Mind Matters (Issue 5): Depression and Epilepsy: The Bidirectional Relationship

Introduction

Epilepsy is a complex disease which is frequently associated with other co-morbid neuropsychiatric diseases such as migraine, anxiety and depression. Epilepsy and depression share a bidirectional relationship as the incidence and prevalence rate for depression is significantly higher both before and after an epilepsy diagnosis. Depression is under-diagnosed and under-treated in patients with epilepsy. Various epidemiological studies have reported the prevalence of depression between 11-60% in patients having recurrent seizures and 3-9% in patients having well-controlled seizure. Community based studies have reported the depression prevalence of 23% in patients with epilepsy.^{1, 2}

• Suicidal tendencies are common in patients with epilepsy and frequently result in mortality. The overall suicide rate in people with epilepsy to be five times higher than in the general population and 25 times greater for patients with complex partial seizures of temporal lobe origin.^2,3

Depression and epilepsy may share a similar pathophysiologic mechanism. Overlapping anatomical regions of nervous system in both the diseases such as temporal, orbitofrontal, and inferior prefrontal areas suggests involvement of similar pathophysiology in both the diseases.  Altered expression and function of specific neurotransmitters have been identified as potential common pathogenic mechanism for depression and epilepsy.¹

• Risk of depression in epilepsy varies based on multiple factors including gender, genetics, seizure type, epileptic focus and socio-economic status.  Complex partial seizures, lack of employment, and treatment of epilepsy with certain drugs like clonazepam, vigabatrin and tiagabine significantly increase the risk of depression in patients with epilepsy.⁴

Depression remains major detrimental factor to the quality of life of even patients with well controlled epilepsy. It has also been associated with poor treatment outcome of the ongoing treatment for epilepsy. Management of depression in patients with epilepsy is sometimes complicated and requires number of factors to be considered. Treatment with psychological interventions such as cognitive behavioural therapy before initiating pharmacological therapy is recommended by several guidelines. Antidepressants could be considered if there is no significant improvement with psychological interventions.^{2, 4}

Diagnosis of Depression in Patients with Epilepsy

Despite the high prevalence of depression in patients with epilepsy it remains under-diagnosed and untreated. Majority of the patients with epilepsy and depression do not report most of the symptoms required for fulfilling the diagnostic criteria. Depression may mimic as the primary depressive disorder, but in a significant percentage of patients, it presents with atypical characteristics. The use of screening self-rating scales may help to identify depressive episodes in patients with epilepsy. However, for a diagnosis to be established an in-depth evaluation is vital. The NICE guidelines recommend assessment of depression by a healthcare professional capable enough to conduct complete mental assessment. The standard psychiatric interviews are usually lengthy and most of the clinicians treating epilepsy are not trained to conduct the same. ^{2, 3, 4}

• Anhedonia, the inability to find pleasure in most activities is an excellent and strong indicator of depression.³

The use of validated self-rating screening tools is the next step that helps in revealing the individuals with depression. The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) (a six-item screening instrument), now validated in several languages to screen for major depressive episodes in patients with epilepsy, is a reliable tool that is easy to use in the neurology outpatient setting as it takes only a few minutes to complete. The score of more than 15 indicates the presence of major depression with 90 per cent specificity and 81 per cent sensitivity. Other screening tools available are the self-reporting BDI-11 and the Center for Epidemiologic Studies – Depression (CESD). ^{3, 4}

Impact of the Bidirectional Relationship between Depression and Epilepsy

Epilepsy as the risk factor for the depression is very well known and it is well established that 1 out of every 3 patients with epilepsy will be suffering from a depressive disorder in the course of their life.⁶ Patients with history of depression have 4 to 7-fold higher risk of developing epilepsy whereas, patients with previous psychiatric diseases have 5 times higher risk of epilepsy.   Clinical data suggests that presence of one disorder facilitates the development of other. This bidirectional relationship suggests the existence of common pathophysiological pathways between both the disorders. The pathophysiologic mechanisms shared by depression and epilepsy are: ^{2, 3}

