Proposed clinical practice guideline for treatment of depression in adults with epilepsy

Members of the Identification, Treatment, and Prevention Task Force of the ILAE Commission on Psychiatry have developed proposed clinical practice guidelines for the treatment of depression in adults with epilepsy. The ILAE guideline process requires obtaining feedback and comments from its members on the proposed guideline. These comments from our international community will be reviewed by the working group before finalizing the guideline.

Please see the Draft clinical practice guidelines for the treatment of depression in adults with epilepsy.

The manuscript is now closed for comments. The revised version of the manuscript is being reviewed by the ILAE and will then be submitted for publication.

Thank you for your help in this important effort of the ILAE.


3 December 2020

I have gone through the Guidelines for the management of Depression.

Please find attached the file with my opinion.

Man Mohan Mehndiratta

30 November 2020

Thank you for the effort to establish a guidance on depression in people with epilepsy, a very important and often underestimated problem. I do apprechiate the thorough methodological approach. I would like to discuss three points:

It is stated that the base line recommendation is the World Federation of Societies of BiologicalPsychiatry (WFSBP) Guidelines for BiologicalTreatment of Unipolar Depressive Disorders, Part1, 2013. These guidelines state “Depending on individual characteristics and/or patient requests, antidepressant treatment might also be indicated in mild depressive episodes, but, in many such cases, psycho- and socio therapeutic approaches alone may be sufficient.” This indicates to me that standard treatment in mild depressive episodes is preferably non-pharmacological. I wonder about the statement suggesting pharmacological therapy in mild depression equally to behavioural or psychotherapy treatment in your draft. As far as I am aware, there is no study in PwE and mild depression assessing antidepressants or even SSRIs nor head to head with behavioural or psychotherapy treatment.

Although you are referring the interictal dysphoric disorder in your text, I am missing any statement of its treatment independent on the classification issues. At least there seems to be some evidence for benefit to SSRI.

Finally, I would like to mention another study on VNS and depression in PwE (Spindler P et al., Effects of vagus nerve stimulation on symptoms of depression in patients with difficult-to-treat epilepsy. Seizure 69 (2019) 77–79) which may have been published after the cut off date in your database research. However, I my view this is very valuable information in a cohort of patients treated with VNS and all being assessed with MADRS and BDI prior and post surgery.

Tim J von Oertzen

30 November 2020

Dear colleagues,

We much appreciate the great effort to encourage epileptologists around the world to skillfully initiate antidepressant pharmacotherapy in their patients with epilepsy and to provide an excellent detailed guidance in this regard. However, we would like to point out some relevant discrepancies between the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) that forms the basis of the employed adaption process and the German guideline of the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN). These discrepancies are likely in part explained by the “primary concern” of the WFSBP guideline “with the biological treatment (including antidepressants, other psychopharmacological medications, electroconvulsive therapy, light therapy, […]) of adults.” whereas the DGPPN guideline focuses systematically on the full scope of available treatment options including psychological treatments. Consequentially, the psychological intervention summary is underdeveloped in the WSBP guideline due to the outlined limitation of the guideline’s scope:

As has been pointed out by the WFSBP guideline, national guidelines vary most in regard to the question of when to use of antidepressants in mild depression. Both DGPPN and WFSBP reference meta-analyses concluding insufficient evidence of clinically meaningful superiority of antidepressants to placebo in adults with mild depression alone (Fournier et al., 2010; Kirsch et al., 2008). Trials in PWE and depression are inconclusive in this regard as they do not differentiate treatment outcome according to severity of depressive symptoms at baseline. In summary, there seems to be insufficient evidence of the efficacy of antidepressants alone in PWE and mild depression. Of course, antidepressants can be used after individualized consideration based on expert opinion. But it does not seem valid to frame the recommendation of antidepressants in PWE with mild depression as evidence-based as is suggested by “WFSBP = 1; ILAE = B”. In fact, the WFSBP recommendation grade 1 is an overall recommendation for four separate recommendations addressing mild, moderate and severe depression, incorrectly suggesting that there is the same level of evidence for all three clinical scenarios.

