S E M I N A R S I N NEUROL,OGY-VOI'UME
11, NO. 2 JUNE 1991
Depression in Patients with Epilepsy: An Overview M a y M Robertson, M.B.Ch.B., M.D., D.P.M., F.R.C.Psych.
terictal depression, the most prevalent and clinically significant syndrome.
PREVALENCE OF INTERICTAL DEPRESSION
It has long been acknowledged that epilepsy may seriously compromise a person's quality of' life,"redisposing some individuals to psychiatric illness. Depression is a serious and probably the most common psychiatric coricomitant of epilepsy, but there have been no epidemiologic studies to document the exact frequency. Nevertheless, it has been shown that some 20% of patients with ternDEPRESSION IN THE CONTEXT OF EPILEPSY poral lobe epilepsy (TLE) become moderately or ~ Victoroff et a17 reseverely d e p r e s ~ e d .Recently, A relationship between depression and epi- ported that 62% of a substantial cohort of patients lepsy has been described since the beginnings of with medically intractable complex partial seizures medical writings. Hippocrates clearly thought epi- had had a history of depression, of whom 38% met lepsy and melancholia were closely related when he rigorous criteria for major depressive illness. What stated: "Melancholics ordinarily become epileptics is important to note is that patients of any age, and epileptics melancholics: of these two states, either sex, and with diverse family and social backwhat determines the preference is the direction the grounds are vulnerable to depression in the setting malady takes; if it bears upon the body, epilepsy, of epilepsy, and those particularly at risk may be if upon the intelligence, melancholy."" Temkin4 those with TLEIcomplex partial seizures (see later). quotes Aretaeus as having said that epileptics were From the management point of view, depression is "languid, spiritless," and dejected, while more re- a serious disorder carrying with it the risk of suicently several authors from Griesinger in the 1850s cide and attempted suicide, both of which are parto White, Barham, Baugh, and Jones in the early ticularly frequent in people with epilepsy. Appro1900s have discussed melancholia specifically in- priate treatment of the depression, with admission to hospital if necessary, is therefore mandatory. terlinked with epilepsy.' Only one study has directly enquired as to In keeping with one of the classifications of psychiatric disorders in epilepsy, there are broadly whether depression occurs more frequently in peotwo major types of depression: peri-ictal (relating ple with epilepsy compared with other disabling to the seizures) and interictal, in which the distur- conditions. Thus, Mendez et als found that the bances are chronic and not directly related to the frequency of interictal depression in communityictal electric discharge. The review will focus on in- based epileptics was greater and prior suicide at-
Senior Lecturer, Academic Department of Psychiatry, University College and Middlesex Schools of' Medicine, Middlesex Hospital, London, United Kingdom Reprint requests: Dr. Robertson, Academic Department of Psychiatry, University College and Middlesex Schools of Medicine, Middlesex Hospital, London W 1N BAA, UK Copyright O 1991 by Thieme Medical Publishers, Inc., 381 Partk Avenue South, New York, NY 10016. All rights reserved.
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That depression is common in the context of epilepsy is undisputed, although only a few studies have defined what exactly is meant by depression or have used recognized diagnostic criteria of depressive illness for entry into investigations. Nevertheless, there has been substantial documentation of the relationship between depression and epilepsy in the literature, and there have been comprehensive reviews on the subject as well.],*This article will attempt to give a brief overview of' the subject and make some suggestions as to the etiology and management of the depression.
LIEPKESSION A N D EPILEPSY-KORERTSON
tients with 'TLE and generalized epilepsy. Patients with neurologic conditions were found to be at significantly greater risk compared with people with epilepsy and other chronic illnesses." 'The question as to whether depression occurs more commonly in people with epilepsy was not asked, but half of the studies included in the epilepsy group reported that the depression scores were raised in people with epilepsy.'.' Dodrill and Batzel" undertook a similar investigation, which included studies that evaluated interictal behavioral features of patients with epilepsy using many objective measures, comparing the index group with patients with cerebral disorders other than epilepsy, chronic medical non-neurologic problems, and normal volunteers. They concluded that individuals with epilepsy have more emotional and psychiatric problems than normal persons, more difficulties than patients with non-neurologic disorders, but approximately the same incidence of these problems as persons with other neurologic disorders. They also suggested that increased emotional and psychiatric problems were not found among patients with 'TLE when compared with patients with other types of epilepsy and that the number of seizure types was far more relevant to emotional or psychiatric problems in epilepsy than was the particular seizure type. Patients with TLE often have more than one seizure type and therefore as a consequence appear to be more maladjusted. The CCEI and the Zung Depression Inventory were used by de Angelis and Vizioli'" to compare the depression scores of two groups of patients with epilepsy with patients who experienced syncopal attacks and another group who had chronic non-neurologic diseases. Results showed that the patients with epilepsy scored no higher than the controls. Several studies based on clinical judgment have also reported depression to be a common symptom or illness in patients with epilepsy.' Controlled studies should be undertaken to determine more exactly the prevalence of interictal depression in people with epilepsy compared with those with other chronic diseases. However, regardless of the source of referral, namely, psychiatric, neurologic, or general practice or disabled employment agency, the majority of findings are remarkably consistent in highlighting the fact that depressive symptomatology is common in patients with epilepsy.
