Epilepsy Research, 12 (1992) 45-50 0920-1211/92/$05.00@ 1992 Elsevier Science Publishers B.V. All rights reserved
45
EPIRES 00477
Interictal depression in epilepsy
A. Indaco, P.B. Carrieri, C. Nappi, S. Gentile and S. Striano Instituteof Neurology, 2nd Medical School, Universiry of Naples (Italy)
(Received 24 February 1992; accepted 5 March 1992) Key words: Depression; Anxiety; Seizure; Antiepileptic drugs
The relation between depression and epilepsy was evaluated in % epileptic out-patients. We found that 50% of epileptic patients fulfilled the DSM-IIIR criteria for depression. The Hamilton Rating Scale for Depression, the Beck Self Depression Inventory and the Zung Anxiety Scale were also used in all patients. The patients with partial seizures with complex semiology (CPS) were more depressed than the patients with primary generalized epilepsy and with partial seizures with elementary semiology. A significant increase in the level of anxiety was also found in the group with CPS compared to the other two groups. No correlations were noted between severity of depression and duration of epilepsy, seizure frequency, socio-economic status, education, and family history of depressive illness. No relationship was observed between anticonvulsant drug levels and depression. We failed to confirm an association between side of epileptic lesion and severity of depression. We suggest that depression in epileptic patients does not represent a psychological reaction to a particular cognitive or physical impairment, but is in some way related to the type of epilepsy.
Introduction There is an accumulation of evidence supporting a relationship between epilepsy and depression. Mulder and Daly6 reported that depression is a non-specific reaction to a chronic illness. However, Kogeorgos et al.= and Mendez et a1.25noted that depression is more frequent and severe in epileptic patients than in subjects with comparable chronic neurologic diseases or physical handicaps. The rate of suicide is 4-5 times greater in epileptic patients than in the general population, and this rate is particularly high in subjects with temporal
Correspondence roe:Dr. A. Indaco, M.D., Institute of Neurology, 2nd Medical School, University of Naples, via S. Pansini 5,80131 Naples, Italy.
lobe epilepsy (TLE)5,6,24. Despite this evidence, the relationship between depression and epilepsy has received scant attention. Robertson _et a1.29suggested that depression in patients with epilepsy represents the outcome of multiple factors in individuals genetically predisposed to a primary or idiopathic affective disorder. Mendez et a1.25proposed a specific epileptic psychosyndrome producing an atypical, endogenous depression, due to a left limbic dysfunction. The aim of this study is to evaluate: (1) the characteristics and frequency of depression in a group of epileptic out-patients; (2) the relationship between depression and epileptic syndromes and electroencephalographic (EEG) focus; and (3) the possible correlation between depression and the duration of epilepsy, seizure frequency and anticonvulsant drugs.
46
Materials and methods Two hundred and sixty-four epileptic out-patients, observed consecutively at the Epilepsy Center of our institute of Neurology, were seen from January to September 1990. The general criteria for eligibility for the present study were age 17 to 60 years, lack of mental retardation or other chronic illness, no evidence of neurologic disability, and no history of alcohol or drug abuse. Subjects with progressive central nervous system lesion and a past history of severe head trauma were excluded. In addition, we used the Mini Mental State Examination (MMS)‘9 to exclude patients with cognitive impairment (a score of 23 or below is indicative of significant cognitive impairment). One of us (S.S.), unaware of the depressive evaluation of the subjects, classified all patients, according to the Proposal for Classification of Epilepsp. Because of these criteria of eligibility and exclusion, no patients with secondary generalized epilepsy or benign childhood partial epilepsy were admitted to the study. Consequently, our group included only patients with primary generalized epilepsy (PGE), partial seizure with elementary semiology (EPS) and partial seizure with complex semiology (CPS). Computed tomography scans of the head and at least one EEG were obtained in all patients. All patients had interictal or ictal epileptiform discharges in at least one EEG recording. The lateraliiation of paroxysmal activity in the patients with partial epilepsy was evaluated, when possible. All patients were receiving one or two of the following antiepileptic drugs (AEDs): phenobarbital (PB), carbamazepine (CBZ), phenytoin (PHT) or valproic acid (VPA). The patients with PGE were taking VPA or PB, or an association of PB and VPA; the patients with EPS or CPS were taking CBZ or PI-IT alone, or an association of CBZ and PB, or of PI-IT and PB. Serum AED levels were dete~ined within 7 days of recruitment. We excluded patients receiving three or more drugs, and subjects with drug serum levels not in the therapeutic range. The epileptic patients finally included in the study were evaluated according to DSM-IIIR criteria for depression2. We interviewed all patients for personal and family psychiatric and epileptic history, seizure onset,
