# How Much Do Benzodiazepines Matter for Electroconvulsive Therapy in Patients With Major Depression?

Lysandre Delamarre, MD,*†‡§‖ Filipe Galvao, MD,†‡§‖ Bénédicte Gohier, MD, PhD,*¶
Emmanuel Poulet, MD, PhD,†‡§‖# and Jerome Brunelin, PhD†‡§‖

**Background:** Electroconvulsive therapy (ECT) is one of the most effective treatments for major depressive disorder (MDD), especially in cases of treatment-resistant MDD. Because of their pharmacological profiles, benzodiazepines (BZDs) are suspected to decrease the efficacy of ECT. This study investigated the effect of BZDs on ECT-induced clinical outcomes and ECT course parameters in patients with MDD.

**Method:** The impact of BZDs on severity of depression (Montgomery-Asberg Depression Rating Scale scores) and on ECT course parameters (seizure threshold, clinical and electroencephalographic seizure duration) was investigated in 70 patients with MDD who received an ECT course using dose-titration method (22 received concomitant BZDs).

**Results:** Lower remission rates (52.0%) and smaller decreases in Montgomery-Asberg Depression Rating Scale scores were observed in the non-BZD group than in the BZD group (81.2%, *P* = 0.02). There were no significant differences between the 2 groups regarding seizure duration and seizure threshold.

**Limitations:** This was a retrospective study. Impact of BZDs on anxiety and cognition was not assessed.

**Conclusions:** Benzodiazepines increased the clinical efficacy of ECT when delivered using dose-titration method and bitemporal stimulation. Further studies are needed to understand the interaction between BZDs and ECT on clinical outcomes.

**Key Words:** electroconvulsive therapy, benzodiazepine, depression, dose-titration method, seizure parameters

(J ECT 2019;35: 184–188)

Major depressive disorder (MDD) is a very frequent and disabling psychiatric condition with a lifetime prevalence of 10.8% in western countries.¹ In cases of severe and/or treatment-resistant MDD episodes, electroconvulsive therapy (ECT) is one of the most effective treatments available, especially in emergency situations when the condition is life-threatening.²,³ The remission rate after an ECT course exceeds 50%,⁴ and the acute clinical effects of ECT are better than those observed following pharmacological approaches in terms of intensity and of time required to observe a beneficial effect,⁵ even in cases of treatment-resistant depression.⁶

The neural mechanisms underlying the clinical effects of ECT on depressive symptoms remain unclear, but some authors have suggested that inhibitory phenomena induced by

the ECT-induced epileptic seizure may account to explain beneficial clinical effects.⁷,⁸ Among the several factors that may have a critical effect on ECT-induced clinical improvements, the quality of tonic-clonic seizure plays a key role.⁹ It has thus been suggested that every intervention that could decrease the quality of tonic-clonic seizure in terms of intensity or duration would interfere with ECT-induced beneficial clinical effects.

In line with this, it has been suggested that drugs with anti-convulsant properties, such as benzodiazepines (BZDs),¹⁰ are known to reduce seizure durations,¹¹ and increase seizure threshold (ST)¹² would affect the clinical efficacy of ECT.¹³,¹⁴ Because BZDs are commonly used in clinical settings to treat anxious comorbidity in patients with MDD,¹⁵ current recommendations from scientific societies³,⁶,¹⁶ suggest gradual reduction or discontinuation of BZDs, before the first ECT.

However, some studies revealed that BZDs had not negative impacts neither on the characteristics of seizures¹⁷,¹⁸ nor on the clinical efficacy of ECT in patients with MDD.¹⁹,²⁰ One can thus hypothesize that BZDs would have a less negative impact on the clinical outcomes of ECT than described in the literature.²¹ Facing these discrepancies between the international recommendations and some recent studies, and because numerous patients addressed for ECT are also treated by BZDs in clinical routine, we developed a current study to investigate the actual impact of BZDs on ECT-induced clinical effect and on ECT course parameters including seizure characteristics in patients with MDD.

