epilepsy and mood disorders

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Epilepsia, 48(Suppl. 9):20–22, 2007 doi: 10.1111/j.1528-1167.2007.01395.x AES ANNUAL COURSE 2006 Epilepsy and mood disorders Andres M. Kanner Department of Neurological Sciences, Rush Medical College, Rush University Medical Center and Rush Epilepsy Center, Chicago, Illinois, U.S.A. SUMMARY Mood disorders (MD) are a frequent comorbid- ity of epilepsy with a negative impact on qual- ity of life. The higher prevalence of MD in peo- ple with epilepsy (PWE) is most likely a reflec- tion of a bidirectional relation between the two conditions, and common pathogenic mechanisms. Treatment of MD in PWE is safe with selective serotonin reuptake inhibitor (SSRIs) and serotonin- norepinephrine reuptake inhibitors (SNRIs), but nonpsychiatrists need to know when to refer these patients to a psychiatrist for further evaluation and treatment. KEY WORDS: Major depressive disorder, Bipolar disorder, Dysthymia, Anxiety disorder, Quality of life in epilepsy, Temporal lobe epilepsy, Frontal lobe epilepsy. P REVALENCE AND CLINICAL MANIFESTATIONS Mood disorders (MD) are the most frequent psychi- atric comorbidity in patients with epilepsy (PWE), with a prevalence of 20–50%; the higher prevalence rates have been typically identified in patients with poorly controlled epilepsy (Kanner, 2003). Mood disorders are a hetero- geneous family of conditions with several clinical ex- pressions each with a different course and therapeutic requirements. They can mimic the primary MD, but in a significant percentage of patients, they present with clin- ical manifestations that do not meet any of the diagnostic criteria of the primary MD listed in the Diagnostic and Sta- tistical Manual of Mental Disorders. In the early twenti- eth century, Kraepelin (1903) and then Bleuler described a MD in PWE consisting of a pleomorphic pattern of symptoms that included affective symptoms with promi- nent irritability intermixed with euphoric mood, fear, and symptoms of anxiety, as well as anergia, pain and insom- nia. Gastaut confirmed these observations. Blumer coined the term “interictal dysphoric disorder” to refer to this type of depression in epilepsy and described its chronic course with recurrent symptom-free periods that responded well to low doses of antidepressant medication (Blumer and Zielinski, 1988). Address correspondence to Andres M. Kanner, MD, Rush Epilepsy Center, Rush University Medical Center, 1653 West Congress Parkway, Chicago, IL 60612, U.S.A. E-mail: [email protected] Blackwell Publishing, Inc. C International League Against Epilepsy Major depressive episode (MDE) is the most frequent type of MD recognized by clinicians with diagnostic screening instruments available. Yet, recognition of a MDE is not sufficient, as they can occur as part of several types of MD, including major depressive disorder (e.g., recurrent MDEs), bipolar disorder, double depression (dysthymia and recurrent MDEs) and have been described in the midst of an interictal dysphoric disorder in PWE. Why should neurologists care? The different types of MD have a dif- ferent course and different therapeutic requirements. For example, in major depressive disorders the use of chronic antidepressant therapy is the treatment of choice. In bipolar disorders, antidepressant may worsen the course by facili- tating the switch to a manic or hypomanic episode and the development of a rapid cycling bipolar disorder which may be pharmacoresistant form. Thus, in these patients, antide- pressant medication should be used with extreme caution and only in combination with mood stabilizing agents. Often, MD occur concurrently with symptoms of anxi- ety and/or full blown anxiety disorders with such comor- bidity increasing the suicide risk which in PWE is already higher than in the general population. A review of 11 stud- ies found the overall suicidal rate in PWE to be five times higher than in the general population and 25 times expected in patients with complex partial seizures of temporal lobe origin (Harris & Barraclough, 1997). Jones et al. found that the lifetime average suicidal rate was 12% in PWE com- pared to 1.1–1.2% in the general population. Finally, depressive episodes can occur during the peri- ictal period only, that is, preceding and/or following the occurrence of epileptic seizures. Postictal symptoms of 20

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Epilepsia, 48(Suppl. 9):20–22, 2007doi: 10.1111/j.1528-1167.2007.01395.x

AES ANNUAL COURSE 2006

Epilepsy and mood disordersAndres M. Kanner

Department of Neurological Sciences, Rush Medical College, Rush University Medical Center and Rush EpilepsyCenter, Chicago, Illinois, U.S.A.

