Which came first? Epilepsy or depression? The author sheds light on a complex relationship.
Dr Mula is Consultant in Neurology and Epileptology at the Atkinson Morley Regional Neuroscience Centre, St George’s University Hospital NHS Foundation Trust and Senior Lecturer at St George’s University, London, UK.
Studies consistently show that depression and mood disorders are comorbid with epilepsy. Data from community-based studies report prevalence rates for mood disorders in 20% to 22% of patients with epilepsy. In selected populations, such as tertiary referral centers or surgery programs, the prevalence is even higher and ranges between 30% and 50%. The wide prevalence ranges seem to be associated with the severity of the seizure disorder. For instance, in patients who are seizure-free, it is estimated only 4% experience depression.1
A complicated relationship
The relationship between depression and epilepsy is complex. A number of epidemiologic studies have suggested that the relationship is not necessarily unilateral but rather bidirectional, with some patients presenting with a psychiatric disorder before the emergence of seizures.2 Such a bidirectional relationship has been noted in other chronic medical conditions such as Parkinson disease, stroke, dementia, diabetes, and cardiovascular disease, which suggests that depression is interlinked with a number of chronic medical conditions.
In the case of epilepsy, various neurobiological and psychosocial variables play a role in this complex relationship. On the psychosocial side, the burden of stigma, social limitations, and the discrimination associated with epilepsy can lead to demoralization and poor self-esteem. On the neurobiological side, the pathophysiology of epilepsy is interlinked with mood problems. Similarly, the involvement of the temporal lobes and the psychotropic effects of antiepileptic drugs seem to be relevant contributors to the increased rates of mood problems in epilepsy.
Children, depression, and epilepsy
Depression has been historically studied and investigated in the context of adult epilepsies, and epidemiological studies of depression in children with epilepsy are limited in comparison. Still, the rates show an increased risk for depression. For instance, a prospective study with a 9-year follow-up of newly diagnosed children with epilepsy reported a 13% prevalence of depression. A large US nationwide survey found depression in 8% of children with current epilepsy, 7% of children with a previous history of seizures, and 2% in control patients.
Similar figures were reported by a UK community-based study of children with epilepsy aged 5 to 15 years who attended schools in Sussex. In addition, 50% of adults with depression usually have a history of an anxiety disorder during childhood.3 For all these reasons it is important to have more data from children with epilepsy.
Getting to the diagnosis
Mood disorders in epilepsy represent a relevant prognostic marker. Depression is not only associated with poor quality of life but also increased rates of adverse effects from medication, increased risk of drug-resistant epilepsy, poor outcomes after surgery, more severe seizures, prolonged post-ictal states, and increased risk of injuries. For this reason, the early detection of mood disorders in epilepsy has considerable implications in the final management of the individual epileptic syndrome.
The phenomenology of depression in patients with epilepsy represented a matter of debate for many years. This point is crucial from a clinical perspective as it implies the need for different clinical instruments to make a diagnosis, different response rates to treatment, the need for different treatment strategies, and ultimately a different prognosis. Although patients with epilepsy develop mood disorders that are identical to those seen outside epilepsy, an increasing number of researchers have pointed out that mood disorders in epilepsy can be characterized by atypical features that are poorly reflected by conventional classificatory systems such as DSM and ICD.
During the 20th century, Blumer coined the term interictal dysphoric disorder to refer to a subtype of somatoform-depressive disorder claimed as typical of patients with epilepsy.4 It was characterized by a component of mood instability associated with anxiety and somatic symptoms. Modern studies pointed out that such a condition is a mood disorder probably not specific to epilepsy, as it is also diagnosed in patients with other neurological problems.
There is also a significant component of comorbid anxiety (social phobia and/or generalized anxiety disorder) and quite evident mood instability. What seems to be typical of patients with epilepsy is the presence of a specific pattern of mood symptoms with dysphoria and mood swings mostly around the seizures. These seem to be responsible for the pleomorphic features of the so-called interictal dysphoric disorder.
All patients with epilepsy should be routinely screened for mood disorders for early identification of any relevant clinical problem. Psychiatric problems are, more often than not, ignored and go untreated, unless they are severe enough to cause major disability. This may be due to the unfamiliarity of neurologists with screening instruments and psychotropic medications used to treat mood disorders.