## METHODS

### Study Design and Sample

Medical files from all the patients with MDD who have received an ECT course between December 2016 and April 2018 in our specialized ECT unit located in “Le Vinatier,” psychiatric hospital, Lyon (France) were retrospectively screened. Inclusion criteria were as follows: unipolar or bipolar MDD according to *Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition*, criteria, indication of ECT, older than 18 years, and no medical contraindication for ECT. Exclusion criteria were as follows: lack of consent, psychotic features, neurodegenerative disease, and lack of a post-ECT clinical evaluation. According to these criteria, among the 187 patients with MDD who received ECT during this period, 70 patients were included.

All patients signed an informed consent to receive ECT and received individual information folder and opposition rights to recording data. The database was approved and registered (Record Number MR-003-2017-002) by the French National Commission for Information Technology, Data Processing, and Civil Liberties (CNIL).

The clinical and sociodemographic characteristics of the patients as well as the ECT treatment-related parameters were collected and are given in the Table 1.

<footnote>From the *Department of Psychiatry and Addictology, University Hospital Center, Angers; †INSERM, U1028, and ‡CNRS, UMR5292, Lyon Neuroscience Research Center; §University Lyon, Lyon; ||Centre Hospitalier le Vinatier, Bron; ¶LPPL, EA 4638, University Angers, Angers; and #Department of Emergency Psychiatry, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.
Received for publication September 22, 2018; accepted November 29, 2018.
Reprints: Lysandre Delamarre, MD, Department of Psychiatry and Addictology, University Hospital Center, 4 rue Larrey, 49933 Angers, France (e-mail: lysandre.delamarre@gmail.com).</footnote>

<footnote>The authors have no conflicts of interest or financial disclosures to report.</footnote>

<footnote>Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.</footnote>

<footnote>DOI: 10.1097/YCT.0000000000000574</footnote>
<table><caption>TABLE 1. Clinical and Sociodemographic Characteristics of Patients With MDD Who Received ECT</caption><thead><tr><th></th><th>BZD</th><th>Non-BZD</th><th>P</th></tr></thead><tbody><tr><td>n</td><td>22 (31.4)</td><td>48 (68.6)</td><td></td></tr><tr><td>Sex</td><td>15 (68.1)</td><td>27 (56.25)</td><td>0.35</td></tr><tr><td>Age, y</td><td>60.5 (14.3)</td><td>61.5 (13.7)</td><td>0.77</td></tr><tr><td>MADRS score, mean ± SD</td><td>37 ± 7.5</td><td>35 ± 8.0</td><td>0.07</td></tr><tr><td>Anxiety (MADRS item 3 inner tension), mean ± SD</td><td>3.4 ± 1.0</td><td>3.1 ± 1.2</td><td>0.40</td></tr><tr><td>Treatment resistance (Maudsley score), mean ± SD</td><td>9.2 ± 1.3</td><td>9.2 ± 1.8</td><td>0.96</td></tr><tr><td>Type of depression</td><td></td><td></td><td>0.77</td></tr><tr><td>Unipolar</td><td>15 (68.1)</td><td>31 (64.5)</td><td></td></tr><tr><td>Bipolar</td><td>7 (31.9)</td><td>17 (35.5)</td><td></td></tr><tr><td>Anesthetic used</td><td></td><td></td><td>0.50</td></tr><tr><td>Propofol</td><td>10 (45.4)</td><td>26 (54.1)</td><td></td></tr><tr><td>Etomidate</td><td>12 (54.6)</td><td>22 (45.9)</td><td></td></tr><tr><td>Electrode placement</td><td></td><td></td><td>0.08</td></tr><tr><td>Bilateral</td><td>22 (100)</td><td>42 (87.5)</td><td></td></tr><tr><td>Unilateral</td><td>0 (0)</td><td>6 (12.5)</td><td></td></tr><tr><td>Concurrent medication</td><td></td><td></td><td></td></tr><tr><td>Antidepressants</td><td>18 (81.8)</td><td>35 (72.9)</td><td>0.42</td></tr><tr><td>SSRI</td><td>4 (18.1)</td><td>4 (8.3)</td><td>0.63</td></tr><tr><td>SNRI</td><td>6 (27.2)</td><td>13 (27)</td><td>0.65</td></tr><tr><td>Tricyclic</td><td>8 (36.3)</td><td>15 (31.2)</td><td>0.71</td></tr><tr><td>Other medication</td><td>3 (13.6)</td><td>7 (14.5)</td><td>0.66</td></tr><tr><td>Mood stabilizer nonlithium</td><td>2 (9)</td><td>8 (36.3)</td><td>0.37</td></tr><tr><td>Antipsychotic</td><td>12 (54.6)</td><td>24 (50)</td><td>0.72</td></tr><tr><td>Lithium</td><td>4 (18.1)</td><td>14 (29.1)</td><td>0.33</td></tr></tbody></table>

