Chapter 15
Psychotic Symptoms of Epilepsy
CQ 15-1

What kinds of psychosis accompany epilepsy and what are theirtreatments?
Summary(1) The majority of psychoses associated with epilepsy are interictal psychoses including alternative psychosis andpostictal psychosis.
(2) For treatment of psychosis, use antipsychotic drugs according to symptoms as for schizophrenia, and if someantiepileptic drugs are suspected to be the cause, consider dose reduction and discontinuation.
(3) A fter remission of psychotic symptoms, taper the antipsychotic agents carefully. In patients with a longduration of psychotic symptoms, taper gradually from 1‒2 months after complete remission.
(4) For postictal psychosis, administer benzodiazepine or a sedating antipsychotic drug to induce sleep during thelucid interval after seizure clustering or during the manic state just before emergence of psychotic symptoms.

Comment(1) Psychosis (psychotic disorder or psychiatric symptoms) is a state of obviously abnormal behaviors such as delusions,pronounced hallucinations with lack of insight, or disorganized languages, disorganized behavior, and catatonic
behavior. In a meta-analysis1), the frequency of psychosis associated with epilepsy was 5.6% (95% CI: 4.8‒6.4%, odds
ratio 7.8) among all patients with epilepsy, and 7% (95% CI: 4.9‒9.1%) among patients with temporal lobe epilepsy.
The frequency of interictal psychosis was 5.2% (95% CI: 3.3‒7.2%) and that of postictal psychosis was 2% (95% CI:1.2‒2.8%). Preictal psychosis and ictal psychosis are rare.	  Interictal psychosis2) is delusional psychosis with strong emotional change, sometimes accompanied by first-rank
symptoms typical of schizophrenia such as feeling of being manipulated, but unlike schizophrenia, emotions arepreserved.	  Alternative psychosis2) is a subtype of interictal psychosis with various emotional symptoms and delusions occurring
when seizures are controlled. The EEG often shows forced normalization (paradoxical normalization), but EEG
examination is not a requisite for the diagnosis. Alternative psychosis sometimes occurs when seizures disappear
following epilepsy surgery3).	  Postictal psychosis2) occurs after seizure clustering (rarely after a single seizure). After a lucid interval of 24 to 48
hours, visual hallucination, auditory hallucination, or delusion occurs within one week. Various hallucination-delusion
states accompanied by emotional changes last from a few days to a few weeks (usually 1‒2 weeks).
(2) For the treatment of psychosis, antipsychotic agents are used as for schizophrenia4). Many antiepileptic drugs induce
hepatic metabolic enzymes and attenuate the effects of antipsychotic agents. Therefore, high-dose antipsychotics may
be needed5). If antiepileptic drugs are suspected to have induced psychotic symptoms, consider dose reduction anddiscontinuation of the antiepileptic drugs4, 5).
(3) After remission of psychotic symptoms, reduce the doses of antipsychotic agents carefully. In patients with prolonged
psychotic symptoms, reduce doses gradually from 1‒2 months after complete remission5).
(4) During the lucid interval after seizure clustering or during the manic state, administration of benzodiazepine or asedating antipsychotic drug to induce sleep may prevent the postictal psychosis or mitigate psychotic symptoms4).

Chapter 15127▪ References
1) Clancy MJ, Clarke MC, Connor DJ, et al. The prevalence of psychosis in epilepsy; a systematic review and meta-analysis. BMC Psychiatry. 2014;
14: 75.
2) Krishnamoorthy ES, Trimble MR, Blumer D. The classification of neuropsychiatric disorders in epilepsy: a proposal by the ILAE Commission on
Psychobiology of Epilepsy. Epilepsy Behav. 2007; 10(3): 349-353.
3) González Mingot C, Gil Villar MP, Calvo Medel D, et al. Epileptic peri-ictal psychosis, a reversible cause of psychosis. Neurologia. 2013; 28(2):81-87.
4) Matsuura M, Fujiwara T, Ikeda A, et al. Diagnosis and treatment guideline for psychotic complications of adult epilepsy. Tenkan Kenkyu. 2006;
24(2): 74-77 (in Japanese).
5) Kerr MP, Mensah S, Besag F, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associatedwith epilepsy. Epilepsia. 2011; 52(11): 2133-2138.

▪ Search formula and secondary reference sourcesepilepsy [majr] AND mental disorders [majr] AND therapy [sh] Filters: Clinical Trial; Meta-Analysis; Multicenter Study; Randomized ControlledTrial; Publication
PubMed = 86128

Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 15-2

How to manage depression and suicide-related behaviors
associated with epilepsy?
Summary(1) Treat epilepsy-associated depression with individualized psychotherapy and antidepressants.
(2) The first-line antidepressants are new antidepressants such as SSRI and SNRI.
(3) A fter recovery from the first episode of depression, carefully taper and discontinue antidepressant. After
recovery from the second or subsequent depression episode, continue antidepressant even after recovery.
(4) For patients with a history of depression, when tapering antiepileptic drugs which also have mood-stabilizing
effect, carefully taper those drugs.
(5) A ntiepileptic drugs may increase suicide-related behaviors. Provide information to patients and their families
regarding the negative psychotropic effects of antiepileptic drugs. Consult with experts in mental health forhigh risk patients.