SUMMARYMood disorders (MD) are a frequent comorbid-ity of epilepsy with a negative impact on qual-ity of life. The higher prevalence of MD in peo-ple with epilepsy (PWE) is most likely a reflec-tion of a bidirectional relation between the twoconditions, and common pathogenic mechanisms.Treatment of MD in PWE is safe with selective

serotonin reuptake inhibitor (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), butnonpsychiatrists need to know when to refer thesepatients to a psychiatrist for further evaluation andtreatment.KEY WORDS: Major depressive disorder, Bipolardisorder, Dysthymia, Anxiety disorder, Quality oflife in epilepsy, Temporal lobe epilepsy, Frontal lobeepilepsy.

PREVALENCE AND CLINICALMANIFESTATIONS

Mood disorders (MD) are the most frequent psychi-atric comorbidity in patients with epilepsy (PWE), witha prevalence of 20–50%; the higher prevalence rates havebeen typically identified in patients with poorly controlledepilepsy (Kanner, 2003). Mood disorders are a hetero-geneous family of conditions with several clinical ex-pressions each with a different course and therapeuticrequirements. They can mimic the primary MD, but in asignificant percentage of patients, they present with clin-ical manifestations that do not meet any of the diagnosticcriteria of the primary MD listed in the Diagnostic and Sta-tistical Manual of Mental Disorders. In the early twenti-eth century, Kraepelin (1903) and then Bleuler describeda MD in PWE consisting of a pleomorphic pattern ofsymptoms that included affective symptoms with promi-nent irritability intermixed with euphoric mood, fear, andsymptoms of anxiety, as well as anergia, pain and insom-nia. Gastaut confirmed these observations. Blumer coinedthe term “interictal dysphoric disorder” to refer to this typeof depression in epilepsy and described its chronic coursewith recurrent symptom-free periods that responded wellto low doses of antidepressant medication (Blumer andZielinski, 1988).

Address correspondence to Andres M. Kanner, MD, Rush EpilepsyCenter, Rush University Medical Center, 1653 West Congress Parkway,Chicago, IL 60612, U.S.A. E-mail: [email protected]

Blackwell Publishing, Inc.C© International League Against Epilepsy

Major depressive episode (MDE) is the most frequenttype of MD recognized by clinicians with diagnosticscreening instruments available. Yet, recognition of a MDEis not sufficient, as they can occur as part of several typesof MD, including major depressive disorder (e.g., recurrentMDEs), bipolar disorder, double depression (dysthymiaand recurrent MDEs) and have been described in the midstof an interictal dysphoric disorder in PWE. Why shouldneurologists care? The different types of MD have a dif-ferent course and different therapeutic requirements. Forexample, in major depressive disorders the use of chronicantidepressant therapy is the treatment of choice. In bipolardisorders, antidepressant may worsen the course by facili-tating the switch to a manic or hypomanic episode and thedevelopment of a rapid cycling bipolar disorder which maybe pharmacoresistant form. Thus, in these patients, antide-pressant medication should be used with extreme cautionand only in combination with mood stabilizing agents.

Often, MD occur concurrently with symptoms of anxi-ety and/or full blown anxiety disorders with such comor-bidity increasing the suicide risk which in PWE is alreadyhigher than in the general population. A review of 11 stud-ies found the overall suicidal rate in PWE to be five timeshigher than in the general population and 25 times expectedin patients with complex partial seizures of temporal lobeorigin (Harris & Barraclough, 1997). Jones et al. found thatthe lifetime average suicidal rate was 12% in PWE com-pared to 1.1–1.2% in the general population.

Finally, depressive episodes can occur during the peri-ictal period only, that is, preceding and/or following theoccurrence of epileptic seizures. Postictal symptoms of

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Epilepsy and Mood Disorders

depression are relatively common. For example in a studyof 100 consecutive patients with refractory epilepsy, 43%reported a median of five symptoms following more than50% of their seizures and having a median duration of24 h (Kanner et al., 2004). These symptoms are not pre-vented by antidepressant medication.

THE IMPACT OF MD ON THE LIFEOF PWE

Five studies of patients with pharmacoresistant epilepsyconsistently demonstrated depression to be the most pow-erful predictor for each domain of health-related qualityof life, even after controlling for seizure frequency, sever-ity, and other psychosocial variables. In addition, peoplewhose depression was untreated used significantly morehealth resources of all types, independently of seizure type,and time since the last seizure. Furthermore, people withmild to moderate depression had two-fold and people withsevere depression, four-fold higher frequency of medicalvisits than nondepressed people. Also, the presence andseverity of depression was found to be a predictor of worsedisability scores, independently of duration of the seizuredisorder (Cramer et al., 2004).