Severity of clinical symptoms was assessed using the MADRS; treatment resistance using the Maudsley method. The values are presented as n (%), unless otherwise indicated.

P value, continuous variables were compared using independent Student t test and categorical variables using χ² test.

Abbreviations: SNRI, serotonin-norepinephrine reuptake inhibitors; SSRI, selective serotonin reuptake inhibitors.

## Concomitant Medication

Among the 70 included patients, 22 (31.4%) received benzodiazepines as concomitant treatment (BZD group) and 48 (68.6%, non-BZD group) did not receive BZDs during the ECT course. Benzodiazepines that were prescribed were lorazepam, alprazolam, oxazepam, prazepam, or diazepam. Benzodiazepines' dose was transform into diazepam-equivalent dose.²² Patients received BZDs from 1 to 3 times a day.

Other medications including antidepressants, antipsychotics, and lithium were also collected.

## Electroconvulsive Therapy Procedures

Electroconvulsive therapy sessions were administered twice a week using the Mecta Spectrum 5000Q (Mecta Corporation). Anesthetic agents were either propofol (dose range = 1–1.5 mg/kg) or etomidate (dose range = 0.15–0.3 mg/kg). Succinylcholine (dose range = 0.5–1 mg/kg) was used as a muscle relaxant. Patients were mostly treated with bitemporal (BT) stimulation, some of them beginning switched to right unilateral (RUL) in the case of major cognitive deficits. The quality of seizure was monitored and recorded (ST, clinical and electroencephalographic [EEG] seizure duration).

## Electroconvulsive Therapy Parameters

Two frontal-mastoid EEG channels were used for EEG recording (seizure duration, ST). The ST was defined as the

minimal electrical stimulus charge (in millicoulombs) eliciting a generalized cerebral seizure lasting at least 20 seconds as measured with EEG, as described in literature.²³ The ST was individually determined with a titration schedule, during the first session. Treatment was administered at 2 times ST for BT and at 6 times ST for RUL.

The duration of clinical seizure was determined using a stop-watch; it was recorded from the termination of the inducing current when the clonic phase was thought to have completely ceased. In addition, a single channel of bifrontal EEG was recorded using the MECTA device. The psychiatrist timed the EEG seizure duration by visual inspection of the MECTA EEG printout. The pulse duration was brief (1 ms) for BT and ultrabrief (0.3 ms) for RUL stimulation.

## Clinical Evaluation

The severity of depressive symptoms was assessed by trained psychiatrists twice throughout the study period using the Montgomery-Asberg Depression Rating Scale (MADRS),²³ one time before the first ECT (baseline measure); one time after the sixth ECT session; and then every other 2 ECT sessions until treatment termination (endpoint). The total number of ECT sessions to deliver was determined by the psychiatrist according to the clinical state of patients using the MADRS.

Remission was defined as a MADRS score of less than 10,²⁵ and response as at least 50% decrease of MADRS score
from baseline when ECT course was stopped. The degree of treatment-resistance depression was assessed using the Maudsley Staging Method.²⁶

## Statistical Analysis

Statistical analyses were carried out using SPSS v.15 with a significance level set at *P* < 0.05. Baseline differences between BZD and non-BZD groups were assessed using two-tailed Student *t* test for continuous variables (eg, age, Maudsley score, MADRS score) and using χ² test for categorical variables (eg, sex, diagnosis, anesthetic, electrode placement).

