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Depression is the most common comorbid condition in epilepsy. The cause of this comorbidity is unknown, and could involve psychosocial consequences of epilepsy, treatment side-effects, seizure manifestations, or common neurobiologic mechanisms. One hypothesis of particular interest is a shared genetic susceptibility to epilepsy and depression. We tested this hypothesis by studying depressive symptoms in families with an identified genetic form of epilepsy: autosomal dominant partial epilepsy with auditory features caused by mutations in the leucine-rich, glioma inactivated 1 gene (LGI1).
A standardized depression screen was administered to 94 individuals from 11 families with mutations in LGI1, including 38 mutation carriers with epilepsy (AC), 11 clinically unaffected mutation carriers (UC), and 45 non-carriers (NC).
Current depressive symptom scores were significantly higher in AC than in NC, an association that remained after excluding depressive symptoms that appeared likely to be caused by antiepileptic medication use. However, scores did not differ between UC and NC.
Although LGI1 mutation carriers who were clinically affected with epilepsy had increased depressive symptoms, mutation carriers without epilepsy did not. These findings suggest that the increase in depressive symptoms in affected individuals from these families is related to epilepsy or its treatment rather than to LGI1 mutations per se.
Depression is the most common comorbid condition in epilepsy, affecting 20–55% of patients (Mendez et al., 1986; Edeh & Toone 1987; Robertson et al., 1987; Baker et al., 1996; Jacoby et al., 1996; Lambert & Robertson 1999; Hesdorffer et al., 2000; Hesdorffer et al., 2006). The cause of this comorbidity is unknown. Possible explanations include psychosocial consequences of epilepsy, treatment side-effects, seizure manifestations, or common neurobiologic mechanisms. While studies have consistently shown an increased risk of depression after epilepsy onset (Edeh & Toone 1987; Jacoby et al., 1996), some data also suggest that depressed individuals have an increased risk of developing epilepsy (Forsgren & Nystrom 1990; Hesdorffer et al., 2000; Hesdorffer et al., 2006). This bidirectional relationship supports the hypothesis of overlapping mechanisms for the two disorders (Kanner 2003; Kanner 2006; LaFrance et al., 2008), which might be mediated by a shared genetic susceptibility or by common environmental risk factors.
The comorbidity of epilepsy with depression is especially striking for temporal lobe epilepsy (TLE) (Edeh & Toone 1987; Perini et al., 1996; Hesdorffer et al., 2000; Quiske et al., 2000; Piazzini et al., 2001; Gaitatzis et al., 2004), suggesting limbic system involvement for both disorders (Kanner & Balabanov 2002; Briellmann et al., 2007; Kanner 2008). So far, only one gene has been identified with a major influence on susceptibility to a form of TLE: the leucine-rich, glioma inactivated 1 gene (LGI1). Mutations in LGI1 have been identified in approximately 50% of families with autosomal dominant partial epilepsy with auditory features (ADPEAF), and have a penetrance of about 67% (Rosanoff & Ottman 2008). ADPEAF is an idiopathic focal epilepsy syndrome with auditory symptoms or receptive aphasia as major ictal manifestations (Ottman et al., 1995; Poza et al., 1999; Winawer et al., 2000; Winawer et al., 2002; Michelucci et al., 2003). These symptoms strongly suggest localization to the lateral temporal lobe, and hence the syndrome has also been called autosomal dominant lateral temporal lobe epilepsy. Psychiatric symptoms, including depression and suicide, were reported in one ADPEAF family with an LGI1 mutation (Chabrol et al., 2007).
We took advantage of this gene identification to investigate the hypothesis of a shared genetic susceptibility to epilepsy and depression. Specifically, we investigated whether mutations in LGI1, which are known to have a strong effect on the risk for epilepsy, also raise the risk for depressive symptoms.
Although the penetrance of mutations in ADPEAF families is relatively high, some family members with mutations remain unaffected with epilepsy. Hence in assessing the possible effects of LGI1 mutations on depression, we studied mutation carriers with and without epilepsy separately, to distinguish the effects of epilepsy or its treatment from those of mutations per se.