THE BIDIRECTIONAL RELATIONBETWEEN MD AND EPILEPSY

Hippocrates observed that people with depressionwere likely to develop epilepsy and vice-versa. Threepopulation-based case-controlled studies confirmed theseobservations (Hesdorffer et al., 2000) and noted that peo-ple with depression had three to seven times higher risk ofdeveloping epilepsy and one study found that a prior his-tory of suicidality was associated with a five-fold greaterrisk of developing epilepsy. The existence of such relation-ship does not imply causality but rather suggests commonpathogenic mechanisms.

Common pathogenic mechanisms in MD and epilepsyinclude abnormalities of common neurotransmitter sys-tems, including serotonin (5HT), norepinephrine (NE),dopamine (DA), glutamate and gamma-amino-butyric acid(GABA). Deficits in 5HT transmission in human depres-sion are thought to be partially related to a paucity of sero-tonergic innervation in terminal areas suggested by low5HT levels in brain, plasma, and platelets and a deficit inserotonin transporter binding sites in postmortem humanbrain (Nestler et al., 2002). A deficit in the density or affin-ity of postsynaptic 5HT1A receptors has been identified inthe hippocampus and amygdala of untreated depressed pa-tients who committed suicide. In addition, impaired sero-tonergic transmission has been associated to defects in thedorsal raphe nuclei of suicide victims with major depres-sive disorders consisting of an excessive density of sero-tonergic somatodendritic impulse suppressing 5HT1A au-

toreceptors. Furthermore, 5HT, NE, and DA in MD are thetransmitter systems targeted by psychotropic drugs in themanagement of MD (Charney et al., 1998).

The role of 5HT and NE in epilepsy has been recog-nized in animal models and in humans with temporal lobeepilepsy (TLE). The role of 5HT and NE has been de-scribed in genetic epilepsy prone rats (GEPR) with itstwo strains, GEPR-3 and GEPR-9. These animals have apredisposition to sound-induced generalized tonic–clonicseizures and, particularly in GEPR-9s, a marked accel-eration of kindling (Jobe et al., 1999). Both have innateserotonergic and noradrenergic pre- and postsynaptic trans-mission deficits. Noradrenergic deficiencies in GEPRs ap-pear to result from deficient arborization of neurons arisingfrom the locus coeruleus, coupled with excessive presynap-tic suppression of NE release in the terminal fields andlack of postsynaptic compensatory up-regulation. Therealso is evidence of deficits in serotonergic arborization inthe GEPR’s brain as well as deficient postsynaptic 5HT1A-receptor density in the hippocampus. Increments of eitherNE or 5-HT transmission can prevent seizure occurrencewhile reduction has the opposite effect. For example, drugsthat interfere with the release or synthesis of NE or 5-HTexacerbate seizures in the GEPRs, including NE storagevesicle inactivators. Conversely, drugs that enhance sero-tonergic transmission, such as the selective serotonin reup-take inhibitor (SSRI) sertraline, result in a dose-dependentseizure frequency reduction in the GEPR that correlates tothe extracellular serotonergic thalamic concentration. The5-HT precursor 5-hydroxy-L-tryptophan (5-HTP) has an-ticonvulsant effects in GEPRs when combined with theSSRI, fluoxetine.

The role of monoamines in epilepsy in humans has beenidentified with the use of positron emission tomography(PET) studies in patients with TLE that targeted the 5HT1A

receptor. A reduced 5HT1A receptor binding was found inmesial temporal structures ipsilateral to the seizure focusin patients with and without hippocampal atrophy. In addi-tion a 20% binding reduction was found in the raphe anda 34% lower binding in the ipsilateral thalamic region tothe seizure focus (Toczek et al., 2003). In a separate PETstudy aimed at quantifying 5HT1A receptor binding in 14patients with TLE, decreased binding was identified in theepileptogenic hippocampus, amygdala, anterior cingulate,and lateral temporal neocortex ipsilateral to the seizure fo-cus, as well as in the contralateral hippocampi and in theraphe nuclei. Clearly, a decrease in 5HT1A binding can beidentified in both patients with TLE and primary major de-pressive disorder.