frequency and clinical features of seizures. Hand preference was determined with the Annett Hand Preference Questionnaire4. We evaluated the duration of the epileptic syndrome and the frequency of seizures, medical status, education, socioeconomic status (divided into five social classes, I being the highest, according to Hollingshead and Redlich”). Seizure frequency in the last 6 months was assessed using a diary card in all patients. The Hamilton Rating Scale for Depression (HRSD)21, the Beck Self Depression Inventory (BSDI)8 to assess the severity of depression, the Zung Anxiety Scale (ZAS)36 to assess the severity of anxiety were also employed in all epileptic patients. All patients were interviewed between 11 a.m. and 1 p.m. in order to avoid mood changes due to diurnal variations. All subjects gave their informed consent. Statistical amlysis
Intergroup comparisons were made using l-way analysis of variance; post-hoc comparisons were conducted using Student’s t-test. Chi-square test with Yates’ correction or Fisher’s exact test was used to evaluate relationship between categorial variables. Pearson’s correlation coefficients were used for pairs of continuous variables. Results Ninety-six patients fulfilled the criteria for inclusion in the present study. The patient characteristics are shown in Table I. Forty-five patients met criteria for PGE, 15 had EPS, 36 had CPS. The three groups did not differ with respect to age, sex, socioeconomic status, education, duration of epilepsy, seizure frequency, or family history of depressive illness (Table I). DSM-HIR The number of patients meeting the DSM-IIIR symptom criteria for depression (major, dysthymic, bipolar) was 48 (50%): 16 with PGE (35.6%), 6 with EPS (40%) and 26 with CPS (72.2%) (Table II). We noted four cases of bipolar depression. Patients with CPS were more frequently depressed than patients belonging to the other two groups (P < 0.05). There were no sig-
47 TABLE I Demographic characteristics
Number of patients Age (years, mean) Sex (M/F) Socioeconomic status, No. (%) I, II III, IV V Education, No. (%) 13 years Not right-handed, No. (%) Duration of epilepsy (years, mean) Frequency of seizures per month (in the last 3 months) (mean + SD) Family history of depression, No. (%)
Generalized epilepsy
Partial epilepsy with elementary semiology
Partial epilepsy with complex semiology
45 29.2 k 8.5 18i27
15 32.6 f 9.1 916
36 31.7 f 6.8 22l14
12 (27) 12 (27)
10 (28)
3 W) 3 (20) 3 (20)
6 (13) 35 (78)
10 (28) 4(11) 32 (89)
8 (18) 2 (4) 5 (11) 15.7 f 5.6
13 (87) 2 (13) 0 (0) 2 (13) 16.7 + 7.4
1.4 f 2.0
3.3 f 5.2
3.7 + 6.0
3 (7)
l(7)
3 (8)
nificant differences in seizure frequency between the epileptic patients who met DSM-IIIR criteria for depression and those who failed to do so in the whole sample and in each group. Severity of depression
Patients with CPS were significantly more depressed than the patients from each of the other two groups on both HRSD and BSDI (Table III). No correlations were noted between severity of depression and duration of epilepsy, seizure frequency, socio-economic status, education, or family history of depressive illness. Furthermore, no prevalence of left-handedness was found in various groups and no correlation was noted between handedness and severity of depression.
4 (11) 0 (0) 7 (19) 18.2 + 7.3
Depression and lateralization of EEG focus
Twenty patients had a left hemispheric focus, 18 patients had a right hemispheric focus, and 13 patients showed ambiguous or bilateral foci. We did not find a significant correlation between EEG focus lateralization and prevalence of depression. In addition, overall right or left hemisphere EEG focus lateralization did not differentiate groups as to the severity of depression. Anxiety The patients with CPS were significantly
more anxious (P < 0.05) than the subjects with PGE and EPS (Table III). We did not find a relationship between anxiety and duration of epilepsy, seizure frequency, socioeconomic status or education.