Subjects were recruited from 11 families participating in previous genetic studies of ADPEAF, including eight families reported previously (Ottman et al., 1995; Winawer et al., 2000; Kalachikov et al., 2002; Winawer et al., 2002; Ottman et al., 2004) and three families newly reported here (Figure 1 and Supplementary Tables e-1 and e-2). Although we are currently investigating ADPEAF families both with and without mutations in LGI1, the current analysis is restricted to families with mutations. Each family had a different mutation in LGI1. The study was approved by the Columbia University Medical Center Institutional Review Board; all subjects gave written informed consent.
The methods for recruitment and clinical data collection have been described elsewhere (Winawer et al., 2003; Ottman et al., 2005; Choi et al., 2006). Briefly, information on each family member was collected using a set of validated semi-structured interviews, usually administered by telephone. Medical records were obtained from the patients’ treating physicians and reviewed for seizure descriptions, histories of etiologic factors, and EEG and neuroimaging data. Some patients were also given a brief neurologic examination and a study EEG. For each subject, a final diagnosis was rendered by experienced epileptologists based on review of all available information. Partial seizures were classified according to the Partial Seizure Symptom Definitions as previously described (Choi et al., 2006). To prevent bias, the epileptologists were blinded to information about other family members when they reviewed each subject’s information.
For the present study, we recontacted previously participating subjects if they had been tested for LGI1 mutations and were believed to be alive and currently at least 18 years old. We classified family members into three groups: affected carriers (AC), unaffected carriers (UC), and non-carriers (NC). Interviewers were blind to genetic status and to study hypotheses.
To detect variants in LGI1, we sequenced the gene’s eight coding exons in DNA extracted from blood or EBV-transformed lymphoblastoid cell lines. Polymerase chain reaction (PCR) primers were placed at the exon boundaries to amplify complete exonic sequences and corresponding intron-exon junctions. PCR amplification products were purified over 96-well glass fiber plates (Whatman, Kent, UK) and sequenced in both directions using dye-terminator chemistry and ABI 3730xl DNA Analyzer (Applied Biosystems, California). Sequence variants were identified by alignment with the LGI1 reference sequence using the Seqman 2 program (DNAstar Inc., Madison, WI) and further verified by visual inspection. Interpretation of the sequence analysis data was performed blind to disease status.
Interviewers administered the depression subsection of the Patient Health Questionnaire (PHQ-9) (Spitzer et al., 1999; Kroenke et al., 2001). The PHQ-9 is a widely used 9-item depression screen and diagnostic tool designed to detect current (i.e., previous 2 weeks) depressive symptoms using a quantitative symptom scale. It has good psychometric properties, a sensitivity of 88% and specificity of 88% for current major depression (Kroenke et al., 2001), and can be administered over the telephone (Pinto-Meza et al., 2005). The PHQ-9 has been used to classify individuals according to current major depression (and sub-threshold depression) in general population settings (Martin et al., 2006) as well as in specific neurologic populations including epilepsy (Haut et al., 2009; Seminario et al., 2009), traumatic brain injury (Fann et al., 2005), and stroke (Williams et al., 2005).
In our analyses, the independent variable was LGI1 mutation status (AC, UC, or NC) and the dependent variable was current depressive symptoms. Depressive symptoms were defined as the sum of the PHQ-9 symptoms as previously recommended (Spitzer et al., 1999). Total symptom scores range between 0–27 with cut-points to identify minimal (0–4), mild (5–9), moderate (10–14), moderately severe (15–19), and severe (≥20) depression (Kroenke et al., 2001). We first compared carriers (both with and without epilepsy) with NC, and then we compared AC with NC. Finally, to exclude a difference related to symptoms of epilepsy or its treatment, we compared UC to NC, thus restricting the comparison to individuals without epilepsy. To control for non-independence of individuals within the same family, analyses were conducted using a random effects model within generalized least squares regression with STATA statistical software (StataCorp 2007).