A number of clinical instruments have been validated in patients with epilepsy for the detection of mood and anxiety disorders: the Beck Depression Inventory, the Hamilton Rating Scale for Depression and the Hospital and Anxiety Scale. However, the Neurological Disorders Depression Inventory for Epilepsy (NDDIE) is now the most well-known screening instrument; it was specifically developed for patients with epilepsy and it is user-friendly and easy to use in a busy outpatient setting.
During the last few years, the International League Against Epilepsy issued a number of publications regarding a pragmatic approach to these problems. Their work is based on evidence from primary psychiatric disorders and should provide practical clinical guidance in addressing mood disorders in patients with epilepsy.
Antidepressants in conjunction with cognitive behavioral therapy are considered first-line treatment for major depression and the majority of anxiety disorders. Historically, the effect of antidepressants on seizure threshold has represented a major concern for clinicians. However, this was an a priori assumption based on early anecdotal reports of patients developing epileptic seizures during treatment and EEG studies showing epileptic abnormalities during treatment with tricyclics. Subsequent studies clarified that the supposedly increased seizure risk was real for a few specific compounds.5
Data from controlled trials and clinical studies show that maprotiline, high doses of tricyclics (> 200 mg daily; especially amitriptyline and clomipramine), or high doses of bupropione (> 450 mg) are associated with an increased risk of seizures.6 However, SSRIs are entirely safe in terms of seizure risk. Sertraline and citalopram have the most data supporting safety. For this reason, sertraline and citalopram are considered first-line treatment.
All clinicians recognize that “start low and go slow” remain the best strategy when approaching complex patients with multiple comorbidities. While low starting doses of antidepressants may be considered reasonable, it should always be kept in mind that this does not mean low target doses-full remission should always be the first goal of an antidepressant treatment. In fact, antiepileptic drugs (AEDs) with inducing properties (ie, carbamazepine, phenytoin, barbiturates) reduce the blood levels of almost all antidepressants, so some patients may require high dosages.
Fighting the double stigma: patient education and support
It is incredibly important to talk to your patients. Mental health issues can be addressed successfully, and there are many resources available. Patients may also be referred to the many association websites, such as the America Epilepsy Society, Epilepsy Foundation-all of which have useful information on depression and epilepsy.
The bigger problem is overcoming the double stigma associated with the diseases: epilepsy carries a stigma as does depression. This double stigma negatively affects both prevention and care efforts. It creates a context in which patients are reluctant to acknowledge mental health issues. It also has strong psychological consequences for those who have uncontrolled epilepsy, including increasing social isolation. For this reason, clinicians should not only inform patients about depression but also discuss stigma and discrimination in health care systems and in the wider community.
Partnering with patients is essential; there should be clear care-pathways with patient involvement. Patients can be encouraged to get involved in a number of ways, including policy-making and strategic planning, formation of support groups, counselling programs, positive living courses, and inclusion in the training of mental health professionals.
1. Baker GA, Jacoby A, Chadwick DW. The associations of psychopathology in epilepsy: a community study. Epilepsy Res. 1996;25:29-39.
2. Mula M. Depression in epilepsy. Curr Opin Neurol. 2017;30:180-186.
3. Kim-Cohen J, Caspi A, Moffitt TE, et al. Prior juvenile diagnoses in adults with mental disorder: developmental follow-back of a prospective-longitudinal cohort. Arch Gen Psychiatry. 2003; 60:709-717.
4. Mula M. The interictal dysphoric disorder of epilepsy: a still open debate. Curr Neurol Neurosci Rep. 2013;13:355.
5. Mula M. The pharmacological management of psychiatric comorbidities in patients with epilepsy. Pharmacol Res. 2016;107:147-153.
6. Alper K, Schwartz KA, Kolts RL, Khan A. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol Psychiatry. 2007;62:345-54.
Mula M. Neuropsychiatric Symptoms of Epilepsy. New York: Springer; 2016.
Mula M. Depression in epilepsy. Curr Opin Neurol. 2017;30:180-186.
Mula M. The pharmacological management of psychiatric comorbidities in patients with epilepsy. Pharmacol Res. 2016;107:147-153.
Mula M, Kanner AM. Treatment of psychiatric disorders in adults with epilepsy. Epilepsia. 2013;54(Suppl 1):1,2.