Prevalence is a measure of the number of cases of a disease existent in the population at a particular point in time. The prevalence of epilepsy (recurrent unprovoked seizures) shows wide variation across studies, but prevalence generally ranges from 4 to 10 per 1,000 population (1,2,3,4). This two- to threefold variation is related in part to varying definitions, but it is also related to true differences in frequency across populations. The prevalence of epilepsy is generally higher in developing countries than in industrialized nations. In industrialized countries, prevalence tends to increase with advancing age, reaching a peak in the oldest age-groups. In contrast, prevalence in developing countries is highest in young adults. These prevalence cases are characterized by chronicity and are therefore highly selected. They are also
characterized by survival following diagnosis. Population-based prevalence cases are akin to cases seen in general medical or neurological clinics. Generally, they have much less severe disease than cases seen at tertiary referral centers. This difference in severity must be taken into account when considering reports of coexistence of psychosis and epilepsy, because most are generated from these tertiary referral centers.

There are only a few total population incidence studies of epilepsy. The incidence of epilepsy in industrialized countries is approximately 50 per 100,000 population per year (5,6). The incidence in developing countries is probably double this rate (3,4,7). Regardless of geographical area, there is an excess incidence in males, and only approximately 35% of cases have a clearly identified antecedent. In industrialized countries, incidence is high in children up to 1 year and in the elderly. This contrasts with the incidence in developing countries, where it generally peaks in childhood and a few new-onset cases are identified in adults after the age of 50.

Lifetime prevalence is often used to estimate the cumulative incidence. Studies of lifetime prevalence query if a person has ever had a disorder in an attempt to determine the risk for developing the disorder up to the age of interview. In contrast, studies of cumulative incidence use incidence data to mathematically arrive at the accumulated risk for a disorder up to a given age. Although, in theory, for conditions with little excess mortality, the lifetime prevalence should accurately reflect cumulative incidence, this is rarely the case. For epilepsy, lifetime prevalence is 50% less than cumulative incidence (8). In developed countries, the cumulative incidence of epilepsy is approximately 1% through age 20 and approximately 5% through age 80 (1); the cumulative incidence for all seizure disorders ranges from 10% to 20% through age 80. The cumulative incidence in developing countries is higher through the adult years.

Attention-deficit hyperactivity disorder (ADHD) occurs in 3% to 5% of children (11) and is characterized by inattention and/or hyperactivity-impulsivity occurring with greater frequency or severity than is usual for the person’s development (12). Symptoms begin before age 7, occur at home and at school or work, cause impairment of developmentally appropriate functioning, and are not due to any other mental
disorder (12). ADHD also occurs in adults with onset of symptoms in childhood. A population-based study in the Netherlands of 1,813 adults aged 18 to 75, reported an ADHD prevalence of 1.0% (95% confidence interval [CI] = 0.6% to 1.6%) (13). This study, besides another (14), has supported the validity of the adult ADHD diagnosis. Family studies of ADHD consistently support a strong familial component. In most of the family studies, there is a two- to eightfold increased risk of ADHD in parents and siblings of children with ADHD (15,16,17,18,10,12). Similarly, among families of adults with ADHD, the risk of ADHD is high in children (21).

Clinically, there is a perception that ADHD is more common among children with epilepsy, because of the seizure disorder or its treatment (22,23). In studies of children with prevalent epilepsy, 28.1% to 39% had “hyperactivity-impulsivity” (24,25), 42.4% had problems with attention (26), and 13.9% had ADHD (27). This is in excess of the 5% prevalence of ADHD in general population samples (11). Large surveys of the general population (24,25) confirm the associations seen in smaller studies of prevalent epilepsy. In the 1988 National Health Interview study (24,25), hyperactivity assessed by the Behavior Problem Index was 5.7-fold more prevalent among 121 children with epilepsy (28.1%), aged 5 to 17, compared with 3,950 controls (4.9%) (25). “Highly impulsive behavior” as assessed by four questions was found among 39% of 118 children with a history of epilepsy, aged 6 to 17, compared with 11% of 11,042 children without a history of epilepsy (24). Although cross-sectional studies in general population samples confirm the association between ADHD and prevalent epilepsy, they have not assessed the time order of the association.