The DGPPN guideline references several meta-analysis that conclude similar efficacy of SSRIs and CBT in patients with depression and therefore recommends psychotherapy OR antidepressants for the treatment of moderate depression. The WFSBP subsection on psychotherapy fails to reference any psychotherapy trials more recent than 2005 and seems to have added only more recent publications that discuss methodological challenges and biases in psychotherapy studies. In line with the evidence referenced in the DGPPN guideline, there is evidence of similar efficacy of SSRIs and CBT in PWE with depression. Therefore, the evidence suggests that psychotherapy OR antidepressants may constitute a first line treatment in moderate depression. Obviously, psychotherapy is not available in most parts of the world. Even in high income countries its availability is capable of much improvement. Of course, guidelines need to consider such contextual factors and propose recommendations that do not run the risk of resulting in under-treatment. Nonetheless, guidelines should advocate best treatment options and thus encourage policy makers to improve inadequate treatment structures.

In recent years, an increasing number of internet-based psychological intervention programs has been established in addition to the classic in person psychotherapeutic interventions. In view of decreased mobility in PWE, internet-based intervention programs may be one way of addressing this access barrier. Two trials have successfully evaluated internet-based programs that significantly decrease depressive symptoms in PWE (Deprexis and Emyna) (1,2). Deprexis is also known in the US (3).

Furthermore, we have the impression that that the expert panel of authors could share more of their epilepsy-specific expertise in regard to the diagnosis and treatment of depression in PWE:
While the severity of depression can be determined by BDI-II scores as noted in the guidance, there are other methods that could be mentioned. We wonder why the NDDI-E is not mentioned even though it is recommended for depression screening in PWE. Moreover, a diagnoses of depression may best be made by a mental health professional, e.g, by a formal in person psychiatric/ psychological assessment. The diagnosis and severity assessment should not be based on the results of a questionnaire alone but on clinical evaluation.

When dealing with the topic of depression in PWE, possible adverse effects of AEDs on psychological health must be considered. Certain commonly used AEDs such as TPM, ZNS and LEV are particularly well known for possible adverse effects on mental health (5,6,7,8). If depression is diagnosed in a PWE, the possible contribution by AEDs must be critically evaluated - especially if there is a temporal connection between the first occurrence or worsening of depressive symptoms and starting a new AED. If a connection is established, a change of AEDs needs to be considered followed by a reassessment of depressive symptoms.

DGfE, German Chapter of the ILAE


1. Schröder J, Brückner K, Fischer A, et al. Efficacy of a psychological online intervention for depression in people with epilepsy: a randomized controlled trial. Epilepsia. 2014;55(12):2069‐2076. doi:10.1111/epi.12833
2. Meyer B, Weiss M, Holtkamp M, et al. Effects of an epilepsy-specific Internet intervention (Emyna) on depression: Results of the ENCODE randomized controlled trial. Epilepsia. 2019;60(4):656-668. doi: 10.1111/epi.14673.
3. Beevers CG, Pearson R, Hoffman JS, et al. Effectiveness of an internet intervention (Deprexis) for depression in a united states adult sample: A parallel-group pragmatic randomized controlled trial. J Consult Clin Psychol. 2017;85(4):367‐380. doi:10.1037/ccp0000171
4. Gilliam FG, Barry JJ, Hermann BP, et al. Rapid detection of major depression in epilepsy: a multicentre study. Lancet. 2006;5: 399–405.
5. White JR, Walczak TS, Marino SE, et al. Zonisamide discontinuation due to psychiatric and cognitive adverse events: acase-control study. Neurology. 2010;75(6): 513-8.
6. Fritz N, Glogau S, Hoffmann J, et al. Efficacy and cognitive side effects of tiagabine and topiramate in patients with epilepsy. Epilepsy Behav. 2005;6(3): 373-81
7. Chen B, Choi H, Hirsch LJ, et al. Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy. Epilepsy Behav. 2017;76:24-31. doi: 10.1016/j.yebeh.2017.08.039.
8. Christian Hoppe C, Elger CE. Depression in epilepsy: a critical review from a clinical perspective. Nat Rev Neurol. 2011 Jul 12;7(8):462-72. doi: 10.1038/nrneurol.2011.104.

30 November 2020

We much appreciate your great effort to provide guidance to epileptologists around the world by following the demanding process of guideline development. We hope that our suggestions do not go beyond the methodological scope of this paper. However, these guidelines obviously reflect the “primary concern” of the World Federation of Societies of Biological Psychiatry “with the biological treatment (including antidepressants, other psychopharmacological medications, electroconvulsive therapy, light therapy, […]) of adults.” And while we agree that epileptologists around the world should be encouraged to diagnose and pharmacologically treat depression in their patients with epilepsy, we also think that the psychological perspective should be taken more into account:

