Review articleTreatment-resistant depression and suicidality
Introduction
Treatment-resistant depression (TRD) is one of the biggest clinical challenges in psychiatry. Firstly, because of its high prevalence: an estimated 44% of patients do not respond to two consecutive antidepressant therapies, and an estimated 33% do not to four (Rush et al., 2006). Secondly, the remnant symptoms lead to loss of quality of life, decreases in productivity, more hospitalizations and higher health care costs (Gibson et al., 2010, Ivanova et al., 2010, Olchanski et al., 2013). Even more important, TRD is a life-threatening disorder, given the extremely high suicide risk: approximately 30% of the patients attempt suicide at least once in their life time (Dunner et al., 2006, Hantouche et al., 2010, Nelsen and Dunner, 1995). This is at least double the life time rate in non-resistant depression (estimated between 8.4% (Bernal et al., 2007) and 15.9% (Chen and Dilsaver, 1996)) and 15 times higher compared with the 1.8% in the general European population (Bernal et al., 2007, Nock et al., 2008).
Given the high suicide risk of TRD patients, it is of paramount importance to track whether specific treatments might impact suicide risk. A regular treatment for TRD is electroconvulsive therapy (ECT), whereas vagal nerve stimulation (VNS), deep brain stimulation (DBS) and ketamine have emerged as (experimental) alternatives over the last two decades. Of these, ECT and ketamine are assumed to abruptly reduce suicidality (Kellner et al., 2005, Murrough et al., 2015), whereas anecdotal reports associate DBS with suicidal ideation in neurologic patients (Foncke et al., 2006, Mahgoub and Kotbi, 2009).
Unfortunately, the literature does not offer a systematic overview of how many patients with TRD attempt or complete suicide following initiation of a treatment, let alone possible differences between treatments. Therefore, with this review we aim to 1) estimate attempted and completed suicide incidences in TRD patients irrespective of treatment and 2) estimate whether specific treatments might increase or decrease these incidences.
Section snippets
Methods
For this review, we define treatment-resistant depression as patients who failed at least two adequate antidepressant therapies (e.g. psychotherapy, antidepressants). This is based on a recent proposal by Conway et al., who defined two failed therapies as the first stage of TRD given the substantial drop in response rates after two failed treatments (Conway et al., 2017). Besides studies which have failure of at least two treatments as an inclusion criterion, we also include trials on
Results
The PubMed search came back with 3046 results, of which we could exclude 2833 on basis of the title and abstract. We inspected the full text of 213 studies, of which we had to exclude 183 for the following reasons: the article did not consider an original study (n = 5); the study did not consider TRD patients (n = 55); follow-up was less than 3 months (n = 27); the study exclusively included adolescents or elderly patients (n = 19), patients with previous suicide attempts (n = 2) or remitted
Discussion
The estimated incidences in TRD patients are 0.47 completed and 4.66 attempted suicides per 100 patient years, irrespective of which treatment is initiated. No evidence was found for systematically increased or decreased incidences in studies following DBS, VNS or ECT.
The incidences are twice and ten times the incidence found in non-resistant patients: 0.22 completed and 0.43 attempted suicides per 100 patient years (Braun et al., 2016). This confirms treatment resistance as a risk factor for
Limitations
The results suggest neither DBS nor VNS nor ECT increases or decreases suicide risk of TRD patients. However, the small number of available studies, most notably of pharmacologic agents, prevents generalization to other treatments. Moreover, the rarity of suicide and the small number of studies limited the power to detect these differences. As mentioned earlier, we had to exclude many studies which did not record or report on attempted and completed suicides. In addition, none of the studies
Conclusion
The overall suicide risk is high in treatment-resistant depressed patients, but current evidence suggest three end of the line treatments (DBS, NVS or ECT) do not differ considering suicide risk. However, the estimate of suicide risk is hampered by a surprising high number of trials not reporting on suicidality at all. Therefore, we would advise to include suicidal behavior as an explicit outcome measure in clinical trials of TRD, including the type of (attempted) suicide for identification of
Author contributions
Isidoor Bergfeld, Mariska Mantione and Damiaan Denys were involved in the design of the research question and search strategy, and drafted the manuscript; Isidoor Bergfeld acquired and analysed the data; all authors were responsible for interpretation of the acquired data and analysis, and critically revised the drafted manuscript. All authors have approved the final submitted version of the manuscript.
Declaration of interest
DD is a member of the advisory board of Lundbeck. DD and RS receive occasional fees from Medtronic for educational purposes. All other authors do not declare conflicts of interests.
Funding sources
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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