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tempts were more common than in a control population with similar socioeconomic and disability levels. 'The authors suggested therefore that depression in epilepsy is more than a nonspecific reaction to a chronic disability, reporting also that a significantly higher than expected number of epileptics were admitted for psychiatric care as a consequence of d e p r e s ~ i o n . ~ The prevalence of interictal depression in the setting of epilepsy can also be deduced from studies investigating psychopathology using standardized psychiatric scales. Many studies using the Minnesota Multiphasic Personality Inventory (MMPI) and other instruments such as the Standard Psychiatric Interview have shown that depression is increased in individuals with epilepsy and higher than in control populations, while several have fi)und higher MMPI depression scores for patients with psychomotor or 'TLE compared with those with generalized seizures (see Robertson)'.'. Others, using alternatives to the MMPI, such as the Present State Examination, the Bear-Fedio Inventory, the Middlesex Hospital Questionairel Crown-Crisp Experiential Index (CCEI) and the General Health Questionaire, have also assessed psychopathology in people with epilepsy. Adult patients with epilepsy have been compared with normal controls; patients from general practices; and patients with locomotor disorders, general neurologic problems, and neuromuscular disorders; and those with epilepsy have been shown to have more depression and anxiety.',' In one study, male but not female epileptic patients scored significantly higher on the depression and free-floating anxiety subscales than did the controls, which difference held true when they were compared with a neurotic outpatient population (taken from the scores from the CCEI manual). The type of symptoms differed with age in that younger patients exhibited anxiety and older patients reported more depression." Margalit and Heiman,"' using standardized psychiatric rating scales, compared children with epilepsy to nonhandicapped children and those with learning disabilities; those with epilepsy had significantly higher levels of trait anxiety than either of the control groups. Data obtained from a literature search that located all published MMPI investigations of patients with epilepsy, other neurologic disorders, and nonneurologic chronic physical disorders suggested the conclusion that patients with epilepsy run a higher risk for psychopathology than members of the general population. No increase of overall psychopathology was found in patients with epilepsy compared with patients with other chronic disorders, and no difference was found between pa-
TYPE AND PHENOMENOLOGY OF DEPRESSION IN EPILEPSY
Several studies have explored specific aspects of the interictal depression encountered in people
183
SEMINARS I N NEUROLOGY
found that a left temporal lobe, depressed epileptic group (see later) had an insignificantly larger number of males and left-handed subjects. No sex differences for the occurrence of depression in epileptics were reported by Victoroff et al.7 PSYCHOSOCIAL CONTRIBUTIONS
Various psychosocial models of depression have been suggested and many of these models may apply to people with epilepsy. Many have reported on the stigma and social prejudice to which they are subject, although others suggest they do not feel stigmatized by their illness.'.' interviewed adult and adolescent Danesi et patients with epilepsy attending a neurologic clinic about their social problems and found that a substantial number had had school problems, or had lost income, friends, or spouses; a few had withdrawn from social activities. They concluded that most problems arose from poor seizure control, caused by poor compliance with antiepileptic medication. Danesi"' subsequently found that approximately one third of patients, despite having seizures, were unable to accept a diagnosis of epilepsy, and of those who were prepared to accept the diagnosis, two thirds were not willing to disETIOLOGY OF DEPRESSION IN PEOPLE close the fact to other people. WITH EPILEPSY Beran and Read" assessed how patients with epilepsy attending a neurologic clinic saw theirGENETIC PREDISPOSITION condition, their role in society, and society's expecGenetic predisposition seems to have been rea- tations of them. The majority thought that people sonably well demonstrated in bipolar illness and with epilepsy had more emotional problems and recurrent unipolar depressions (for review see mood swings compared with those without, and Gurling I"). Hancock and Bevilacqua2" reported there was a trend for the patients to consider themthat one in four of their depressed epileptics had a selves less well endowed with many positive attrifamily history of successful suicide. Mendez et alH butes. Dodrill and colleagues"~'%ssessed the psyfound that their group of 20 depressed epileptics chosocial problems among adults with epilepsy in had less family history of effective illness than their a national study using the self-rating Washington depressed control group, whereas Robertson et all7 Psychosocial Seizure Inventory and documented found that 25% of their cohort of 66 depressed that emotional, interpersonal, vocational, and fiepileptics had a family history of psychiatric illness, nancial concerns were common, as well as probof which the most common illness was depression. lems coping with epileptic attacks. Arntson et al"" T h e exact contribution of genetic endowment to also assessed psychosocial consequences of having depression in epileptics remains unclear. Brent et epilepsy and found that the epilepsy sample difa12' found that a differential prevalence of depres- fered from normal controls. Anxiety was the most sion between medication groups [phenobarbital frequently reported problem, followed closely by (PB) and carbamazepine (CBZ)-see later] was depression. In Fenton's studyVepression in rnale noted only in those with a family history of major epileptic patients was significantly related to undepressive disorder among first-degree relatives. employment. Hermann"' argued the case for epilepsy being GENDER a human analogue of the learned helplessness theDepression in the general population is more ory of depression put forward by Seligman and common in women than men," and in depressed colleagues,"'~"" predominantly applied to animal epileptic populations this has also been shown to models. Hermann3' proposed that epilepsy is a % uother ut s t u d i e ~ , ~high . ~ psychopathologic risk disorder, because afbe the case in ~ o m e ~ ~ , ' ~ , ~not 184 in which males predominated. Altshuler et a124 fected individuals are constantly exposed to unpre-
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with epilepsy. Those based on clinical judgment have described the depression as either "reactive"" or "endogenous."'~aliaand Harper'" and Robertson et al,17using standardized rating scales, documented that the majority of individuals were rated as nonendogenous on the Levine-Pilowsky and Newcastle Scales. As measured by standardized rating scales, the severity of the depression ~ features of depresseems to be m ~ d e r a t e " ' . 'and sion are high anxiety, neuroticism, hostility, sadness, obsessionalism, dependence, and altered sexual interest.l"IH In one series, 13 of 66 were psychotic,17 and in another, depressed epileptics were shown to have significant paranoia, irritability, humorlessness, an abnormal affect, and significantly less self-pity, brooding, guilt, somatization, anxiety, and hopelessness than did control subject~.~ Depressed epileptics have also been shown to have had a significant past history of depressive illness, deliberate drug overdosage, and self-harm,'"18 but no more so than a depressed group without epilep~y.~ Only 2 of 66, however, had a history of bipolar disorder."
VOLUME 11, NUMBEK 2 JUNE 1991
DEPRESSION AND EPILEPSY-ROBERTSON
EFFECT OF EPILEPSY AND SEIZURE VARIABLES
lepsy variables, such as age of onset of epilepsy, the presence of an intracranial lesion, seizure freIn quency, type, or site or side of le~ion."'~.'~,""~" the study by Robertson et al,I7 however, the severity of the depression correlated significantly with the duration of the epilepsy, and an association was found between complex partial seizures and a past history of depression, whereas Mignone et a14' found that the depression scores were higher for those epileptics with late onset of fits.