  • A clarification between first line medications versus first line treatment needs to be made: The abstract mentions SSRIs as first choice medications. However, the abstract and the main body of the guidelines should reflect, based on the evidence presented, that the recommended first line treatment for depression includes medication and psychotherapy.
  • There is insufficient evidence that antidepressants are superior to placebo in adults with mild depression. As you have pointed out, it is not possible to differentiate treatment outcome according to severity of depressive symptoms at baseline in study participants with epilepsy and depression. Therefore, there is also insufficient evidence for the efficacy of antidepressants in adult patients with epilepsy and mild depression. Hence, we would be hesitant to frame a strong recommendations for antidepressants in mild depression as evidence-based. Of course, they can be used after individualized consideration based on formal diagnosis.
  • Since evidence exists for similar efficacy of SSRIs and CBT (not only in adults with epilepsy and depression but also in adult patients with depression alone) psychotherapy OR antidepressants may constitute a first line treatment in moderate depression. Of course, psychotherapy is not available in most parts of the world. Even in high income countries its availability is capable of much improvement. While guidelines need to consider such realities of health care professionals, they should not release policy makers of their responsibility to improve them.
  • The psychological intervention summary is underdeveloped. There is not much information presented here to provide a real “take away” for the reader. We would suggest that you add more detail to this section. This includes:
    • Psychological interventions should be mentioned as a subsection under 7.1 FIRST LINE TREATMENT and go before “other” treatments as there is more evidence for psychological interventions than the “others”.
    • The guidelines should summarize common CBT techniques used to treat depression.
    • A clear differentiation between psychoeducation and skills based psychotherapy should be made, e.g. by providing short definitions for each treatment modality.
    • The guidelines should differentiate more clearly at what stage during the treatment of depression psychoeducation (e.g. when delivering the diagnosis and as a supportive treatment in persistent mild depression) should be used and when psychotherapy should be used (e.g. for the treatment of moderate and severe depression).
    • It may be misleading to lump psychoeducation, self-management and behavioral activation behavioral treatments. It might be more comprehensive to refer to self-management and behavioral activation as “other skills-based psychological interventions”.
    • In view of these comments mentioned above it might be better to label light therapy differently and leave out the term “behavioral therapy” completely.

Apart from these comments related to the main focus of our Task Force, we have a few additional comments:

  • It should be included in the methods which professions were involved in the development of these guidelines.
  • It would be helpful if you included additional columns in Table 1:
    • Clinical trials’ definition of a depressive diagnoses e.g., SCID interview or otherwise (and the percentage of people in a mild, moderate and severe range within the trial, if available).
    • Details on adverse events or deterioration as in number of patients who deteriorated.    
  • It appears that at least one CBT trial (Gandy et al., 2014) is still included even though it met the exclusion criteria of “assessment of depressive symptoms in PWE without a diagnosis of depression”. A few trials are likely to have been excluded based on this criterion. However, these details are not included in the PRISMA Figure.
  • Figure 1 is not clear.

ILAE Psychology Task Force

30 November 2020

I felt it would be beneficial to have more outline on the effects of psychological models in Depression. It would have felt a little more holistic to includes the impact of psychotherapy and CBT. I was also wondering if it would be beneficial to outline the 'other behavioural interventions' that are mentioned in the article. There is a strong focus on the impact of pharmacotherapy, I was wondering about the impact of psychology alongside pharmacotherapy as well. I found ECT got a little more attention than psychological interventions although it is less common.


19 November 2020

Livanova Medical Affairs is pleased to see the multinational effort to create a clinical practice guideline for treatment of depression in adults with epilepsy. We agree that it is a crucial topic in epilepsy management and the availability of practical guidelines will surely improve patient care on a wide level. As manufacturer of vagus nerve stimulators (VNS) for drug-resistant epilepsy (DRE) and treatment resistant depression (TRD), we would like to provide some comments on the section of the draft on VNS that we believe will be helpful to strengthen the mission of the guidelines in improving patient care. Below you can find our observations and recommendation of how to address them.

Read full comment including images and citations

We hope that these points can contribute some additional perspectives on the VNS section. We congratulate you and the guidance committee in your effort that will have evident impact in the care for patients with epilepsy in depression

Best regards,
Maxine Dibué-Adjei
Dario Mirski

16 November 2020

The ILAE Neuropsychology Task Force welcomes clinical practice guidelines in the important area of depression in adults with epilepsy. We fully appreciate all of the work that has gone into this manuscript. Following our review of the draft we are agreed that the manuscript would be strengthened if more prominence in the text was given to the value of psychological treatments for depression in this group, particularly given the strong evidence-based recommendations of the ILAE Psychology Task Force for psychological treatments for people with epilepsy (Michaelis et al, 2018). Although acknowledged, this body of evidence deserves more prominence in this proposed guideline. Psychological vs pharmacological treatments for depression is a false dichotomy and a combination of both approaches yields optimal results in adults with depression. Clinical psychologists and neuropsychologists play important roles in the treatment of depression in this population. We feel that the clinical utility of these guidelines would also be strengthened if these roles were given more prominence in the manuscript.