• Abnormal CNS activity of several neurotransmitters, particularly serotonergic (5-hydroxytryptamine,), norepinephrine, dopamine, GABA-ergic, and glutamate. In primary depression, reduced activity of these neurotransmitters has been identified as one of the major pathogenic mechanisms.  Available evidences on neurotransmitter activity in both epilepsy and depression suggest that the occurrence of one may facilitate the development of the other, and vice versa. ^1,3
• Common changes in structure of brain have been identified in patients with depression and those with epilepsy. Structural changes, presenting as atrophy of temporal, orbitofrontal and frontal-lobe structures, in the amygdala, hippocampus, entorhinal cortex, temporal lateral neocortex, as well as in the inferior prefrontal and mesial-frontal cortex, and to a lesser degree, of the thalamic nuclei and basal ganglia. ^3,4
• Functional abnormalities in temporal and frontal lobes have been observed. PET scanning has shown decreased 5-HT1A binding in patients with major depression involving the temporal cortex, hippocampus and amygdala. Similarly, studies in epilepsy patients have shown significantly reduced 5HT1A binding at the area of epileptic focus. ^2,4
• Abnormal functioning of the hypothalamic–pituitary– adrenal axis has been seen in patients with both the disease. ³

Hippocrates in 400 BC was the first to suggest this type of bidirectional relationship between depression and epilepsy when he wrote, “Melancholics ordinarily become epileptics, and epileptics melancholics: what determines the preference is the direction the malady takes; if it bears upon the body, epilepsy, if upon the intelligence, melancholy”. ²

The causes of depression in patients with epilepsy are multifactorial. Depressive disorders in epilepsy may be mediated by neurobiological, iatrogenic, neurochemical and anatomical mechanisms and often they result from the interplay of all of these mechanisms.^{2, 4}

Clinical Presentation of Depression in Patients with Epilepsy

Depression in patients with epilepsy is categorized as per the temporal relation with seizure occurrence. Its symptoms can present during the 48 to 72 hours preceding a seizure (pre-ictal symptoms of depression), they can be an expression of an actual seizure (ictal symptoms of depression) or can occur within 120 hours after a seizure (postictal symptoms of depression). Symptoms which occur prior or after seizure are referred as peri-ictal symptoms whereas those which are unrelated to occurrence of seizures are identified as inter-ictal seizures. Peri-ictal and inter-ictal both frequently occur simultaneously with an exacerbation in severity of symptoms during the postictal period. ^{4, 5}

Pre-ictal Symptoms

It represents as a cluster of dysphoric symptoms for several hours or 2-3 days prior to onset of seizures. Preictal symptoms are frequently reported as dysphoric mood, irritability or motor hyperactivity. In children, dysphoric moods lead to irritability, poor frustration tolerance, motor hyperactivity and aggressive behaviour and these changes more accentuated during the 24 hours prior to the occurrence of seizure. ^{4, 5}

Ictal Symptoms

Ictal symptoms of depression are the expressions of a simple partial seizure and occur more commonly in temporal lobe epilepsy. Ictal depression is second most common type of ictal effect and the feelings of anhedonia with guilt and suicidal thoughts are the most common symptoms. As the ictus evolves from a simple to a complex partial seizure the ictal symptoms of depression may result in alteration of consciousness. ^{4, 5}

Post-ictal Symptoms

Postictal symptoms of depression are relatively common and were significantly associated with more postictal cognitive deficits. Symptoms of postictal depression usually last for several hours but in some cases, it can last for up to two weeks. It occurs in focal epilepsies especially those with a temporal or frontal epileptic focus. Many times, it can lead to suicide attempts; which makes it necessary to keep close follow up of patients with known postictal depression. ^{4, 5}

Inter-ictal Symptoms

Inter-ictal depression is the most common presentation of affective disorders among patients with epilepsy. The clinical presentation closely resembles a dysthymic disorder. Symptoms include fatigue, anxiety, anhedonia, irritability, and labile mood. Symptoms can be intermittent and patient has symptom-free periods. Interictal depression can present as major depressive disorder or any of the other mood disorders included in the DSM-IV classification. Many of these patients do not meet DSM-IV criteria for these mood disorders. Despite the higher prevalence rate, inter-ictal depression is generally not reported by patients and goes unrecognized by healthcare professionals. ^{4, 5}

Impact of Untreated Depression in Epilepsy Patients

Untreated depression can have severe consequences on the health of patients with epilepsy. When left untreated, depression may last for 6 months to 2 years in 90% to 95% of cases, while 5% to 10% patients could have symptoms persist for more than 2 years. Depression in patients with epilepsy is associated with a significantly higher suicide rate than in the general population. People with epilepsy have lifetime average suicide rate of 12% whereas it was 1.1% to 1.2% in the general population. ^{3, 4}