The three new families with LGI1 mutations had clinical features consistent with those of previously reported families (Figure 1 and Tables e-1 and e-2). In Family I (Figure 1), we identified a missense mutation in exon 8 (1477G>A counting from the initiation codon) resulting in the substitution of a conserved amino acid residue (Gly493Arg). This family contains seven individuals with idiopathic epilepsy, with an average age at onset of 16 years (range 11–35) (Supplementary Table e-1). Six of these individuals were classified as having focal epilepsy and the remaining one was unclassifiable. All six of those with focal epilepsy had either ictal auditory symptoms (N=3), ictal receptive aphasia (N=2), or both (N=1) (Supplementary Table e-2).
Family J (Figure 1) has a mutation in exon 6 (598delT) predicted to cause protein truncation. The family contains five individuals with idiopathic focal epilepsy (age at onset: average 15, range 8–35 years), four of whom had both auditory symptoms and receptive aphasia. One additional individual (II:2), who also carried the mutation, had an isolated unprovoked seizure associated with multiple sclerosis, and also reported auditory symptoms. One other individual (I:1) had an acute symptomatic seizure as an allergic reaction to penicillin, and another (I:2) was reported to have had epilepsy but could not be classified further.
In Family K (Figure 1), we identified a mutation in exon 8 (1636-1637delCA) predicted to cause protein truncation. This family contains 11 individuals with idiopathic epilepsy (age at onset: average 18, range 11–38 years), but information was sufficient for further classification in only six of them, all of whom had focal epilepsy. Among these six individuals, two had auditory symptoms and one had both auditory symptoms and receptive aphasia. In addition, one individual (III:9) had an isolated unprovoked seizure, and another (III:18) had symptomatic epilepsy associated with a traumatic brain injury with loss of consciousness lasting more than 30 minutes. Although mutation status in III:18 is unknown because he declined to donate blood for the study, he reported both auditory symptoms and aphasia (Supplementary Table e-2). Finally, four individuals (IV:13, IV:15, IV:16, and IV:21) were reported by other family members to have had seizures, but this information could not be confirmed because they declined to participate.
To analyze the risk of depression, we included eight previously reported families with LGI1 mutations in addition to the three new families reported here (Kalachikov et al., 2002; Ottman et al., 2004). In these 11 families, 121 individuals met inclusion criteria (46 AC, 15 UC, and 60 NC), of whom 94 (78%) participated (38 AC, 11 UC, and 45 NC), 10 (8%) refused, eight (7%) had died or were physically unable to participate, and nine (7%) could not be contacted after multiple attempts. After exclusion of the individuals who had died or were unable to participate, the participation rate was 83% (94/113), a rate that was not significantly associated with gender, education, age, ethnicity, or comparison group (AC, UC, or NC).
Table 1 shows the demographic characteristics and depression outcomes of the participating subjects. Among the 45 participating NC, 12 (27%) were married-in relatives who were not genetically-related to LGI1 carriers. The three comparison groups did not differ in the distribution of gender or number of family members with epilepsy. Although NC were older than carriers (average age: AC 45 years, UC 44 years, NC 52 years, p=0.03 for carriers vs. noncarriers), age at interview was not associated with current depression. Therefore, none of these would confound the relationship between carrier status and depression in this sample.
Current depressive symptom severity scores were significantly higher in carriers than in NC, both in the analysis of the two carrier groups combined (p=0.01, Table 1) and in the analysis restricted to AC (p=0.002, Table 1). However, current symptom severity scores were not higher in UC than in NC (p=0.96). Table 1 shows the distribution of depression symptoms by LGI1 carrier group and severity categories (e.g., mild, moderate, severe). Scores in the moderate to severe range (score ≥10) were found in 16% of AC, 7% of NC and none of UC.
One possible explanation for the increase of depressive symptoms in AC is the use of antiepileptic drugs (AEDs), since side-effects of some AEDs may mimic depressive symptoms. To evaluate this possibility, we repeated the analysis after excluding five items in the PHQ-9 that appeared most likely to be associated with AED use: sleeping difficulties, feeling tired or having little energy, appetite changes, concentration difficulties, and moving or speaking slowly or feeling restless. In this analysis the risk remained higher in all carriers vs. NC (p=0.015) and in AC vs. NC (p=0.007).
