Chance of response to an antidepressant: what should we say to the patient?
Authors: Tilman Steinert
Journal: World Psychiatry (2018)

Talking with patients appropriately is considered as one of the key competences of psychiatrists. “I would like to prescribe you the antidepressant X against your depression. According to available evidence, it will be helpful for one in five patients of your type”. This seems to be the truth according to meta-analyses and Cochrane reviews1, 2. Numbers needed to treat (NNTs) are considered as an illustrative and rather exactly calculable result of randomized controlled trials (RCTs) and meta-analyses which can easily be understood and communicated. Still, a communication as mentioned above would sound disastrous to the patient. But, would it be ethical to withhold this information, although the doctor is well aware of it? The World Health Organization considers “health-related education and information” as an “underlying determinant of health”3. Most developed countries provide detailed legal frameworks on the duty of physicians to inform patients comprehensively on suggested treatments, and failure to do so might entail legal consequences. Within the last decades, patient's rights have been increasingly strengthened in many countries, and jurisdiction has outlined explicitly in how much detail patients must be informed. Ethically, the respect for patient's autonomy requires informed consent for all medical procedures. On the other hand, the ethical principles of “beneficence” and “non-maleficence” demand that physicians should do what is helpful for their patients and avoid what might have negative consequences without further benefit4. Giving hope is one of the most powerful instruments of doctors, and that applies particularly to depression, a condition in which hopelessness is a key symptom5. The role of unspecific factors in the treatment of depression is indicated by the high placebo response in drug trials. On average, 36% of patients receiving placebo reached the defined “response” criterion in antidepressant trials after the year 2000, whilst the corresponding rate under antidepressant treatment was 46%6. Analyses show that the placebo effect has even increased within past decades, possibly due to heightened expectations of clinicians and patients6. Vice versa, a higher chance and subsequent expectation to receive a placebo in antidepressant trials decreases the placebo effect7. Hence, communications as the above mentioned that diminish or even intentionally erode expectations are likely to decrease the chance of a good outcome and thus mean harm for the patient. This poses a difficult ethical dilemma between the duty to inform the patient before obtaining informed consent and the necessity to provide the best available therapy which, in this case, includes giving hope. Help for the clinician in reconciling this dilemma comes from an unexpected source: from statistics. The basic question is whether the NNT does indeed indicate how many patients respond to a certain treatment and how many do not. This is suggested by the term and rarely questioned. However, what NNTs are and what they are not has been recently clarified7. Valid response rates are mostly unknown and difficult to determine. Actually, repeated individual cross-over testing would be required to eliminate several sources of variance and determine the real response rate. Recently, it could be demonstrated that even in mice the response rate under treatment with selective serotonin reuptake inhibitors was significantly dependent on the circumstances of the environment8. In everyday practice, key predictors of the individual response rate are in fact the “health care system” and the variable “doctor”7. And this brings us back to our initial discussion: whether an antidepressant works in the next episode is not only dependent on the results of available RCTs, but also on the circumstances under which the treatment takes place, and, least but not last, what the doctor himself says or does. RCTs are conducted under defined circumstances with the control group receiving considerable psychological attention and support through study workers. This is a common explanation for the small observed effect sizes in those studies. NNTs are an abstract measure which is based on arbitrary dichotomous definitions of “response”, “recovery” or whatsoever, calculated from the differences between drug response and placebo response in these trials under artificial conditions. Even if we assume that all patients benefit from a certain therapy to an identical degree, some of them would achieve the defined “response” or “recovery” threshold and others would not, depending on the efficacy of the therapeutic intervention and the individual baseline level. This is substantially different from interventions with dichotomous outcomes, e.g. death vs. recovery. In conditions with a dimensional character, which is the nature of most mental disorders, remission rates do not indicate individual ben efit. Therefore, NNTs are basically a statistical construct which allows us to determine easily in illustrative figures how effective an intervention is and whether one is more effective than another. But they do not at all indicate an individual likelihood of a positive outcome. Thus, the clinician's dilemma can be solved successfully: never use NNTs or response rates to explain chances and risks to patients. Tilman Steinert Department of Psychiatry and Psychotherapy, Ulm University, Ulm; Centers for Psychiatry Suedwuerttemberg, Ravensburg, Baden-Wuerttemberg, Germany