In addition changes in common structures have beenidentified including atrophy of temporal- and frontal-lobesin patients with primary major depressive and bipolar dis-orders and in PWE. These changes have been identifiedwith high-resolution MRI and volumetric measurements ofthe amygdala, hippocampus, entorhinal cortex, temporal

Epilepsia, 48(Suppl. 9):20–22, 2007doi: 10.1111/j.1528-1167.2007.01395.x

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lateral neocortex, as well as of the prefrontal, orbito-frontal, and mesial-frontal cortex, and to a lesser degree,of the thalamic nuclei and basal ganglia (Sheline, 2003).It is not surprising that PWE whose seizure foci are intemporal and frontal lobes have a higher prevalence ofMD.

TREATMENT CONSIDERATIONS

Based on the anticonvulsant effects of serotonergic andnoradrenergic agents demonstrated in animal models itwould be reasonable to infer that the use of antidepres-sant drugs are safe in PWE, a concept that has been con-trary to the common belief of many clinicians. A recentstudy suggests a “protective” effect of SSRI and serotonin-norepinephrine reuptake inhibitors (SNRI) in depressedpatients: Alper et al. compared the incidence of seizures be-tween depressed patients randomized to placebo and SSRIs(citalopram, fluoxetine, fluvoxamine), the SNRI venlafax-ine and the α2 antagonist mirtazapine in the course ofregulatory studies submitted to the Food and DrugAdministration (Alper et al., 2007). The seizure fre-quency among patients randomized to placebo was 1501.5seizures/100,000 years, while that of patients randomizedto the antidepressants was 534.8 seizures/100,000 years.Clearly depressed patients have a higher incidence ofseizures than the general population, especially in thoserandomized to placebo.

It is my opinion that the following type of MD shouldbe referred to psychiatrists from the time they are identi-fied: any major depressive disorder that fails to remit aftertwo trials with antidepressant drugs, any bipolar disorderor a psychotic depressive episode and any MD complicatedwith suicidal ideation. For patients with MDE, dysthymicdisorder or interictal dysphoric disorder, the first line oftreatment should include an SSRI that has no pharmacoki-netic interaction with AEDs, such as escitalopram or citalo-pram. If symptoms persist at maximal doses, a trial with anSNRI such as venlafaxine or duloxetine should be consid-ered. Patients who fail to respond to a second trial shouldbe referred to a psychiatrist, as they may be suffering frompharmacoresistant MD. Four antidepressants should not beused in PWE: clomipramine, maprotiline, amoxapine, andbupropion.

An important obstacle to the treatment of MD in PWE isfailure of recognition by the treating physician. To min-imize this problem, a six-item screening instrument, theneurological disorders depression inventory for epilepsy

(NDDI-E), recently was validated to screen for MDE s inPWE (Gilliam et al., 2006). It takes only 3 min to completewith score of ≥14 suggestive of a major depressive episodemandating and a more in-depth evaluation. The NDDI-Eminimizes the effects of confounding factors such as ad-verse events from antiepileptic drugs or associated cogni-tive problems.

Disclosure of Conflicts of InterestThe contributing author to this article have declared

the following conflicts of interest: Dr. Kanner has actedas a paid consultant to Glaxo-Smith-Kline, UCB, Novar-tis, Valeant Pharmaceuticals, Abbott, Shyre Laboratories,Cyberonics and Ortho McNeill. He has received researchfunding from Glaxo-Smith-Kline and Novartis.

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Blumer D, Zielinski J. (1988) Pharmacologic treatment of psychiatric dis-orders associated with epilepsy. J Epilepsy 1:135–150.

Charney DS, Berman RM, Miller HL. (1998) Treatment of depression. In:Schatzberg AF, Nemeroff CB, eds. Textbook of Psychopharmacology,Second Edition. American Psychiatric Association Press; Washing-ton, DC, pp. 705–732.

Cramer JA, Blum D, Fanning K, Reed M; Epilepsy Impact Project Group.(2004) The impact of comorbid depression on health resource utiliza-tion in a community sample of people with epilepsy. Epilepsy Behav5:337–342.

Gilliam FG, Barry JJ, Hermann BP, Meador KJ, Vahle V, Kanner AM.(2006) Rapid detection of major depression in epilepsy: a multicentrestudy. Lancet Neurol5:399–405.

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Hesdorffer DC, Hauser WA, Annegers JF, Cascino G. (2000) Major de-pression is a risk factor for seizures in older adults. Annals of Neurol-ogy 47:246–249.

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Epilepsia, 48(Suppl. 9):20–22, 2007doi: 10.1111/j.1528-1167.2007.01395.x