Further comments from Christoph Helmstaedeter's group in Bonn:

  • Introduction: "overall prevalence" - lifetime? one year? cutoff date?
  • Results: Adherence rates in the drug treatment arms must be reported.
  • It should be stated more clearly whether or not a control condition was available and how the RRs were in the control group (data, p-values, effect sizes).
  • We would recommend to more clearly distinguish between formal psychotherapy and other behavioral interventions.
  • The authors may want to check the following studies on psychotherapeutic treatments of depression in epilepsy for appropriateness (from Elger & Hoppe 2017, Seizure; Table 1)
    • Au A, Chan F, Li K, Leung P, Li P, Chan J. Cognitive-behavioral group treatment program for adults with epilepsy in Hong Kong. Epilepsy Behav 2003;4:441–6.
    • Davis GR, Armstrong HE Jr, Donovan DM, Temkin NR. Cognitive-behavioral treatment of depressed affect among epileptics: preliminary findings. J Clin Psychol 1984;40:930-5.
    • Gillham RA. Refractory epilepsy: an evaluation of psychological methods in outpatient management. Epilepsia 1990;31:427-32.
    • Lundgren T, Dahl J, Melin L, Kies B. Evaluation of acceptance and commitment therapy for drug refractory epilepsy: a randomized controlled trial in South Africa--a pilot study. Epilepsia 2006;47:2173-9.
    • Lundgren T, Dahl J, Yardi N, Melin L. Acceptance and Commitment Therapy and yoga for drug-refractory epilepsy: a randomized controlled trial. Epilepsy Behav 2008;13:102-8.
    • Schröder J, Brückner K, Fischer A, Lindenau M, Köther U, Vettorazzi E et al. Efficacy of a psychological online intervention for depression in people with epilepsy: a randomized controlled trial. Epilepsia 2014;55:2069-76.
    • Tang V, Poon WS, Kwan P. Mindfulness-based therapy for drug-resistant epilepsy: An assessor-blinded randomized trial. Neurology 2015;85:1100-7.
    • Thompson NJ, Walker ER, Obolensky N, Winning A, Barmon C, DiIorio C, et al. Distance delivery of mindfulness-based cognitive therapy for depression: project UPLIFT. Epilepsy Behav 2010;19:247–54.
    • McLaughlin DP, McFarland K. A randomized trial of a group based cognitive behavior therapy program for older adults with epilepsy: the impact on seizure frequency, depression and psychosocial well-being. J Behav Med 2011;34:201–7.
    • Tan SY, Bruni J. Cognitive-behavior therapy with adult patients with epilepsy: a controlled outcome study. Epilepsia 1986;27:225-33.
  • The proposed classification of depression according BDI score ranges seems highly debatable. Drug treatment or psychotherapy is generally not indicated until a diagnosis has been made on the basis of internationally consented criteria for depression (which is almost impossible if BDI is below 19). Thus, the proposal in this paper is at risk to induce (drug) overtreatment. Also, "mild depression" is usually considered to be a weaker form of depression which fulfills the criteria and this is what psychotherapy is good for. Psychotherapy is usually not indicated at a BDI
  • There is a general recommendation to combine drug treatment with psychotherapy. Patients may not want to undergo psychotherapy or have difficulty to organise it but it must be offered by doctors in any case independently from severity (given a diagnosed depression fulfilling established criteria).
  • The recommendations do not adequately account for the mostly low evidence class of the drug trials and the better methodology in behavioral treatment trials. To our opinion, there is no compelling evidence for specific drug treatment guidelines in PWE and the general guidelines should be applied. In the general guidelines, however, psychotherapy has been strengthened strongly during the last decade which is not adequately reflected in the recommendations of the current manuscript.

Sallie Baxendale

14 November 2020

Timely and important guidelines, no particualr concerns I welcome them.

Hannah Cock

27 October 2020

The report recommends a referral to a psychiatrist only in the case of suicidal ideation. Clinical psychologists also conduct SI assessments and treat or refer for emergency inpatient.

Janelle Wagner