TABLE II Type of depression (according to DSM-IIIR criteria) in epileptic groups
Not depressed, No. (%) Depressed, No. (%) Major depression Dysthymic depression Bipolar depression
Generalized epilepsy
Partial epilepsy with elementary semiology
Partial epilepsy with complex semiology
Total
29 (64.4) 16 (35.6) 2 (4.4) ll(24.4) 3 (6.6)
9 (60.0) 6 (40.0) 1 (6.7) 5 (33.3) 0 (0.0)
10 (27.8) 26 (72.2) 4 (11.1) 21 (58.3) l(2.8)
48 (50.0) 48 (50.0) 7 (7.3) 37 (38.5) 4 (4.2)
48 TABLE III Severity ofdepression
HRSD BSDI ZAS
in epileptic groups ~mean t SD)
Generalized epilepsy
Partial epilepsy with elementary semiology
Partial epilepsy with complex semiology
11.1 rf 7.1 9.4 + 7.0 34.2 rt 8.1
10.7 f 6.1 7.6 k 4.9 33.7 rt 6.9
18.0 rt 7.4** 17.1 rt 9.3** 38.6 F 7.g*
**P < 0.001, and *P < 0.05, compared to generalized epilepsy and partial epilepsy with elementary semiology.
Antiepileptic drugs Fifty-seven patients were receiving two AEDs (a combination of two of the following drugs: PB, CBZ, PHT, or VPA), 39 were on monotherapy (15 with PB, 18 with CBZ, and 6 with VPA). There were no differences in the AED levels between the patients meeting DSM-IIIR criteria for depression and those who failed to do so, in the whole sample and in each group. No relationships were noted between AED levels and ratings of depression or anxiety within any group. Furthermore, patients receiving CBZ either in mono- or in ~l~herapy were not significantly less depressed or less anxious than patients receiving other AEDs. The mean HRSD, BSDI, and ZAS scores of patients in monotherapy were compared with those of patients in polytherapy and no significant differences were found. Discussion In this study we found that 50% of all our epileptic patients had depressive illness. The patients with CPS were more depressed than the patients of the other two groups. Our findings are in agreement with those of Standage and Fenton32 who reported depression in 60% of epileptic patients, and of Mendez et al.*’ who noted depression in 55% of 175 epileptic out-patients. The phenomenology of depression was studied in 20 depressed epileptic in-patients and was found to be characterized by ‘endogenous’ rather than ‘neurotic” features25; in our study the type of depression was dysthymi~ in the majority of epileptic subjects. We noted a low incidence of bipolar depression, in agreement with other authors29*33,35.It has pre-
viously been reported that patients with TLE were more depressed than other epileptics”~‘7,34. Subjects with TLE have a 25fold greater risk of suicide than would be expected6. Roy3’, in a study on 42 epileptics, found that current affective symptoms were significantly associated with a past history of neurotic disorder but not with TLE. Roberston et alzY evaluated 66 epileptic patients who fulfilled the Research Diagnostic Criteria for a major depressive disorder; they did not find a correlation between type, severity and features of depression and type of epilepsy, while a past history of depression correlated with CPS. Some investigators have found an association between a right hemisphere focus and manic-depressive disorderslx, or sadness’. However, other studies suggest that there is a relationship between left TLE and depression1~‘“,25,27.We failed to confirm the association between focus laterahzation and depression, in agreement with Robertson et al. “‘. Betts’ noted that AED therapy can interfere with the normal response to stress, and can determine depression. Brent et a1.r’ noted that therapy with PB was associated with higher rates of depression, as compared with CBZ treatment or with no drugs. In the present study, we did not observe a correlation between PB and depression. Dalbyi2 reported that 11 of 18 patients with psychomotor attacks and periodic depression, when treated with CBZ, had an improvement in mood and behaviour; this improvement occurred in spite of inadequate seizure control. In addition, Dalby13 described a positive psychotropic effect of CBZ in about 50% of 40 investigations on over 2000 patients with epilepsy. Rodin and SchmaltzX, using the Bear-Fedio inventory in 148 epileptic patients, found an inverse correlation between CBZ serum levels and total scores on the scale, and with subscores of elation, philosophical interests, sense of destiny, aitered sexuality, and h~ergraphia. Dodrill and Troupinr4 showed an improvement in alertness and mental functioning in epileptic patients receiving CBZ. Andrewes et al.3 noted that higher CBZ levels in epileptic patients on monotherapy corresponded to lower rating scale scores for anxiety, depression and fatigue. Robertson et alB studied patients with epilepsy and major de-
49 pression and found that patients taking PB were more depressed,, whereas patients receiving CBZ were less depressed and less anxious. Recently, behavioural Dodrill” reported favourable changes in 47% of 34 studies on behavioural effects of CBZ in epileptic subjects: the changes most commonly reported are decreased anxiety and depression, increased cooperation, decreased aggression. In the present study, we did not find a correlation between CBZ serum levels and total scores on HRSD, BSDI, and ZAS. This is consistent with the study of Altshuler et al.‘, who were unable to report a significant relationship between depression or anxiety ratings and anticonvulsant drugs, including CBZ. We observed a high level of interictal anxiety in patients with PCS, as reported by previous authors28*29.Betts’ reported that many patients became frightened of their attacks and developed an anxiety state. However, we did not find a correlation between anxiety and the frequency of sei-
zures, and we think the anxiety may be correlated with the type of epilepsy, because our results show that anxiety is more frequent in patients with CPS. The pathogenetic significance of depression in epileptics is unclear and even controversial. In this study, we confirmed a strong association between depression and CPS, but we failed to demonstrate a link between side of epileptic lesion and depression. However, our results do not support the hypothesis that depression represents a behavioural effect of neurochemical responses to brain injury for asymmetrical hemispheric distribution of a neural substrate for mood. In conclusion, we suggest that depression in epileptic patients does not represent a psychological reaction to a particular cognitive or physical impairment, but is in some way related to the type of epilepsy. Nevertheless, the role of physiological mechanisms underlying mood and the way in which this mechanism might provide the emotional regulation in patients with CPS are unclear.
