in PC settings. However GPs' proper assessment of the benefit of ADs, depends on his ability to make a fine distinction between "the scientifically proven effect of an AD for a certain condition" and "the potential benefit of an AD at the right dose for a specific patient presenting with several psychiatric or non-psychiatric conditions". Besides the GP's decision is based not only on biomedical observations, but also follows a bio-psychosocial model in which patient-centeredness and the environment are taken into account. The major benefit of this study is to understand better and justify GPs' AD prescription behaviour.
Implications for Future Research
On the whole, the guideline agencies often stressed a lack of head-to-head comparative trials assessing the clinical effectiveness of the drugs, which would allow physicians to prioritise the choice of therapy for a given condition. This is impossible without any involvement from healthcare institutions. Another challenge is to better understand the way physicians prescribe ADs in actual PC settings. We currently know that GPs' decisions are shaped by a combination of diseases and psychosocial influences. The potential benefit of a prescription for a patient cannot be assessed without incorporating all of the dimensions of actual prescription. This requires a strict comparison that directly assesses the prescriptions, indications and patients' environment, based on observational cohort studies to collect data on medical conditions, psychosocial environment and prescriptions in PC settings.