• Patients with epilepsy have five times higher suicidal tendencies than general population and 25 times higher for patients with complex partial seizures of temporal lobe origin. ^{2, 3}

Depression is the most powerful predictor of health-related reduction in quality of life. In patients with recurrent seizures, it appears to have a stronger association with quality of life than does the seizure rate. Even the patients who have seizure control in terms of its frequency and its severity have overall poor quality of life.  ²

In addition, depression in people with epilepsy significantly increases the economic burden due to high healthcare costs associated with the management. Mild-to-moderate depression doubles the medical visits compared with non-depressed controls, while severe depression was associated with a four- times higher medical visits.^{2, 4}

Treatment of Depression in Epilepsy Patients

Treatment of depression in people with epilepsy is very complicated due to several factors including pro-convulsive effect of antidepressants, drug-drug interactions, and limited options for alteration of anti-epileptic therapy due to exacerbation of depression. Treatment should be progress in a stepwise manner taking iatrogenic causes into consideration. Psychological interventions such as cognitive behavioural therapy (CBT) are recommended by NICE guidelines before initiation of pharmacological treatment. Significant positive effects have been reported with CBT on mood of the patients with epilepsy. Antidepressant therapy should be initiated only if the psychological intervention fails to have significant improvement.^2,6

Depressive episodes in patients with epilepsy may result from the following:

• Discontinuation of an anti-epileptic drug with mood stabilizing property, such as carbamazepine, valproic acid, or lamotrigine,
• Introduction or increase in the dose of anti-epileptic drug having negative psychotropic effects, such as phenobarbital, topiramate, vigabatrin. ⁶

Selective serotonin receptor inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are recommended as first-line antidepressant therapy in patients with epilepsy. Efficacy of various SSRIs and SNRIs are mentioned in table 1. SSRIs are generally considered safe and well tolerated and the incidences of convulsions are low with their use.  Escitalopram has better tolerability and fewer drug interactions. Tricyclic antidepressants (TCAs) are the drugs of choice when SSRIs and SNRIs are not available as treatment option. There is no difference in efficacy among SSRIs, SNRIs, and TCAs, but TCAs are associated with lower tolerability and higher toxicity as compared to two other classes of drugs. ^{2, 6}

Limited data is available with the use of other antidepressants such as monoamine oxidase inhibitors (MAOIs) or trazodone, but they have a low potential for developing seizures. Other treatment modalities such as electroconvulsive therapy, vagal nerve stimulation and transcranial magnetic stimulation can be used in patients with severe refractory depression.⁶

Conclusion

Depression in patients with epilepsy is bidirectional and heterogeneous with atypical manifestation. The causes of depression in patients with epilepsy are multifactorial and probably involve common pathophysiological mechanisms. Remarkably high prevalence of depressive disorders in patients with epilepsy suggests appropriate diagnosis and routine investigation about depressive symptoms in them. Since depression has a significant negative impact on the quality of life of patients, and can affect treatment outcomes, its recognition and timely treatment becomes very vital. Treatment with anti-depressant drugs of the SSRI or SNRI class of antidepressants and cognitive behavior therapy has been shown as effective modalities in the management of depressive and anxiety disorders in patients with epilepsy.

References

1. Josephson CB, Lowerison M, Vallerand I, et al. Association of Depression and Treated Depression with Epilepsy and Seizure Outcomes: A Multicohort Analysis. JAMA Neurol. 2017 Feb 27. doi:10.1001/jamaneurol.2016.5042
2. Taoufik A, Khalid Z, Ahmed S, et al. Depressive disorders in patients with epilepsy: Why should neurologists care? Health. 2013; 5 (6A1): 14–20.
3. Kanner AM. Depression and epilepsy: A new perspective on two closely related disorders. Epilepsy Curr. 2006; 6 (5): 141–6.
4. Muzerengi S, Moor CC. What do we know about depression in people with epilepsy? Progress in Neurology and Psychiatry. 2013. March/April: 20–24.
5. Balabanov A, Kanner AM. Unrecognized and untreated: Preventing and treating depression in patients with epilepsy. Psychiatric Times, Nov-2004.
6. Kanner AM. The treatment of depressive disorders in epilepsy: What all neurologists should know? Epilepsia. 2013; 54 Suppl 1: 3–12.