Comment(1) In a meta-analysis of epilepsy and depression1), the overall prevalence of active (current or in the past year) depression
was 23.1% (95% CI: 20.6‒28.3%), with an odds ratio of 2.77 (95% CI: 2.09‒3.67). The lifetime prevalence was
13.0% (95% CI: 5.1‒33.1%) with an odds ratio of 2.20 (95% CI: 1.07–4.51).	  Treatments include individualized supportive psychotherapy, psychoeducation, cognitive behavioral therapy(CBT), and antidepressants2). According to systematic reviews3, 4), antidepressants and CBT are effective. Especially,
CBT tailored to individual patient is useful.
(2) The first-line antidepressants are new antidepressant that are less likely to exacerbate seizures, such as a selective
serotonin reuptake inhibitor (SSRI) and serotonin‒noradrenaline reuptake inhibitor (SNRI). Start with a low dose to
reduce adverse effects and increase until the therapeutic effect appears.	  Among SSRIs, enzyme inhibitors such as fluvoxamine may increase serum concentrations of antiepileptic drugs.	  When lithium carbonate is used in combination with antiepileptic drugs, adverse effects such as seizure exacerbationand neurotoxicity may occur. Pay special attention to encephalopathy when combined with carbamazepine.
(3) For the first depression episode, continue antidepressants for around 6 months even after recovery. From the secondor subsequent depression episode, continue antidepressants for around 2 years after recovery.
(4) In patients with a history of mood disorder, carefully taper antiepileptic drugs with mood-stabilizing effect(carbamazepine, oxcarbazepine, valproate, and lamotrigine) when tapering those drugs.
(5) Provide information to patients and families regarding the negative psychotropic effect of antiepileptic drugs.
Especially, pay attention to suicidal ideation in patients with a history of mental disorders.	  In patients with a history of suicidal ideation, avoid antiepileptic drugs that induce depression. In patients with ahistory of episodic behavioral disorders, pay attention to the manifestation of depression in association with a seizurefree state, and consult a mental health expert for patients at high risk of these symptoms2).	  A systematic review reported no sufficient evidence for a significant association between antiepileptic drugs andsuicide-related behaviors5). However, expert consensus from the ILEA Task Force on Therapeutic Strategies proposed
the followings.6) (1) Although some antiepileptic drugs may induce psychiatric symptoms and lead to suicidal tendency,
its rate is very low and the actual suicidal risk is yet to be established. (2) Suicide in epilepsy is multifactorial. Even inpatients with some suicide risk factors, treatment should not be withdrawn. (3) When starting or switching antiepilepticdrugs, we (attending doctors) should tell patients to report any mode changes and suicidal ideation when they appear.
(4). In clinical trials, information on psychiatric adverse effects caused by antiepileptic drugs should be collected,
including family and past history of psychiatric disorders, past history of suicidal behaviors, and screening result using
a suicide scale.

Chapter 15129

▪ References1) Fiest KM, Dykeman J, Patten SB, et al. Depression in epilepsy: a systematic review and meta-analysis. Neurology. 2013; 80(6): 590-599.
2) Kerr MP, Mensah S, Besag F, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associatedwith epilepsy. Epilepsia. 2011; 52(11): 2133-2138.
3) Mehndiratta P, Sajatovic M. Treatments for patients with comorbid epilepsy and depression: A systematic literature review. Epilepsy Behav. 2013;
28(1): 36-40.
4) Gandy M, Sharpe L, Perry KN. Cognitive behavior therapy for depression in people with epilepsy: a systematic review. Epilepsia. 2013; 54(10):1725-1734.
5) Ferrer P, Ballarín E, Sabaté M. Antiepileptic drugs and suicide: a systematic review of adverse effects. Neuroepidemiology. 2014; 42(2): 107-120.
6) Mula M, Kanner AM, Schmitz B, et al. Antiepileptic drugs and suicidality: an expert consensus statement from the Task Force on Therapeutic
Strategies of the ILAE Commission on Neuropsychobiology. Epilepsia. 2013; 54(1): 199-203.

▪ Search formula and secondary reference sources
epilepsy AND (mental disorders OR depression OR mood OR suicide) Cochrane = 303
epilepsy [majr] AND (depress* OR suicide) Filters: Clinical Trial; Meta-Analysis; Multicenter Study; Randomized Controlled Trial; Publication
date from 2008/01/01 to 2015/12/31; English; Japanese
PubMed = 104

130Part I

The Clinical Practice Guidelines for Epilepsy 2018