References
ingstone, Edinburgh, 1974, pp. 326-338. 10 Brent, D.A., Crumrine, P.K., Varma, R., Brown, R.V. and Allan, M.J., Phenobarbital treatment and major depressive disorder in children with epilepsy: a naturalistic follow-up, Pediatrics, 6 (1990) 1086-1090. 11 Brown, SW., McGowan, M.E.L. and Reynolds, E.H., The influence of seizure type and medication on psychiatric symptoms in epileptic patients, Br. J. Psychiatry, 148
1 Altshuler, L.L., Devinsky, O., Post, R.M. and Theodore, W., Depression, anxiety and temporal lobe epilepsy. Laterality of focus and symptoms, Arch. Neural., 47 (1990) 284-288. 2 American
Psychiatric Association, Diagnostic and Statis3rd edn. revised, American Psychiatric Association, Washington, DC, 1987. Andrews, D.G., Bullen, J.G., Tomlinson, L., Elwes, R.D.C. and Reynolds, E.H., A comparative study of the cognitive effects of phenytoin and carbamazepine in new referrals with epilepsy, Epilepsia, 27 (1986) 128-134. Annett, M., A classification of hand preference by association analysis, Br. J. Psycho/. , 61 (1970) 303-332. Barraclough, B.M., Suicide and epilepsy. In: E.H. Reynolds and M.R. Trimble (Eds.), Epilepsy and Psychiatry, Churchill Livingstone, New York, NY, 1981, pp. 72-76. Barraclough, B.M., The suicide rate of epilepsy, Acta Psytical Manual of Mental Diseases,
3
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chiatr. Stand.,
(1986) 300-304. 12 Dalby, M.A., Antiepileptic
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76 (1987) 339-345.
7 Bear, D.M. and Fedio, P., Quantitative
analysis of interictal behavior in temporal lobe epilepsy, Arch. Neural., 34 16
(1977) 454-467. 8 Beck, A.T., Ward, C.H., Mendelson, M., Mock, J. and Er-
baugh, J., An inventory for measuring depression, Gen. Psychiatry,
Arch.
4 (1961) 561-568.