ICTAL FEAR AND FEAR OF SEIZURES
Three groups have examined fear, both ictal and interictal, and its relationship to psychopathology. Hermann et al45nvestigated patients with ictal fear and controls, using the MMPI, and results suggested that patients who have ictal fear run a higher risk of psychopathology, scoring higher on five subscales, including depression. Strauss et a14" reported that fear, the most common ictal emotion, was associated equally with left and right temporal lobe foci. With respect to interictal fear, however, patients with foci on left and right feared different things, and men with foci on the right side had less fear than those with foci on the left. Mittan4*assessed patients' fears about their epilepsy and evaluated psychopathology. T h e "high fear" group scored significantly higher on many of the depression-related psychiatric rating scales than did the "low fear" group. By contrast, the "low fear" group scored within riormal limits when compared to test norms. MittanJQherefore suggested that the level of patients' fears may be a strong predictor of the presence of psychopathology.
The temporal relationship between seizures and mood has been known for some time. Infrequently, reports of peri-ictal depression have been documented, although not many would qualify as depressive illness. Having said that, I must add that the lowered mood often warranted treatment with antiepileptic drugs and improved on treatment. One could therefore argue that in these instances the seizures (or increase thereof) contribute to the lowering of mood. For a full discussion of peri-ictal THE LATERALITY HYPOTHESIS depression see Robertson.',' When one considers interictal depression, sevF l ~ r - H e n r ~ :suggested '~ that when patients eral authors have noted a decrease in seizure frequency prior to the onset of the lowered m~od,~","".~" had a combination of TLE and psychosis, a domiwhereas others found that depression was associ- nant-side pathology was more likely to be related ated with an increase in seizures."." Patients with to a schizophreniform presentation, whereas a intractable TLE were administered measures of nondominant abnormality was associated with a depression and locus of control both preopera- manic-depressive psychosis. Although the former tively and postoperatively (anterior temporal lo- suggestion has been reaffirmed by several authors, bectomy)."" 'There was a significant preoperative the association of affective illness and the nondomrelationship between depression and an external inant hemisphere has been noted by only a few aulocus of control, but this relationship no longer thors (for review see Trimble and R o b e r t ~ o n ~ ~ ) existed postoperatively. Postoperative declines in Several studies have subsequently addressed depression were independent of any alterations in the laterality hypothesis and have shown that, conlocus of control. Moreover, depression declined trary to the original suggestion, the left side is ~~ significantly only in patients rendered completely more implicated in d e p r e s ~ i o n ' " ' ~ , " "whereas seizure-free. others have found no left-right difference^.^",^" Many investigators have found depressive Mendez et alGuggested that the left temporal lobe symptomatology not to be intimately related to epi- was specifically involved in the depression. This 185
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dictable, uncontrollable, aversive events (seizures) that produce a pattern of emotional, motivational, and cognitive disorders initially presenting as anxiety, but, if prolonged, depression. Secondly, individuals with epilepsy suffer discrimination, a higher incidence of employment difficulties, social exclusion, and lower marital rates, and are predisposed to cognitive impairment due to cerebral is imdamage or antiepileptic medication.l."his portant when one considers that many of these problems and the reactions of society to epileptics are more often than not neither predictable nor under the control of the individual."' Hermann and Whitman2" assessed a wide variety of psychosocial, epilepsy, and medication variables and related them to self-reported depressive symptomatology in a sample of adults with epilepsy. 'The following variables were predictive of increased depression: increase in stressful life events, poor adjustment to seizures, and financial stress. Others have also found stressful life events and family discord to be instrumental in provoking depression in people with epilepsy."',"
S E M I N A R S I N NEUKOLOGY
ANTICONVULSANTS AND MOOD As early as 197 1, C:BZ was noted to have a psychotropic effect in patients with epilepsy."' Since then, there have been many studies showing the psychotropic action of CBZ in this population, including studies from several independent centers that have documented significant associations between levels of CBZ o r its breakdown product in blood cerebrospinal fluid, o r both, and a positive psychotropic action.'.' Robertson et all7 found that patients receiving PB were more depressed than those not receiving the drug, whereas patients on CBZ were less depressed and had lower trait anxiety. Smith and Collins" measured the mood and behavior of' patients with epilepsy on a variety of antiepileptic drugs and found that CBZ did not affect mood adversely, whereas phenytoin, PB, and primidone affected the behavior adversely, with PB and primidone being the worst offenders. Recently, Victoroff et al' reported that barbiturates were a possible etiologic factor in depressive illness. Other antiepileptic drugs have been reported to alter mood. Ring and Reynolds5" reported depression as an unwanted side effect of vigabatrin, whereas valproic acid has been shown to be a useful adjunct in manic-depressive illness, depression, and mania,:'%nd clonazepam has also been reported as antimanic." Several investigators have reported an increased risk of suicide and attempted suicide in people with epilepsy, with PB being particularly implicated.2~,%j-6oE p il eptics make more medically serious suicide attempts, show more premeditation, and have higher suicidal intent that d o nonepileptic attempters."'
THE BIOCHEMICAL LINK AND FOLIC ACID IN DEPRESSED EPILEPTIC POPULATIONS
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Another possible etiologic factor to be considered is folic acid (FA). Decreased values of
serum FA have been reported in depression, in epilepsy, in psychiatrically ~ m p a i r e depileptic patients, and especially in depressed epileptics.'.' Although the literature concerning the biologic theories of depression is vast, it is noteworthy that many of the abnormalities documented in depressives are also found in people with epilepsy. Thus, abnormalities of norepinephrine, dopamine, and gamma-aminobutyric acid and malfunctioning of the hypothalamic-pituitary axis have been implicated in both conditions. T h e topic has been thoroughly reviewed by Robertson.'