When time order is examined, it is seen that ADHD is associated with increased risk for developing epilepsy. This has been shown in case-control studies of children with epilepsy (28,29,30) and in cohort studies of select populations of children with ADHD (31,32,33,34). In two case-control studies of children with incident unprovoked seizure (28,29), behavioral disturbances before the onset of first seizure were more frequent than among controls. In one study of 148 children with first unprovoked seizure and 89 seizure-free sibling controls, attention problems as assessed by the Child Behavior Checklist were 2.4-fold more common before identification of the first seizure (8.1%) than in controls (3.4%) (28). In an analysis of a population-based case-control study conducted among Icelandic children (30), children with incident unprovoked seizure were 2.5-fold more likely than age- and gender-matched controls to have a history of ADHD (95% CI = 1.1 to 5.5), meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria before seizure onset. The association was restricted to ADHD-predominantly inattentive type (odds ratio [OR] = 3.7; 95% CI = 1.1 to 13). When the occurrence of new-onset seizures is examined in select samples with ADHD (31,32,33,34), the percentage of children who develop unprovoked seizures (0.2% to 2%) (31,32,34) is greater than the expected rate, because the average annual incidence of seizures is approximately 0.0470 per year in children aged 5 to 16 (29). Therefore, there is an increased risk for developing unprovoked seizures in children with ADHD, and the reported increased risk is smaller in case-control studies than in cohort studies (28,30), which were limited by small numbers of ensuing unprovoked seizures during short follow-up periods in select populations (31,32,33,34).

Community-based studies suggest a point prevalence of depression of 2% to 4%, although estimates are higher in studies of select populations (9,35,36,37). Prevalence is higher in females, and point prevalence is
highest in the adult population. Prevalence increases as one goes from community to primary care settings to inpatients. (This may be a phenomenon of importance in studies of psychiatric disease and epilepsy.) The lifetime prevalence of major depression approaches 20% in some studies and is higher in females (38,39).

Incidence based on first episode or first treatment for major depression varies markedly among studies, but is consistently higher in females (40,41,42,43). Incidence has been reported to be 1 to 2 per 1,000 per year in males and 3 to 5 per 1,000 in females. In the epidemiological catchment area studies, an incidence of 2% per year was reported. This is similar to the incidence recently reported in Finland (44). There are time trends in incidence, with an increasing incidence in middle-aged males reported in more recent studies. In Sweden, cumulative incidence up to age 70 was 27% in males and 46% in females. In studies from the United States, cumulative incidence was reported to be approximately 17%.

The prevalence and the incidence of bipolar disorder are far lower than those for major depression. The incidence of bipolar disorder peaks in 21- to 25-year-olds at 16.4 per 100,000 population (45). The 1-year prevalence of bipolar disorder ranges from 0.2% to 1.1% (46) with a lifetime prevalence of 1.5% to 2.0% (46).

Many cross-sectional studies have examined the association between depression and epilepsy (47,48,49,50), but these studies are not useful for establishing whether epilepsy leads to depression or depression leads to epilepsy. Five studies have examined the temporal relationship, and in only three an appropriate comparison group was identified. In a hospital case series of 51 patients with late-onset epilepsy and possible psychiatric diagnosis, Dominian et al. (51) noted that 16% had a history of depression before the initial seizure. This hospitalized group probably includes more severe forms of epilepsy, and there was no control group.

In a population-based, case-control study of patients with newly diagnosed adult-onset epilepsy, depression was found to be seven times more common among cases than among age- and sex-matched controls (p = 0.03) (52). When analyses were restricted to cases with a “localized onset” seizure, depression was 17 times more common among cases than among controls (p = 0.002). Because patients responded to the questionnaire 4 to 6 weeks after the diagnosis of their first seizure, it is possible that responses were not limited to depression preceding the first diagnosis of epilepsy.

