Elsevier

Journal of Affective Disorders

Volume 235, 1 August 2018, Pages 362-367
Journal of Affective Disorders

Review article
Treatment-resistant depression and suicidality

https://doi.org/10.1016/j.jad.2018.04.016Get rights and content

Highlights

  • Attempted and completed suicide rates are high in treatment-resistant depression.

  • No differences in incidences were identified following DBS, VNS or ECT.

  • Many clinical trials do not report on suicidal behavior accurately.

Abstract

Background

Thirty percent of patients with treatment-resistant depression (TRD) attempt suicide at least once during their lifetime. However, it is unclear what the attempted and completed suicide incidences are in TRD patients after initiating a treatment, and whether specific treatments increase or decrease these incidences.

Methods

We searched PubMed systematically for studies of depressed patients who failed at least two antidepressant therapies and were followed for at least three months after initiating a treatment. We estimated attempted and completed suicide incidences using a Poisson meta-analysis. Given the lack of controlled comparisons, we used a meta-regression to estimate whether these incidences differed between treatments.

Results

We included 30 studies investigating suicidality in 32 TRD samples, undergoing deep brain stimulation (DBS, n = 9), vagal nerve stimulation (VNS, n = 9), electroconvulsive therapy (ECT, n = 5), treatment-as-usual (n = 3), capsulotomy (n = 2), cognitive behavioral therapy (n = 2), ketamine (n = 1), and epidural cortical stimulation (n = 1). The overall incidence of completed suicides was 0.47 per 100 patient years (95% CI: 0.22–1.00), and of attempted suicides 4.66 per 100 patient years (95% CI: 3.53–6.23). No differences were found in incidences following DBS, VNS or ECT.

Limitations

Suicidality is poorly recorded in many studies limiting the number of studies available.

Conclusions

The completed and attempted suicide incidences are high (0.47 and 4.66 per 100 patient years respectively), but these incidences did not differ between three end of the line treatments (DBS, VNS or ECT). Given the high suicide risk in TRD patients, clinical trials should consider suicidality as an explicit outcome measure.

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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