MANAGEMENT Interictal depressive phenomena are common in patients with epilepsy and the treatment should initially be directed toward the identification and possible cause of the problem. Thus, if a patient is undergoing a depressive reaction on acquiring the label of epilepsy, the support and help of a social worker who has knowledge of epilepsy and experience in its management can help the person "work through" his o r her grief."' Several studies have indicated that a high seizure frequency interferes with psychosocial functioning and may masquerade as depression. Behavioral methods of decreasing seizure frequency ought to be considered, using biofeedback techniques, operant conditioning, and relaxation (see Robertson'). Psychotherapy is important in the treatment of people with depression, especially when one considers the psychosocial causes of mood changes and the literature on stigma and epilepsy. O n e may opt for supportive therapy alone o r a combination of formal psychotherapy (such as cognitive, interpersonal, o r behavioral approaches) and antidepressants, which, as recently shown, is more effective than either treatment alone (see Robertson'). Assessment and rationalization of the patient's antiepileptic medication regimen is also important, and improvement in the mental state of patients with a reduction of polypharmacy has been reported (see Robertson') If monotherapy is possible and all other factors, such as type of epilepsy, are taken into account, CBZ would seem the most appropriate antiepileptic agent. What is the role of antidepressants? It is well known that virtually all antidepressants that are not monoamine oxidase inhibitors (MAOIs) lower the seizure threshold; those most likely to be implicated with seizures are maprotiline, mianserin, trazodone, and clomipramine, whereas the drugs that are less likely to be associated are doxepin, fluvoxamine, viloxazine, protriptyline, bu-
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has recently been reaffirmed by other^.'.'^ 'The latter group documented that these left-sided TI,E patients scored significantly higher than the other groups on self-ratings for depression and that the difference could not be accounted for by factors such as duration of epilepsy, employment status, education, age of onset of seizures, o r antiepileptic medication. No significant difference in the level of anxiety was found among the groups.
VO1,UME I I , N U M B E R 2 JUNE 1991
DEPRESSION AND EPILEPSY-ROBERTSON
&
'
on the left side appear to be more common is as -yet uncertain.'.* Akiskal and McKinney" propose an attractive model: depressive illness is a "psychobiological final conlmon pathway," the culmination of various processes that converge on areas of the diencephalon that modulate arousal, mood, motivation, and psychomotor function. T h e specific form that the depressive illness will take in a given individual depends on the interaction of several factors: (1) genetic vulnerability (as suggested by some studies); (2) developmental events (and their disruption by epileptic seizures); (3) psychosocial events (such as stigma); physiologic stressors (again, for example, a seizure), which impinge on diencephalic function; and (4) personality traits. In many studies trait anxiety, obsessionality, neuroticism, and hostility were much higher when compared with other populations and only some but not all of these could have been accounted for by depressive illness."" Finally, the relationship between depression and epilepsy is complex, and treatment, which can also be complex, is best handled by someone well versed in both disorders.
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triptyline, and the MAOIs: no seizures have ever been reported in association with iproniazid, isocarboxazid, or tranylcypromine. Viloxazine should probably be avoided, however, because of its potential to cause antiepileptic drug toxicity. Thus, at present, doxepin, fluvoxamine, protriptyline, nortriptyline, and the MAOIs appear to be safest. In addition, it may be wise to prescribe a riorlsedating or less sedative antidepressant, because most antiepileptic drugs that the patient will be taking have sedative side effects. Many clinicians, however, prefer to use antidepressants they know well, and commence with small doses, increasing the dose gradually (see Robertson'). Finally, electroconvulsive therapy (ECT) is particularly important to consider when suicide is a real danger or in cases of severe paranoid agitation in which the patient's seizure frequency appears to have diminished prior to the onset of the depression. Paradoxically, some of these patients appear to have a particularly high seizure threshold during the administration of ECT (See Robertson').
CONCLUSIONS Interictal depressive symptomatology occurs frequently in people with epilepsy. Several studies using standardized rating scales have shown the depression scores to range from moderate to severe, which is similar to that found in studies on depressed patients without epilepsy."Wany of these would therefore qualify as having a depressive illness. A number of variables have been suggested with regard to the pathogenesis of the depression. Provoking factors include genetic predisposition, social stigmatization, unemployment, adverse life events, patients' fears, and a past history of depressive illness. The phenomenology of the depression does not seem intimately linked with epilepsy variables (such as age at onset of epilepsy, seizure frequency, and presence of an intracranial lesion) with some exceptions. Thus, antiepileptic drugs can affect the mental state, and the longer the duration of epilepsy the more severe the depression. The laterality hypothesis of depression in this population has not only not been upheld, but many studies have shown the left side to be implicated, with some emphasis on the TLE/complex partial seizure patients. Whether this is specific, as sug. ' ~because the left hemisphere gested by ~ o m e , ~or and frontotemporal areas seem particularly vulnerable as far as psychopathology is concerned, or because when focal abnormalities are found, foci