17
9 Betts, T.A., A follow-up study of a cohort of patients with
epilepsy admitted to psychiatric care in an English city. In: P. Harris and C. Mawdsley (Eds.), Epilepsy - Proceedings of the Hans Berger Centenary Symposium, Churchill Liv-
18
and psychotropic effect of carbamazepine (Tegretol) in the treatment of psychomotor epilepsy, Epilepsia, 12 (1971) 325-334. Dalby, M.A., Behavioral effects of carbamazepine. In: J.K. Penry and D.D. Daly (Eds.), Advances in Neurology, Vol. 11, Raven Press, New York, NY, 1975, pp. 331-343. Dodrill, C.B. and Troupin, AS., Psychotropic effects of carbamazepine in epilepsy: a double-blind comparison with phenytoin, Neurology, 27 (1977) 1023-1028. Dodrill, C.B., Behavioral effects of antiepileptic drugs. In: D. Smith, D. Treimanm and M. Trimble (Eds.), Advances in Neurology, Vol. 55, Raven Press, New York, NY, 1991, pp. 213-224. Dominian, J., Serafetinides, E.A. and Dewhurst, M., A follow-up study of late-onset epilepsy: II. Psychiatric and social findings, Br. Med. J., 1 (1963) 431-435. Dongier, S., Statistical study of clinical and electroencephalographic manifestations of 536 psychotic episodes occurring in 516 epileptics between clinical seizures, Epilepsia, 1 (1959/60) 117-142. Flor-Henry, P., Psychosis and temporal lobe epilepsy, Epi-
50 lepsia, 10 (1%9) 363-395. 19 Folstein, M.F., Folstein, S.E. and McHugh, P.R., MiniMental-State: a practical method for grading the cognitive state of patients for the clinician, 1. Psych&r. Res., 12 (1975) 189- 198. 20 Gastaut, H., A proposed completion of the current international classification of the epilepsies. In: F.C. Rose (Ed.), Research Progress in Epilepsy, Pitman, London, 1983, pp. 8-13. 21 Hamilton, M., A rating scale for depression, J. Neural. Neurosurg. Psychiatry, 23 (1960) 56-62. 22 Hollingshead, A.B. and Redlich, F.C., Social Class and Mental Illness, John Wiley and Sons, New York, NY, 1958. 23 Kogeorgas, J., Fonagy, P. and Scott, D.F., Psychiatric symptom patterns of chronic epileptics attending a neurological clinic: a controlled investigation, Br. J. Psychiatry, 140 (1982) 236-242. 24 Matthews, W.S. and Barabas, G., Suicide and epilepsy: a review of the literature, Psychosomatics, 22 (1981) 515-524. 25 Mendez, M.F., Cummings, J.L. and Benson, D.F., Depression in epilepsy. Significance and phenomenology, Arch. Neurol., 43 (1986) 766-770. 26 Mulder, D.W. and Daly, D., Psychiatric symptoms associated with lesions of temporal lobe, J. Am. Med. Ass., 150 (1952) 173-176. 27 Nielsen, H. and Kristensen, O., Personality correlates of sphenoidal EEG-foci in temporal lobe epilepsy, Acta Neurol. Stand., 64 (1981) 289-300.
28 Perini, G. and Mendius, R., Depression and anxiety in complex partial seizures, J. Nerv. Menr. Dti., 172 (1984) 287-290. 29 Robertson, M.M., Trimble, M.R. and Townsend, H.R.A., Phenomenology of depression in epilepsy, Epilepsia, 28 (1987) 364-372. 30 Rodin, E.A., and Schmaltz, S., The Bear-Fedio personality inventory and temporal lobe epilepsy, Neurology, 34 (1984) 591-5%. 31 Roy, A., Some determinants of affective symptoms in epileptics, Can. J. Psychiatry, 24 (1979) 554-556. 32 Standage, K.F. and Fenton, G.W., Psychiatric symptom profiles of patients with epilepsy: a controlled investigation, Psychol. Med., 5 (1975) 152-160. 33 Toone, B.K., Garralda, M.E. and Ron, M.A., The psychoses of epilepsy and the functional psychoses: a clinical and phenomenological comparison, Br. J. Psychiarry, 141 (1982) 256-261. 34 Victoroff, J.I., Benson, D.F., Engel, J. Jr., Grafton, S. and Mazziotta, J.C., Interictal depression in patients with medically intractable complex partial seizures: electroencephalography and cerebral metabolic correlates, Ann. Neural., 28 (1990) 221. 35 Wolf, P., Manic episodes in epilepsy. In: H. Akimoto, H. Kazamatsuri, M. Seino and A.A. Ward Jr. (Eds.), Advances in Epilepfology, XIIIth Epilepsy International Symposium, Raven Press, New York, NY, 1982, pp. 237-240. 36 Zung, W.W.K., A rating instrument for anxiety disorders, Psychosomatics, 12 (1971) 371-375.
45
EPIRES 00477
Interictal depression in epilepsy
A. Indaco, P.B. Carrieri, C. Nappi, S. Gentile and S. Striano Instituteof Neurology, 2nd Medical School, Universiry of Naples (Italy)
(Received 24 February 1992; accepted 5 March 1992) Key words: Depression; Anxiety; Seizure; Antiepileptic drugs
The relation between depression and epilepsy was evaluated in % epileptic out-patients. We found that 50% of epileptic patients fulfilled the DSM-IIIR criteria for depression. The Hamilton Rating Scale for Depression, the Beck Self Depression Inventory and the Zung Anxiety Scale were also used in all patients. The patients with partial seizures with complex semiology (CPS) were more depressed than the patients with primary generalized epilepsy and with partial seizures with elementary semiology. A significant increase in the level of anxiety was also found in the group with CPS compared to the other two groups. No correlations were noted between severity of depression and duration of epilepsy, seizure frequency, socio-economic status, education, and family history of depressive illness. No relationship was observed between anticonvulsant drug levels and depression. We failed to confirm an association between side of epileptic lesion and severity of depression. We suggest that depression in epileptic patients does not represent a psychological reaction to a particular cognitive or physical impairment, but is in some way related to the type of epilepsy.