Since depressive symptoms were increased in AC but not in UC, we considered whether depressive symptom scores were associated with epilepsy severity, as measured by the lifetime history of secondarily generalized tonic-clonic seizures (SGTCs). Among AC whose diagnostic interviews were completed ≥5 years after epilepsy onset (N=33), those who had a history of ≥4 SGTCs (N=24) had higher depressive symptom scores than those with <4 SGTCs (N=9) (4.9 vs. 2.3, p=0.15). When this analysis was restricted to 22 individuals interviewed for depressive symptoms <5 years after the diagnostic interviews were done (so that the information on number of SGTCs was more current), the difference was larger (5.6 vs.1.2, p=0.05).
Our objective was to determine whether depressive symptoms are increased in LGI1 carriers and if so, to test whether this increase could be attributed to a shared genetic risk for epilepsy and depression. If LGI1 mutations raised risk for depression in addition to raising risk for epilepsy, we would expect an increase in depressive symptoms in mutation carriers, regardless of whether or not they were clinically affected with epilepsy. While current depressive symptom scores were higher in LGI1 mutation carriers than in non-carriers, this increase was restricted to carriers who were clinically affected with epilepsy. This association remained even after restricting depressive symptoms to those less likely to be caused by AED use.
Two other studies have administered the PHQ-9 to patients with epilepsy (Haut et al., 2009; Seminario et al., 2009). One of these (Haut et al., 2009) assessed depressive symptoms in elderly individuals with localization-related epilepsy (42% remote symptomatic). The mean PHQ-9 total depressive symptom score, 4.2, was similar to the mean in affected individuals in our study. The other study (Seminario et al., 2009) assessed depressive symptoms in a sample of patients attending an epilepsy clinic, including individuals with various epilepsy types (localization-related, idiopathic generalized, symptomatic generalized) and individuals with nonepileptic seizures. The mean PHQ-9 total depressive symptom score was 6 overall (range = 6.07–12.33) and 29% of subjects had scores in the moderate to severe range as compared to 16% in the present study.
To distinguish the effects of LGI1 mutations from those of epilepsy or its treatment, we examined depressive symptoms in affected and unaffected mutation carriers separately, compared with non-carriers within the same families. One limitation of our study was the small number of UC. However, we found no evidence of increased depressive symptoms in UC; in fact, mean current depressive symptom scores were the same for UC and NC (1.9, Table 1).
Another limitation of our study relates to the instrument used to detect depression. The PHQ-9 only screens for current depressive symptoms, and thus our findings are restricted to a short time window (i.e., previous two weeks). Since genetic effects could manifest at any age, subsequent studies should use diagnostic instruments that assess lifetime history of depression.
Our observation of increased depressive symptoms in LGI1 mutation carriers with epilepsy, but not in mutation carriers who are clinically unaffected, suggests that the increased risk for depression probably results from epilepsy or its treatment rather than from LGI1 mutations per se. The higher depressive symptom scores we observed in individuals with ≥4 SGTCs than in those with fewer SGTCs are consistent with this interpretation. An explanation related to treatment appears unlikely because depressive symptoms remained increased in mutation carriers with epilepsy after excluding symptoms most likely to be AED-related, although studies of untreated individuals would be needed to confirm this. An effect of LGI1 mutations on the risk for depressive symptoms, if any, must be restricted to individuals in which the mutation is “penetrant” – i.e., those who have both an LGI1 mutation and some other unidentified factor that interacts with the mutation to raise seizure risk. Finally, we note that since the study was restricted to families with mutations in LGI1, these findings cannot be generalized to other genetic and nongenetic causes of epilepsy.
We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
The authors thank the families who participated in this study. None of the authors has any relevant financial interest or conflicts in the submitted publication material. This study was supported by grants from National Institute of Neurological Disorders and Stroke (K23NS054981 [to GAH], R01NS036319 [to RO], and R01NS043472 [to RO]).
DISCLOSURE OF CONFLICTS OF INTEREST
None of the authors has any conflict of interest to disclose.