REFERENCES 1. Robertson MM. Depression in patients with epilepsy reconsidered. In: Pedley TA, Meldrum BS, eds. Recent advances in epilepsy, vol 4. Edinburgh: Churchill Livingstone, 1988:205-40 2. Robertson MM. T h e organic contribution to depressive illness in patients with epilepsy. J Epilepsy 1989;2: 189230 3. Lewis A]. Melancholia: a historical review. J Ment Sci 1934;80: 1-42 4. Temkin 0.T h e falling sickness. J o h n Hopkins Press, Baltimore, 1971 5. Scambler G. Sociological aspects of epilepsy. In: Hopkins A , ed. Epilepsy. New York: Demos Publications, 1987 6. Currie S, Heathfield KWG, Henson RA, Scott DF. Clinical course and prognosis of temporal lobe epilepsy. A survey of 666 patients. Brain 1971;94: 173-90 7. Victoroff J I , Benson DF, Engel J Jr, et al. Interictal depression in patients with medically intractable complex partial seizures: electroencephalography a n d cerebral metabolic correlates. Ann Neurol 1990;28:221 8. Mendez MF, Cummings JL, Benson DF. Depression in epilepsy. Arch Neurol 1986;43:766-70 9. Fenton GW. Minor psychiatric morbidity in people with epilepsy: evidence for a gender difference. Presented at the annual meeting of the Royal College of Psychiatrists, Southampton, United Kingdom, July 8-10, 1986 10. Margalit M, Heiman T. Anxiety a n d self-dissatisfaction in epileptic children. J Soc Psychiatry 1983;29:220-4 11. Whitman S, Hermann BP, Gordon AC. Psychopathology in epilepsy: how great is the risk? Biol Psychiatry 1984;2:213-36 12. Dodrill CB, Batzel LW. Inter-ictal behavioral features of patients with epilepsy. Epilepsia 1986;27(Suppl 2): S64-76 13. d e Angelis G , Vizioli R. Epilepsy a n d depression. In: Parsonage M, Grant RHE, Craig A , Ward AAJ Jr, eds. Ad-
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vances in epileptology: XlVth epilepsy international symposium. New York: Raven Press, 1983: 203-6 Mulder DW, 1)aly I). l'sychiatric syriiptoms associated with lesions of the temporal lobe. JAMA 1952;150: 173-6 Betts TA. A follow-up study of a cohort of' patients with epilepsy admitted to psychiatric care in an Er~glislicity. In: Harris t', Mawdsley C , eds. Epilepsy: I'roceedings of the Hans Berger centenary symposium. Ediriburgh: Churchill Livingstone, 1974:326-38 Palia SS, Harper MA. Mood disorders iri epilepsy: a survey of' psychiatric patients. Presented at the Annual Meeting of'the Royal College of Psychiatt-ists. 'l'he Uriiversity 'of ~ o u t h a m p t o n~ \ i t e d Kingdom, ,July 8-10, 1986 Robertson MM, Tririible MR, Ihwnsentl HKA. T h e phenomenology of' depression in epilepsy. Epilepsia 1987;28:364-72 Roy A. Some determinants of affective syniptotns in epileptics. Can J Psychiatry 1979;24:554-56 Gurling HMI). Recent advances in the genetics of psychiatric disorder. I990 Human Genetic 1nfi)rmatiori: Science, Law a n d Ethics. Chichester: Wiley, 1990; 48-62 Hancock J C , Bevilacqua AR. Temporal lobe tiysrhyttiniia and inlpulsive o r suicidal behavior: preliri~inaryrepor-t. South Meti J 107 1 ;li4: 1 189-93 Brent DA, C:rumrtne PK, Varma KK, et al. Phetiobarbital treatment a n d major depressive disorder iri children with epilepsy. Pediatrics 1987;80:909-17 Bird J , Harrison (;. Examination notes in psychiatry, 2ritl ed. Bristol: Wright, 1987 Hermann UP, Whitrnan S. Psychosocial predictors of' interictal depressiori. J Epilepsy 1989:2:23 1-7 Altshuler I.I., 1)evirisky 0 , Post KM, l'heodore W. Depression, anxiety, a n d temporal lobc epilepsy. 1.aterality of' focus and symptoms. Arch Neur-ol 1990; 47:284-8 Danesi MA, Odusote KA, Roberts 00, Atlu EO. Social problems of adolescent and adult epileptics in a tleveloping country, as seen in Lagos, Nigeria. Epilepsia 1981;22:689-96 Danesi MA. Patient perspectives on epilepsy in a developing country. Epilepsia 1984;25: 184-90 Beran KG, Read .I'. Patient perspectives of epilepsy. (:liii Exp Neurol 198 I; l7:56-69 Dodrill
11, NO. 2 JUNE 1991
Depression in Patients with Epilepsy: An Overview M a y M Robertson, M.B.Ch.B., M.D., D.P.M., F.R.C.Psych.
terictal depression, the most prevalent and clinically significant syndrome.
PREVALENCE OF INTERICTAL DEPRESSION
It has long been acknowledged that epilepsy may seriously compromise a person's quality of' life,"redisposing some individuals to psychiatric illness. Depression is a serious and probably the most common psychiatric coricomitant of epilepsy, but there have been no epidemiologic studies to document the exact frequency. Nevertheless, it has been shown that some 20% of patients with ternDEPRESSION IN THE CONTEXT OF EPILEPSY poral lobe epilepsy (TLE) become moderately or ~ Victoroff et a17 reseverely d e p r e s ~ e d .Recently, A relationship between depression and epi- ported that 62% of a substantial cohort of patients lepsy has been described since the beginnings of with medically intractable complex partial seizures medical writings. Hippocrates clearly thought epi- had had a history of depression, of whom 38% met lepsy and melancholia were closely related when he rigorous criteria for major depressive illness. What stated: "Melancholics ordinarily become epileptics is important to note is that patients of any age, and epileptics melancholics: of these two states, either sex, and with diverse family and social backwhat determines the preference is the direction the grounds are vulnerable to depression in the setting malady takes; if it bears upon the body, epilepsy, of epilepsy, and those particularly at risk may be if upon the intelligence, melancholy."" Temkin4 those with TLEIcomplex partial seizures (see later). quotes Aretaeus as having said that epileptics were From the management point of view, depression is "languid, spiritless," and dejected, while more re- a serious disorder carrying with it the risk of suicently several authors from Griesinger in the 1850s cide and attempted suicide, both of which are parto White, Barham, Baugh, and Jones in the early ticularly frequent in people with epilepsy. Appro1900s have discussed melancholia specifically in- priate treatment of the depression, with admission to hospital if necessary, is therefore mandatory. terlinked with epilepsy.' Only one study has directly enquired as to In keeping with one of the classifications of psychiatric disorders in epilepsy, there are broadly whether depression occurs more frequently in peotwo major types of depression: peri-ictal (relating ple with epilepsy compared with other disabling to the seizures) and interictal, in which the distur- conditions. Thus, Mendez et als found that the bances are chronic and not directly related to the frequency of interictal depression in communityictal electric discharge. The review will focus on in- based epileptics was greater and prior suicide at-
Senior Lecturer, Academic Department of Psychiatry, University College and Middlesex Schools of' Medicine, Middlesex Hospital, London, United Kingdom Reprint requests: Dr. Robertson, Academic Department of Psychiatry, University College and Middlesex Schools of Medicine, Middlesex Hospital, London W 1N BAA, UK Copyright O 1991 by Thieme Medical Publishers, Inc., 381 Partk Avenue South, New York, NY 10016. All rights reserved.
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That depression is common in the context of epilepsy is undisputed, although only a few studies have defined what exactly is meant by depression or have used recognized diagnostic criteria of depressive illness for entry into investigations. Nevertheless, there has been substantial documentation of the relationship between depression and epilepsy in the literature, and there have been comprehensive reviews on the subject as well.],*This article will attempt to give a brief overview of' the subject and make some suggestions as to the etiology and management of the depression.