Introduction There is an accumulation of evidence supporting a relationship between epilepsy and depression. Mulder and Daly6 reported that depression is a non-specific reaction to a chronic illness. However, Kogeorgos et al.= and Mendez et a1.25noted that depression is more frequent and severe in epileptic patients than in subjects with comparable chronic neurologic diseases or physical handicaps. The rate of suicide is 4-5 times greater in epileptic patients than in the general population, and this rate is particularly high in subjects with temporal
Correspondence roe:Dr. A. Indaco, M.D., Institute of Neurology, 2nd Medical School, University of Naples, via S. Pansini 5,80131 Naples, Italy.
lobe epilepsy (TLE)5,6,24. Despite this evidence, the relationship between depression and epilepsy has received scant attention. Robertson _et a1.29suggested that depression in patients with epilepsy represents the outcome of multiple factors in individuals genetically predisposed to a primary or idiopathic affective disorder. Mendez et a1.25proposed a specific epileptic psychosyndrome producing an atypical, endogenous depression, due to a left limbic dysfunction. The aim of this study is to evaluate: (1) the characteristics and frequency of depression in a group of epileptic out-patients; (2) the relationship between depression and epileptic syndromes and electroencephalographic (EEG) focus; and (3) the possible correlation between depression and the duration of epilepsy, seizure frequency and anticonvulsant drugs.
46
Materials and methods Two hundred and sixty-four epileptic out-patients, observed consecutively at the Epilepsy Center of our institute of Neurology, were seen from January to September 1990. The general criteria for eligibility for the present study were age 17 to 60 years, lack of mental retardation or other chronic illness, no evidence of neurologic disability, and no history of alcohol or drug abuse. Subjects with progressive central nervous system lesion and a past history of severe head trauma were excluded. In addition, we used the Mini Mental State Examination (MMS)‘9 to exclude patients with cognitive impairment (a score of 23 or below is indicative of significant cognitive impairment). One of us (S.S.), unaware of the depressive evaluation of the subjects, classified all patients, according to the Proposal for Classification of Epilepsp. Because of these criteria of eligibility and exclusion, no patients with secondary generalized epilepsy or benign childhood partial epilepsy were admitted to the study. Consequently, our group included only patients with primary generalized epilepsy (PGE), partial seizure with elementary semiology (EPS) and partial seizure with complex semiology (CPS). Computed tomography scans of the head and at least one EEG were obtained in all patients. All patients had interictal or ictal epileptiform discharges in at least one EEG recording. The lateraliiation of paroxysmal activity in the patients with partial epilepsy was evaluated, when possible. All patients were receiving one or two of the following antiepileptic drugs (AEDs): phenobarbital (PB), carbamazepine (CBZ), phenytoin (PHT) or valproic acid (VPA). The patients with PGE were taking VPA or PB, or an association of PB and VPA; the patients with EPS or CPS were taking CBZ or PI-IT alone, or an association of CBZ and PB, or of PI-IT and PB. Serum AED levels were dete~ined within 7 days of recruitment. We excluded patients receiving three or more drugs, and subjects with drug serum levels not in the therapeutic range. The epileptic patients finally included in the study were evaluated according to DSM-IIIR criteria for depression2. We interviewed all patients for personal and family psychiatric and epileptic history, seizure onset,