Changes in clinical ratings (MADRS scores) before and after ECT course and changes in ECT parameters (number of ECT sessions, seizure parameters) were compared between groups using paired Student *t* test. χ² tests were undertaken to compare treatment number of remitters/responders between groups after ECT course.

## RESULTS

### Sample

There were no differences at baseline regarding sociodemographic and clinical (severity of depression, level of treatment resistance, severity of anxiety measured by MADRS item 3 score: inner tension) characteristics between the 2 groups (Table 1). In the BZD group, the dose of BZDs received varied from 5 to 50 mg/d (mean ± SD = 17.4 ± 14 mg).

### Impact of BZD on ECT-Induced Clinical Effects

There were a higher number of remitters (81.8% vs 52.0%, *P* = 0.017) and greater ECT-induced clinical changes measured by MADRS scores between baseline and endpoint (*P* = 0.017) in the BZD group than in the non-BZD group. There was no statistically significant difference between groups regarding MADRS scores at endpoint and regarding the number of responders per group (Table 2).

## Impact of BZD on Parameters of ECT Course

There was no significant difference between the groups regarding the number of ECT sessions received and the characteristics of seizure (ST, clinical, and EEG seizure duration) (Table 2).

## DISCUSSION

This study investigated the impact of BZDs on ECT-induced clinical outcomes and on ECT course parameters in patients with MDD.

Regarding the clinical outcomes, we found significant lower remission rates (52.0%) in the non-BZD group than in the BZD group (81.2%). Electroconvulsive therapy also induced smaller decreases in MADRS scores in patients who did not receive BZDs than in patients who received BZDs. Although the difference was not statistically significant, we also observed lower response rates and higher MADRS scores at endpoint in the non-BZD than in the BZD group. Regarding ECT course parameters, the total number of ECT treatments received and seizure characteristics (clinical and EEG seizure duration, ST) were similar between the 2 groups. However, we observed that EEG seizure duration was lower in the non-BZD (34.9 ± 10.5 s) group than in the BZD group (39.9 ± 10.4 s), although this difference did not reach statistical significance (*P* = 0.06).

Our results are consistent with other studies showing that BZDs had no impact on the clinical efficacy of ECT in patients with MDD,¹⁴,²⁷ especially when patients received BT stimulation.¹⁹ Indeed several studies reported that BZDs decrease efficacy of RUL but not of BT stimulation.¹³,¹⁴ Because, in our study, all the patients included in the BZD group received BT stimulation, we could not investigate this effect in our sample. It is important to note that most of the studies investigating the effect of BZDs on ECT-induced clinical effect used seizure duration as the main outcome measure,¹¹,¹²,²⁸⁻³⁰ establishing a direct relationship between seizure parameters and clinical efficacy of ECT. However, it has been reported that seizure duration alone was not a good marker of the clinical efficacy of ECT.³¹ In the current study, despite a significant effect of BZDs in ECT-induced