LIEPKESSION A N D EPILEPSY-KORERTSON
tients with 'TLE and generalized epilepsy. Patients with neurologic conditions were found to be at significantly greater risk compared with people with epilepsy and other chronic illnesses." 'The question as to whether depression occurs more commonly in people with epilepsy was not asked, but half of the studies included in the epilepsy group reported that the depression scores were raised in people with epilepsy.'.' Dodrill and Batzel" undertook a similar investigation, which included studies that evaluated interictal behavioral features of patients with epilepsy using many objective measures, comparing the index group with patients with cerebral disorders other than epilepsy, chronic medical non-neurologic problems, and normal volunteers. They concluded that individuals with epilepsy have more emotional and psychiatric problems than normal persons, more difficulties than patients with non-neurologic disorders, but approximately the same incidence of these problems as persons with other neurologic disorders. They also suggested that increased emotional and psychiatric problems were not found among patients with 'TLE when compared with patients with other types of epilepsy and that the number of seizure types was far more relevant to emotional or psychiatric problems in epilepsy than was the particular seizure type. Patients with TLE often have more than one seizure type and therefore as a consequence appear to be more maladjusted. The CCEI and the Zung Depression Inventory were used by de Angelis and Vizioli'" to compare the depression scores of two groups of patients with epilepsy with patients who experienced syncopal attacks and another group who had chronic non-neurologic diseases. Results showed that the patients with epilepsy scored no higher than the controls. Several studies based on clinical judgment have also reported depression to be a common symptom or illness in patients with epilepsy.' Controlled studies should be undertaken to determine more exactly the prevalence of interictal depression in people with epilepsy compared with those with other chronic diseases. However, regardless of the source of referral, namely, psychiatric, neurologic, or general practice or disabled employment agency, the majority of findings are remarkably consistent in highlighting the fact that depressive symptomatology is common in patients with epilepsy.
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tempts were more common than in a control population with similar socioeconomic and disability levels. 'The authors suggested therefore that depression in epilepsy is more than a nonspecific reaction to a chronic disability, reporting also that a significantly higher than expected number of epileptics were admitted for psychiatric care as a consequence of d e p r e s ~ i o n . ~ The prevalence of interictal depression in the setting of epilepsy can also be deduced from studies investigating psychopathology using standardized psychiatric scales. Many studies using the Minnesota Multiphasic Personality Inventory (MMPI) and other instruments such as the Standard Psychiatric Interview have shown that depression is increased in individuals with epilepsy and higher than in control populations, while several have fi)und higher MMPI depression scores for patients with psychomotor or 'TLE compared with those with generalized seizures (see Robertson)'.'. Others, using alternatives to the MMPI, such as the Present State Examination, the Bear-Fedio Inventory, the Middlesex Hospital Questionairel Crown-Crisp Experiential Index (CCEI) and the General Health Questionaire, have also assessed psychopathology in people with epilepsy. Adult patients with epilepsy have been compared with normal controls; patients from general practices; and patients with locomotor disorders, general neurologic problems, and neuromuscular disorders; and those with epilepsy have been shown to have more depression and anxiety.',' In one study, male but not female epileptic patients scored significantly higher on the depression and free-floating anxiety subscales than did the controls, which difference held true when they were compared with a neurotic outpatient population (taken from the scores from the CCEI manual). The type of symptoms differed with age in that younger patients exhibited anxiety and older patients reported more depression." Margalit and Heiman,"' using standardized psychiatric rating scales, compared children with epilepsy to nonhandicapped children and those with learning disabilities; those with epilepsy had significantly higher levels of trait anxiety than either of the control groups. Data obtained from a literature search that located all published MMPI investigations of patients with epilepsy, other neurologic disorders, and nonneurologic chronic physical disorders suggested the conclusion that patients with epilepsy run a higher risk for psychopathology than members of the general population. No increase of overall psychopathology was found in patients with epilepsy compared with patients with other chronic disorders, and no difference was found between pa-
TYPE AND PHENOMENOLOGY OF DEPRESSION IN EPILEPSY
Several studies have explored specific aspects of the interictal depression encountered in people
183
SEMINARS I N NEUROLOGY
found that a left temporal lobe, depressed epileptic group (see later) had an insignificantly larger number of males and left-handed subjects. No sex differences for the occurrence of depression in epileptics were reported by Victoroff et al.7 PSYCHOSOCIAL CONTRIBUTIONS
Various psychosocial models of depression have been suggested and many of these models may apply to people with epilepsy. Many have reported on the stigma and social prejudice to which they are subject, although others suggest they do not feel stigmatized by their illness.'.' interviewed adult and adolescent Danesi et patients with epilepsy attending a neurologic clinic about their social problems and found that a substantial number had had school problems, or had lost income, friends, or spouses; a few had withdrawn from social activities. They concluded that most problems arose from poor seizure control, caused by poor compliance with antiepileptic medication. Danesi"' subsequently found that approximately one third of patients, despite having seizures, were unable to accept a diagnosis of epilepsy, and of those who were prepared to accept the diagnosis, two thirds were not willing to disETIOLOGY OF DEPRESSION IN PEOPLE close the fact to other people. WITH EPILEPSY Beran and Read" assessed how patients with epilepsy attending a neurologic clinic saw theirGENETIC PREDISPOSITION condition, their role in society, and society's expecGenetic predisposition seems to have been rea- tations of them. The majority thought that people sonably well demonstrated in bipolar illness and with epilepsy had more emotional problems and recurrent unipolar depressions (for review see mood swings compared with those without, and Gurling I"). Hancock and Bevilacqua2" reported there was a trend for the patients to consider themthat one in four of their depressed epileptics had a selves less well endowed with many positive attrifamily history of successful suicide. Mendez et alH butes. Dodrill and colleagues"~'%ssessed the psyfound that their group of 20 depressed epileptics chosocial problems among adults with epilepsy in had less family history of effective illness than their a national study using the self-rating Washington depressed control group, whereas Robertson et all7 Psychosocial Seizure Inventory and documented found that 25% of their cohort of 66 depressed that emotional, interpersonal, vocational, and fiepileptics had a family history of psychiatric illness, nancial concerns were common, as well as probof which the most common illness was depression. lems coping with epileptic attacks. Arntson et al"" T h e exact contribution of genetic endowment to also assessed psychosocial consequences of having depression in epileptics remains unclear. Brent et epilepsy and found that the epilepsy sample difa12' found that a differential prevalence of depres- fered from normal controls. Anxiety was the most sion between medication groups [phenobarbital frequently reported problem, followed closely by (PB) and carbamazepine (CBZ)-see later] was depression. In Fenton's studyVepression in rnale noted only in those with a family history of major epileptic patients was significantly related to undepressive disorder among first-degree relatives. employment. Hermann"' argued the case for epilepsy being GENDER a human analogue of the learned helplessness theDepression in the general population is more ory of depression put forward by Seligman and common in women than men," and in depressed colleagues,"'~"" predominantly applied to animal epileptic populations this has also been shown to models. Hermann3' proposed that epilepsy is a % uother ut s t u d i e ~ , ~high . ~ psychopathologic risk disorder, because afbe the case in ~ o m e ~ ~ , ' ~ , ~not 184 in which males predominated. Altshuler et a124 fected individuals are constantly exposed to unpre-
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with epilepsy. Those based on clinical judgment have described the depression as either "reactive"" or "endogenous."'~aliaand Harper'" and Robertson et al,17using standardized rating scales, documented that the majority of individuals were rated as nonendogenous on the Levine-Pilowsky and Newcastle Scales. As measured by standardized rating scales, the severity of the depression ~ features of depresseems to be m ~ d e r a t e " ' . 'and sion are high anxiety, neuroticism, hostility, sadness, obsessionalism, dependence, and altered sexual interest.l"IH In one series, 13 of 66 were psychotic,17 and in another, depressed epileptics were shown to have significant paranoia, irritability, humorlessness, an abnormal affect, and significantly less self-pity, brooding, guilt, somatization, anxiety, and hopelessness than did control subject~.~ Depressed epileptics have also been shown to have had a significant past history of depressive illness, deliberate drug overdosage, and self-harm,'"18 but no more so than a depressed group without epilep~y.~ Only 2 of 66, however, had a history of bipolar disorder."