In a population-based, case-control study of incidence of cases of epilepsy of unknown cause in older adults, Hesdorffer et al. (53) noted that DSM-III-R (54) depression before the date the patient’s initial seizure came to medical attention was 3.7 times more common among cases than among controls after adjusting for medical therapies for depression. This increased risk was more prominent among cases with partial-onset seizures. Among cases, major depression occurred closer to the index date compared with controls, suggesting that pathophysiology leading to depression may lower seizure threshold.

A hospital-based retrospective cohort study compared the risk for developing epilepsy in 13,748 patients hospitalized for major depression or bipolar disorder with the risk in 81,380 controls hospitalized for osteoarthritis and 69,149 controls hospitalized for diabetes (55). Although the risk for epilepsy was increased over a 10-year period in patients with hospitalized depression compared with “controls,” adjustment for alcohol or drug “abuse” diminished the difference. Generalizability of these findings is limited because the study is based on people hospitalized for depression, whereas most people meeting the criteria for major depression do not seek medical care for depression.

A recent Icelandic population-based study of 324 people comprising children,
aged 10 and older, and adults with first unprovoked seizure or newly diagnosed epilepsy and 647 controls found that major depression diagnosed according to DSM-IV criteria was associated with a 1.7-fold increased risk for developing epilepsy (95% CI = 1.1 to 2.7) (56). This study also found a 5.2-fold increased risk associated with bipolar disorder that was not statistically significant.

These five studies consistently demonstrate that depression increases the risk for developing epilepsy. Because depression is associated with increased risk for developing unprovoked seizure, a common underlying etiology is suggested.

Depression is associated with an increased risk for neurological conditions other than epilepsy. At least two studies reported a higher than expected risk of depression before the onset of Parkinson’s disease. In a study of consecutive patients with Parkinson’s disease, Mayeux et al. (57) found that 20% were depressed before the onset of clinical symptoms. Similarly, in a study of the effect of levodopa treatment on idiopathic Parkinson’s disease, 22% of 178 cases were severely depressed before disease onset (58). Depression that precedes the onset of Parkinson’s disease may represent a symptom associated with striatal nigral degeneration, or the accompanying neurotransmitter changes may increase the risk of disease by making the brain vulnerable to other insults (59).

In patients with multiple sclerosis, depression has been reported months or even years before the onset of clinical symptoms. Matthews (60) and Goodstein and Ferrell (61) each reported three patients with multiple sclerosis in whom depression heralded the onset of other more typical neurological symptoms. These authors argued that depression is as much a neurological symptom of multiple sclerosis as gait disturbance. Depression occurred in 26% of patients with multiple sclerosis before the onset of symptom, but not in controls with other chronic neurological conditions matched for age, sex, and degree of disability (62).

Depression may also be a risk factor for Alzheimer’s disease. Studies clearly demonstrated an association between risk for epilepsy and dementia in general and Alzheimer’s disease in particular. The EURODEM collaborative reanalysis of 11 case-control studies of NINCDS-ADRDA or Alzheimer’s disease diagnosed as per DSM-III criteria found that a history of depression at least 1 year before the onset of Alzheimer’s disease was more common among late-onset cases than among controls (63). Alzheimer’s cases diagnosed after age 70 were more than four times likely to be diagnosed with depression within 10 years of disease and twice as likely to be diagnosed with depression more than 10 years before onset or diagnosis of Alzheimer’s disease.

The consistency and strength of the association between prior depression and subsequent neurological diseases of the brain, including epilepsy, are compelling. It is difficult to attribute this association to a prodrome of the neurological disorder, particularly for epilepsy, because the association between depression and neurological diseases remains, even when limited to depression occurring many years before neurological diagnosis. The prevalence of depression before developing epilepsy is remarkably consistent across these diseases: 21% of patients before their first unprovoked seizure (29,30); 20% to 22% of patients before the onset of idiopathic Parkinson’s disease (57,58); and 26% of patients before the onset of multiple sclerosis (62). Collectively, these studies suggest that alterations in neurotransmitter function associated with depression may increase susceptibility to neurological diseases.