<table><caption>TABLE 2. Impact of BZDs on ECT-Induced Clinical Effects and on Parameters of ECT Course in Patients With MDD Receiving Concomitant Treatment With BZDs or Without BZDs</caption><thead><tr><th></th><th>BZD</th><th>Non-BZD</th><th>t or χ²</th><th>P</th></tr></thead><tbody><tr><td>n</td><td>22</td><td>48</td><td></td><td></td></tr><tr><td>Impact of BZD on ECT-induced clinical effects</td><td></td><td></td><td></td><td></td></tr><tr><td>MADRS score after the last ECT, mean ± SD</td><td>8.3 ± 7.2</td><td>13.0 ± 10.6</td><td>-1.85</td><td>0.07</td></tr><tr><td>Change in MADRS, mean ± SD</td><td>-28.9 ± 10.5</td><td>-21.9 ± 11.5</td><td>2.43</td><td><strong>0.02*</strong></td></tr><tr><td>No. responders</td><td>20 (90.9)</td><td>34 (70.8)</td><td>-1.87</td><td>0.06</td></tr><tr><td>No. remitters</td><td>18 (81.8)</td><td>25 (52.0)</td><td>-2.43</td><td><strong>0.02*</strong></td></tr><tr><td>Impact of BZD on ECT course parameters</td><td></td><td></td><td></td><td></td></tr><tr><td>No. ECT sessions received, mean ± SD</td><td>13.3 ± 4.3</td><td>14.4 ± 4.0</td><td>-1.01</td><td>0.31</td></tr><tr><td>ST, mean ± SD, mC</td><td>198.5 ± 152.7</td><td>179.4 ± 114.4</td><td>0.58</td><td>0.46</td></tr><tr><td>Clinical seizure duration, mean ± SD, s</td><td>28.0 ± 10.3</td><td>24.0 ± 10.0</td><td>1.53</td><td>0.13</td></tr><tr><td>EEG seizure duration, mean ± SD, s</td><td>39.9 ± 10.4</td><td>34.9 ± 10.5</td><td>1.87</td><td>0.06</td></tr></tbody></table>

Clinical symptoms were assessed before and after the last ECT session using the MADRS. The values are presented n (%) of responders (at least 50% at MADRS) and remitters (MADRS <10), unless otherwise indicated.

Bold data indicates statistically significant.

*P* value, continuous variables were compared using independent Student *t* test and categorical variables using χ² test.

mC indicates millicoulombs.
clinical effect, we observed no significant effect of BZDs on ST and seizure duration. These results contrast with some older studies reporting that BZDs increased ST¹³ but are in accordance with most recent studies reporting no effect of BZDs on ST.³² Further studies are needed to disentangle the effects of BZDs on ECT-induced clinical efficacy and on seizure parameters.

To the best of our knowledge, the current study is the first to highlight a significant beneficial effect of BZDs on ECT efficacy. To explain such a beneficial effect, one can hypothesize that BZDs, by improving anxiety, would potentiate the clinical efficacy of ECT on depression. To discern more precisely this effect, it would be interesting for future studies to assess specifically anxiety symptoms using standardized clinical rating scales.

One of the hypotheses concerning the mechanisms of action of ECT is the anticonvulsant effect of it. In this idea, another explanation for our results should be that BZDs potentiate the anticonvulsant effect of ECT. Indeed, the clinical effect of ECT has been associated with an increase in the GABA receptors uptake in cortical regions.³³ The concomitant use of GABAergic drugs such as BZDs may potentiate this GABAergic effect during ECT course.

Before any conclusion, we should acknowledge some limitations of our study. First, it is a retrospective study based on collected data. However, this methodology also allowed including a relative homogeneous, large, and naturalistic sample of patients with severe depression (n = 70, baseline MADRS >30). Second, we have used titration method to determine the ST leading to stimulate at 2× ST in BT placement and 6× ST in RUL placement. This method could mask the potential effect of BZDs on seizure duration, but it also has permitted the examination of the effects of BZDs on ST. Third, it is important to take into account the prescription of other concomitant pharmacotherapy (antidepressant, mood stabilizer, antipsychotic, and lithium),³⁴ the type of depression (bipolar, unipolar), and the type of anesthetic drugs used that also can have an influence on ECT efficacy. These factors should, however, not have influenced current results because there were no differences between the 2 groups regarding them. Finally, our study did not allow to examine cognitive adverse effects of ECT that can also be modulated by BZD.³⁵

In conclusion, this study shows that BZDs can increase ECT-induced clinical effect in patients with MDD when patients received BT ECT with titration-dose method. Those beneficial effects are not underpinned by a modulation of ECT course parameters including seizure characteristics. Thus, given our results, we suggest clinicians not to systematically stop BZDs intake before any ECT course and, to think in some cases, to introduce BZDs to increase ECT-induced clinical effects. More researches are needed to understand the interaction between BZDs and ECT on clinical outcomes.

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