VOLUME 11, NUMBEK 2 JUNE 1991
DEPRESSION AND EPILEPSY-ROBERTSON
EFFECT OF EPILEPSY AND SEIZURE VARIABLES
lepsy variables, such as age of onset of epilepsy, the presence of an intracranial lesion, seizure freIn quency, type, or site or side of le~ion."'~.'~,""~" the study by Robertson et al,I7 however, the severity of the depression correlated significantly with the duration of the epilepsy, and an association was found between complex partial seizures and a past history of depression, whereas Mignone et a14' found that the depression scores were higher for those epileptics with late onset of fits.
ICTAL FEAR AND FEAR OF SEIZURES
Three groups have examined fear, both ictal and interictal, and its relationship to psychopathology. Hermann et al45nvestigated patients with ictal fear and controls, using the MMPI, and results suggested that patients who have ictal fear run a higher risk of psychopathology, scoring higher on five subscales, including depression. Strauss et a14" reported that fear, the most common ictal emotion, was associated equally with left and right temporal lobe foci. With respect to interictal fear, however, patients with foci on left and right feared different things, and men with foci on the right side had less fear than those with foci on the left. Mittan4*assessed patients' fears about their epilepsy and evaluated psychopathology. T h e "high fear" group scored significantly higher on many of the depression-related psychiatric rating scales than did the "low fear" group. By contrast, the "low fear" group scored within riormal limits when compared to test norms. MittanJQherefore suggested that the level of patients' fears may be a strong predictor of the presence of psychopathology.
The temporal relationship between seizures and mood has been known for some time. Infrequently, reports of peri-ictal depression have been documented, although not many would qualify as depressive illness. Having said that, I must add that the lowered mood often warranted treatment with antiepileptic drugs and improved on treatment. One could therefore argue that in these instances the seizures (or increase thereof) contribute to the lowering of mood. For a full discussion of peri-ictal THE LATERALITY HYPOTHESIS depression see Robertson.',' When one considers interictal depression, sevF l ~ r - H e n r ~ :suggested '~ that when patients eral authors have noted a decrease in seizure frequency prior to the onset of the lowered m~od,~","".~" had a combination of TLE and psychosis, a domiwhereas others found that depression was associ- nant-side pathology was more likely to be related ated with an increase in seizures."." Patients with to a schizophreniform presentation, whereas a intractable TLE were administered measures of nondominant abnormality was associated with a depression and locus of control both preopera- manic-depressive psychosis. Although the former tively and postoperatively (anterior temporal lo- suggestion has been reaffirmed by several authors, bectomy)."" 'There was a significant preoperative the association of affective illness and the nondomrelationship between depression and an external inant hemisphere has been noted by only a few aulocus of control, but this relationship no longer thors (for review see Trimble and R o b e r t ~ o n ~ ~ ) existed postoperatively. Postoperative declines in Several studies have subsequently addressed depression were independent of any alterations in the laterality hypothesis and have shown that, conlocus of control. Moreover, depression declined trary to the original suggestion, the left side is ~~ significantly only in patients rendered completely more implicated in d e p r e s ~ i o n ' " ' ~ , " "whereas seizure-free. others have found no left-right difference^.^",^" Many investigators have found depressive Mendez et alGuggested that the left temporal lobe symptomatology not to be intimately related to epi- was specifically involved in the depression. This 185
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dictable, uncontrollable, aversive events (seizures) that produce a pattern of emotional, motivational, and cognitive disorders initially presenting as anxiety, but, if prolonged, depression. Secondly, individuals with epilepsy suffer discrimination, a higher incidence of employment difficulties, social exclusion, and lower marital rates, and are predisposed to cognitive impairment due to cerebral is imdamage or antiepileptic medication.l."his portant when one considers that many of these problems and the reactions of society to epileptics are more often than not neither predictable nor under the control of the individual."' Hermann and Whitman2" assessed a wide variety of psychosocial, epilepsy, and medication variables and related them to self-reported depressive symptomatology in a sample of adults with epilepsy. 'The following variables were predictive of increased depression: increase in stressful life events, poor adjustment to seizures, and financial stress. Others have also found stressful life events and family discord to be instrumental in provoking depression in people with epilepsy."',"
S E M I N A R S I N NEUKOLOGY
ANTICONVULSANTS AND MOOD As early as 197 1, C:BZ was noted to have a psychotropic effect in patients with epilepsy."' Since then, there have been many studies showing the psychotropic action of CBZ in this population, including studies from several independent centers that have documented significant associations between levels of CBZ o r its breakdown product in blood cerebrospinal fluid, o r both, and a positive psychotropic action.'.' Robertson et all7 found that patients receiving PB were more depressed than those not receiving the drug, whereas patients on CBZ were less depressed and had lower trait anxiety. Smith and Collins" measured the mood and behavior of' patients with epilepsy on a variety of antiepileptic drugs and found that CBZ did not affect mood adversely, whereas phenytoin, PB, and primidone affected the behavior adversely, with PB and primidone being the worst offenders. Recently, Victoroff et al' reported that barbiturates were a possible etiologic factor in depressive illness. Other antiepileptic drugs have been reported to alter mood. Ring and Reynolds5" reported depression as an unwanted side effect of vigabatrin, whereas valproic acid has been shown to be a useful adjunct in manic-depressive illness, depression, and mania,:'%nd clonazepam has also been reported as antimanic." Several investigators have reported an increased risk of suicide and attempted suicide in people with epilepsy, with PB being particularly implicated.2~,%j-6oE p il eptics make more medically serious suicide attempts, show more premeditation, and have higher suicidal intent that d o nonepileptic attempters."'