frequency and clinical features of seizures. Hand preference was determined with the Annett Hand Preference Questionnaire4. We evaluated the duration of the epileptic syndrome and the frequency of seizures, medical status, education, socioeconomic status (divided into five social classes, I being the highest, according to Hollingshead and Redlich”). Seizure frequency in the last 6 months was assessed using a diary card in all patients. The Hamilton Rating Scale for Depression (HRSD)21, the Beck Self Depression Inventory (BSDI)8 to assess the severity of depression, the Zung Anxiety Scale (ZAS)36 to assess the severity of anxiety were also employed in all epileptic patients. All patients were interviewed between 11 a.m. and 1 p.m. in order to avoid mood changes due to diurnal variations. All subjects gave their informed consent. Statistical amlysis
Intergroup comparisons were made using l-way analysis of variance; post-hoc comparisons were conducted using Student’s t-test. Chi-square test with Yates’ correction or Fisher’s exact test was used to evaluate relationship between categorial variables. Pearson’s correlation coefficients were used for pairs of continuous variables. Results Ninety-six patients fulfilled the criteria for inclusion in the present study. The patient characteristics are shown in Table I. Forty-five patients met criteria for PGE, 15 had EPS, 36 had CPS. The three groups did not differ with respect to age, sex, socioeconomic status, education, duration of epilepsy, seizure frequency, or family history of depressive illness (Table I). DSM-HIR The number of patients meeting the DSM-IIIR symptom criteria for depression (major, dysthymic, bipolar) was 48 (50%): 16 with PGE (35.6%), 6 with EPS (40%) and 26 with CPS (72.2%) (Table II). We noted four cases of bipolar depression. Patients with CPS were more frequently depressed than patients belonging to the other two groups (P < 0.05). There were no sig-
47 TABLE I Demographic characteristics
Number of patients Age (years, mean) Sex (M/F) Socioeconomic status, No. (%) I, II III, IV V Education, No. (%) 13 years Not right-handed, No. (%) Duration of epilepsy (years, mean) Frequency of seizures per month (in the last 3 months) (mean + SD) Family history of depression, No. (%)
Generalized epilepsy
Partial epilepsy with elementary semiology
Partial epilepsy with complex semiology
45 29.2 k 8.5 18i27
15 32.6 f 9.1 916
36 31.7 f 6.8 22l14
12 (27) 12 (27)
10 (28)
3 W) 3 (20) 3 (20)
6 (13) 35 (78)
10 (28) 4(11) 32 (89)
8 (18) 2 (4) 5 (11) 15.7 f 5.6
13 (87) 2 (13) 0 (0) 2 (13) 16.7 + 7.4
1.4 f 2.0
3.3 f 5.2
3.7 + 6.0
3 (7)
l(7)
3 (8)
nificant differences in seizure frequency between the epileptic patients who met DSM-IIIR criteria for depression and those who failed to do so in the whole sample and in each group. Severity of depression
Patients with CPS were significantly more depressed than the patients from each of the other two groups on both HRSD and BSDI (Table III). No correlations were noted between severity of depression and duration of epilepsy, seizure frequency, socio-economic status, education, or family history of depressive illness. Furthermore, no prevalence of left-handedness was found in various groups and no correlation was noted between handedness and severity of depression.
4 (11) 0 (0) 7 (19) 18.2 + 7.3
Depression and lateralization of EEG focus
Twenty patients had a left hemispheric focus, 18 patients had a right hemispheric focus, and 13 patients showed ambiguous or bilateral foci. We did not find a significant correlation between EEG focus lateralization and prevalence of depression. In addition, overall right or left hemisphere EEG focus lateralization did not differentiate groups as to the severity of depression. Anxiety The patients with CPS were significantly
more anxious (P < 0.05) than the subjects with PGE and EPS (Table III). We did not find a relationship between anxiety and duration of epilepsy, seizure frequency, socioeconomic status or education.
TABLE II Type of depression (according to DSM-IIIR criteria) in epileptic groups
Not depressed, No. (%) Depressed, No. (%) Major depression Dysthymic depression Bipolar depression
Generalized epilepsy
Partial epilepsy with elementary semiology
Partial epilepsy with complex semiology
Total
29 (64.4) 16 (35.6) 2 (4.4) ll(24.4) 3 (6.6)
9 (60.0) 6 (40.0) 1 (6.7) 5 (33.3) 0 (0.0)
10 (27.8) 26 (72.2) 4 (11.1) 21 (58.3) l(2.8)
48 (50.0) 48 (50.0) 7 (7.3) 37 (38.5) 4 (4.2)
48 TABLE III Severity ofdepression
HRSD BSDI ZAS
in epileptic groups ~mean t SD)
Generalized epilepsy
Partial epilepsy with elementary semiology
Partial epilepsy with complex semiology
11.1 rf 7.1 9.4 + 7.0 34.2 rt 8.1
10.7 f 6.1 7.6 k 4.9 33.7 rt 6.9
18.0 rt 7.4** 17.1 rt 9.3** 38.6 F 7.g*
**P < 0.001, and *P < 0.05, compared to generalized epilepsy and partial epilepsy with elementary semiology.
Antiepileptic drugs Fifty-seven patients were receiving two AEDs (a combination of two of the following drugs: PB, CBZ, PHT, or VPA), 39 were on monotherapy (15 with PB, 18 with CBZ, and 6 with VPA). There were no differences in the AED levels between the patients meeting DSM-IIIR criteria for depression and those who failed to do so, in the whole sample and in each group. No relationships were noted between AED levels and ratings of depression or anxiety within any group. Furthermore, patients receiving CBZ either in mono- or in ~l~herapy were not significantly less depressed or less anxious than patients receiving other AEDs. The mean HRSD, BSDI, and ZAS scores of patients in monotherapy were compared with those of patients in polytherapy and no significant differences were found. Discussion In this study we found that 50% of all our epileptic patients had depressive illness. The patients with CPS were more depressed than the patients of the other two groups. Our findings are in agreement with those of Standage and Fenton32 who reported depression in 60% of epileptic patients, and of Mendez et al.*’ who noted depression in 55% of 175 epileptic out-patients. The phenomenology of depression was studied in 20 depressed epileptic in-patients and was found to be characterized by ‘endogenous’ rather than ‘neurotic” features25; in our study the type of depression was dysthymi~ in the majority of epileptic subjects. We noted a low incidence of bipolar depression, in agreement with other authors29*33,35.It has pre-
viously been reported that patients with TLE were more depressed than other epileptics”~‘7,34. Subjects with TLE have a 25fold greater risk of suicide than would be expected6. Roy3’, in a study on 42 epileptics, found that current affective symptoms were significantly associated with a past history of neurotic disorder but not with TLE. Roberston et alzY evaluated 66 epileptic patients who fulfilled the Research Diagnostic Criteria for a major depressive disorder; they did not find a correlation between type, severity and features of depression and type of epilepsy, while a past history of depression correlated with CPS. Some investigators have found an association between a right hemisphere focus and manic-depressive disorderslx, or sadness’. However, other studies suggest that there is a relationship between left TLE and depression1~‘“,25,27.We failed to confirm the association between focus laterahzation and depression, in agreement with Robertson et al. “‘. Betts’ noted that AED therapy can interfere with the normal response to stress, and can determine depression. Brent et a1.r’ noted that therapy with PB was associated with higher rates of depression, as compared with CBZ treatment or with no drugs. In the present study, we did not observe a correlation between PB and depression. Dalbyi2 reported that 11 of 18 patients with psychomotor attacks and periodic depression, when treated with CBZ, had an improvement in mood and behaviour; this improvement occurred in spite of inadequate seizure control. In addition, Dalby13 described a positive psychotropic effect of CBZ in about 50% of 40 investigations on over 2000 patients with epilepsy. Rodin and SchmaltzX, using the Bear-Fedio inventory in 148 epileptic patients, found an inverse correlation between CBZ serum levels and total scores on the scale, and with subscores of elation, philosophical interests, sense of destiny, aitered sexuality, and h~ergraphia. Dodrill and Troupinr4 showed an improvement in alertness and mental functioning in epileptic patients receiving CBZ. Andrewes et al.3 noted that higher CBZ levels in epileptic patients on monotherapy corresponded to lower rating scale scores for anxiety, depression and fatigue. Robertson et alB studied patients with epilepsy and major de-
49 pression and found that patients taking PB were more depressed,, whereas patients receiving CBZ were less depressed and less anxious. Recently, behavioural Dodrill” reported favourable changes in 47% of 34 studies on behavioural effects of CBZ in epileptic subjects: the changes most commonly reported are decreased anxiety and depression, increased cooperation, decreased aggression. In the present study, we did not find a correlation between CBZ serum levels and total scores on HRSD, BSDI, and ZAS. This is consistent with the study of Altshuler et al.‘, who were unable to report a significant relationship between depression or anxiety ratings and anticonvulsant drugs, including CBZ. We observed a high level of interictal anxiety in patients with PCS, as reported by previous authors28*29.Betts’ reported that many patients became frightened of their attacks and developed an anxiety state. However, we did not find a correlation between anxiety and the frequency of sei-
zures, and we think the anxiety may be correlated with the type of epilepsy, because our results show that anxiety is more frequent in patients with CPS. The pathogenetic significance of depression in epileptics is unclear and even controversial. In this study, we confirmed a strong association between depression and CPS, but we failed to demonstrate a link between side of epileptic lesion and depression. However, our results do not support the hypothesis that depression represents a behavioural effect of neurochemical responses to brain injury for asymmetrical hemispheric distribution of a neural substrate for mood. In conclusion, we suggest that depression in epileptic patients does not represent a psychological reaction to a particular cognitive or physical impairment, but is in some way related to the type of epilepsy. Nevertheless, the role of physiological mechanisms underlying mood and the way in which this mechanism might provide the emotional regulation in patients with CPS are unclear.
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