THE BIOCHEMICAL LINK AND FOLIC ACID IN DEPRESSED EPILEPTIC POPULATIONS
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Another possible etiologic factor to be considered is folic acid (FA). Decreased values of
serum FA have been reported in depression, in epilepsy, in psychiatrically ~ m p a i r e depileptic patients, and especially in depressed epileptics.'.' Although the literature concerning the biologic theories of depression is vast, it is noteworthy that many of the abnormalities documented in depressives are also found in people with epilepsy. Thus, abnormalities of norepinephrine, dopamine, and gamma-aminobutyric acid and malfunctioning of the hypothalamic-pituitary axis have been implicated in both conditions. T h e topic has been thoroughly reviewed by Robertson.'
MANAGEMENT Interictal depressive phenomena are common in patients with epilepsy and the treatment should initially be directed toward the identification and possible cause of the problem. Thus, if a patient is undergoing a depressive reaction on acquiring the label of epilepsy, the support and help of a social worker who has knowledge of epilepsy and experience in its management can help the person "work through" his o r her grief."' Several studies have indicated that a high seizure frequency interferes with psychosocial functioning and may masquerade as depression. Behavioral methods of decreasing seizure frequency ought to be considered, using biofeedback techniques, operant conditioning, and relaxation (see Robertson'). Psychotherapy is important in the treatment of people with depression, especially when one considers the psychosocial causes of mood changes and the literature on stigma and epilepsy. O n e may opt for supportive therapy alone o r a combination of formal psychotherapy (such as cognitive, interpersonal, o r behavioral approaches) and antidepressants, which, as recently shown, is more effective than either treatment alone (see Robertson'). Assessment and rationalization of the patient's antiepileptic medication regimen is also important, and improvement in the mental state of patients with a reduction of polypharmacy has been reported (see Robertson') If monotherapy is possible and all other factors, such as type of epilepsy, are taken into account, CBZ would seem the most appropriate antiepileptic agent. What is the role of antidepressants? It is well known that virtually all antidepressants that are not monoamine oxidase inhibitors (MAOIs) lower the seizure threshold; those most likely to be implicated with seizures are maprotiline, mianserin, trazodone, and clomipramine, whereas the drugs that are less likely to be associated are doxepin, fluvoxamine, viloxazine, protriptyline, bu-
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has recently been reaffirmed by other^.'.'^ 'The latter group documented that these left-sided TI,E patients scored significantly higher than the other groups on self-ratings for depression and that the difference could not be accounted for by factors such as duration of epilepsy, employment status, education, age of onset of seizures, o r antiepileptic medication. No significant difference in the level of anxiety was found among the groups.
VO1,UME I I , N U M B E R 2 JUNE 1991
DEPRESSION AND EPILEPSY-ROBERTSON
&
'
on the left side appear to be more common is as -yet uncertain.'.* Akiskal and McKinney" propose an attractive model: depressive illness is a "psychobiological final conlmon pathway," the culmination of various processes that converge on areas of the diencephalon that modulate arousal, mood, motivation, and psychomotor function. T h e specific form that the depressive illness will take in a given individual depends on the interaction of several factors: (1) genetic vulnerability (as suggested by some studies); (2) developmental events (and their disruption by epileptic seizures); (3) psychosocial events (such as stigma); physiologic stressors (again, for example, a seizure), which impinge on diencephalic function; and (4) personality traits. In many studies trait anxiety, obsessionality, neuroticism, and hostility were much higher when compared with other populations and only some but not all of these could have been accounted for by depressive illness."" Finally, the relationship between depression and epilepsy is complex, and treatment, which can also be complex, is best handled by someone well versed in both disorders.
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triptyline, and the MAOIs: no seizures have ever been reported in association with iproniazid, isocarboxazid, or tranylcypromine. Viloxazine should probably be avoided, however, because of its potential to cause antiepileptic drug toxicity. Thus, at present, doxepin, fluvoxamine, protriptyline, nortriptyline, and the MAOIs appear to be safest. In addition, it may be wise to prescribe a riorlsedating or less sedative antidepressant, because most antiepileptic drugs that the patient will be taking have sedative side effects. Many clinicians, however, prefer to use antidepressants they know well, and commence with small doses, increasing the dose gradually (see Robertson'). Finally, electroconvulsive therapy (ECT) is particularly important to consider when suicide is a real danger or in cases of severe paranoid agitation in which the patient's seizure frequency appears to have diminished prior to the onset of the depression. Paradoxically, some of these patients appear to have a particularly high seizure threshold during the administration of ECT (See Robertson').
CONCLUSIONS Interictal depressive symptomatology occurs frequently in people with epilepsy. Several studies using standardized rating scales have shown the depression scores to range from moderate to severe, which is similar to that found in studies on depressed patients without epilepsy."Wany of these would therefore qualify as having a depressive illness. A number of variables have been suggested with regard to the pathogenesis of the depression. Provoking factors include genetic predisposition, social stigmatization, unemployment, adverse life events, patients' fears, and a past history of depressive illness. The phenomenology of the depression does not seem intimately linked with epilepsy variables (such as age at onset of epilepsy, seizure frequency, and presence of an intracranial lesion) with some exceptions. Thus, antiepileptic drugs can affect the mental state, and the longer the duration of epilepsy the more severe the depression. The laterality hypothesis of depression in this population has not only not been upheld, but many studies have shown the left side to be implicated, with some emphasis on the TLE/complex partial seizure patients. Whether this is specific, as sug. ' ~because the left hemisphere gested by ~ o m e , ~or and frontotemporal areas seem particularly vulnerable as far as psychopathology is concerned, or because when focal abnormalities are found, foci
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