Depression and Epilepsy
Psychiatric disorders in epilepsy often remain unrecognized and untreated. Yet, patients with epilepsy are at increased risk for depression. Prompt diagnosis and treatment, when indicated, is important for their well-being.
Hippocrates was the first to describe a relationship between epilepsy and depression in the 5th century BC: "Melancholics ordinarily become epileptics, and epileptics melancholics: what determines the preferences is the direction the malady takes; if it bears upon the body, epilepsy, if upon the intelligence, melancholy" (Lewis, 1934).
Mood disorders are the most common psychiatric comorbidity in patients with epilepsy, but often remain unrecognised and untreated. The presence of depression in patients with refractory epilepsy is one of the most important variables to have an impact on the quality of life, even more so than the seizure frequency and severity (Perrine, 1995; Lehrner, 1999). The depressed people with epilepsy had increased seizure frequency, poorer compliance, greater unemployment and higher medical use compared with the nondepressed people with epilepsy (Ettinger, 2002).
Although neurologists and psychiatrists have researched various aspects of psychopathology in epilepsy, the treatment of psychiatric disorders in epilepsy has received little attention. The literature on psychiatric management techniques in epilepsy remains largely "opinion-led", with evidence from randomised, controlled trials being scant, with few systematic investigations having been conducted. Brain dysfunction, social isolation and vocational difficulty may contribute to the increased prevalence of depressive disorders in epilepsy, but the specific mechanisms are not completely understood.
The brain regions commonly involved in various types of epilepsies, such as the hippocampus and amygdala in temporal lobe epilepsy and subcortical nuclei in idiopathic generalized epilepsies, are important structures in the current models of depression.
Epilepsy is one of the most common neurological disorders. The life-time prevalence of epilepsy in the general population is 3%, with a point-prevalence of 0.6 % (Annegers, 1999).
Depression fourth largest medical problem
Depressive disorders rank fourth in the list of the most pressing medical problems worldwide (Akiskal, 2000). It has been estimated that up to 26% of women and 12% of men will experience a depressive disorder in their lifetime with point-prevalence numbers of depression at 2–9% in women and 1–3% in men.The incidence of the disorder is increasing, especially in the young (Akiskal, 2000; APA, 2000; Edeh, 1987; Jacoby 1996).
The differing prevalence rates of depression reported in patients with epilepsy are unclear because of methodological considerations, different source of population and the severity of the epilepsy. For major depression the comorbidity rate ranges from 8–48% with a mean of 29% (Hermann, 2000). Reports studying community-based populations with epilepsy found point prevalence of depression ranging from 9–22% in patients with uncontrolled or partially controlled seizures (Edeh, 1987; Jacoby, 1996), whereas only 4% of a group of 350 seizure-free patients with epilepsy were found to have depression (Jacoby, 1996). Medically intractable epilepsy and inpatients have a higher prevalence of depression, ranging from 27–58% (Victoroff, 1994; Robertson, 1994; Boyd, 1982; Indaco, 1992).
Bipolar disorder uncommon
Bipolar disorder is uncommon in patients with epilepsy. In contrast to estimated general population prevalence rates of up to 2%, small studies of bipolar disorder prevalence among patients with epilepsy have reported rates of 1% (Wiegartz, 1999; Reynolds, 1991). The mood stabilising effect of some anti-epileptic drugs (AED) may be an explanation for the lower rate.
Temporal lobe epilepsy (TLE), history of epilepsy treatment at a tertiary treatment centre and a history of psychiatric hospitalisation are predictive risk factors for suicide (Kanner, 1999).
The attempted suicide rate among patients with epilepsy is four times higher than that of the general population (Barraclough, 1987).
Among the potential neurobiological and psychosocial determinants, epilepsy variables such as seizure type (TLE and partial seizures), severity (depression increases with increased seizure severity), frequency (either increased or decreased), medication and laterality (leftsided) of temporal lobe focus have been associated with depression. Depression is also likely to be more common in patients with TLE and partial epilepsies overall, than those with primary generalised epilepsies (Robertson, 1994; Lambert, 1999; Barry, 2001).
However, not all studies report similar results. Manchanda (1995) assessed patients with TLE, non-temporal lobe focal epilepsy, or multifocal onset/generalized epilepsy, and found no significant difference in psychiatric morbidity among the different foci.
Increased as well as decreased seizure frequency has been reported by those who have depression and also prior to onset of depression (Hermann, 2000; Betts, 1974; Mendez, 1993).
These findings raise the question as to whether seizures are a form of electroconvulsive selftherapy in some patients or the seizures may be an example of forced normalisation. Forced normalisation may be a factor in the paradoxical onset of depression in patients with epilepsy whose seizures suddenly become well-controlled by treatment (Krishnamoorthy, 2002).
The lowering of folic acid levels by some antiepileptic drugs may also influence (increase) the expression of depression in patients with epilepsy. Patients who allow the seizures to take control over their lives (external control) appear more prone to depression than those patients who "live" their lives despite the disorder (internal control) (Barry, 2003).
Findings in neuropsychological testing (Hermann, 1991) suggesting development of frontal lobe dysfunction may be a necessary component in the genesis of depression. This is supported by SPECT studies showing bilaterally decreased glucose metabolism in the inferior frontal areas of patients with TLE. However, the finding of frontal hypoperfusion in patients with epilepsy and depression (Bench, 1995) may not be specific for epilepsy, but may be a feature of depression in general.
The first step in the management is the correct diagnosis. Organic factors have to be ruled out, including subclinical seizure activity, AED toxicity, side effects, interactions, metabolic and endocrinal disturbances.There should be a high level of suspicion for depression when evaluating a patient with epilepsy. If a diagnosis of a mood disorder is made, assessment of its severity is required. Since there is a greater risk for suicide in patients with epilepsy, specific enquiry is necessary.
Diagnosis often missed
In more than two thirds of patients with a depressive disorder the diagnosis is missed. There are several reasons why depression in patients with epilepsy is unrecognised and is under-treated, even when recognized (Coyle, 1995; Hirschfeld, 1997, Hermann, 2000). One of the most important is the misconception, which is true not only in epilepsy, by physicians and patients that mood disorders that appear to be a reaction to medical illness require no treatment and is judged as a normal adaptation process. If a patient meets the criteria for a depressive disorder for any reason, clinical management and treatment is indicated.
Another reason is that clinicians usually fail to enquire about psychiatric symptoms and there might be a lack of time to fully investigate the depressive complaints of their patients. There are also signs that the patients tend to minimize their psychiatric symptoms for fear of being further stigmatised.
Differing clinical manisfestations
Depression in patients with epilepsy does not necessarily follow the conventional descriptions in ICD-10 and DSM-IV. The clinical manifestations of certain types of mood disorders in epilepsy differ from the mood disorders in non-epileptic patients, which might be another reason for the low numbers of recognition.
Possibly "unique" syndromes of depression exist. This could include interictal dysphoric disorders, prodromal dysphoric disorders, ictal depression, postictal dysphoric disorders and specific phobic fears, such as of seizures or social phobia because of recurrent seizures. Prodromal dysphoric disorders tend to be short-lived and herald a seizure by appearing some hours earlier, but can be recognized days before a seizure.
Postictal dysphoria shows symptoms of anergia, irritability, anxiety or headaches, as well as depressed mood with a median duration of 24 hours (Kanner 2003).
Efficacy of antidepressants
Antidepressants effectively treat about 65% of psychiatric patients with uncomplicated major depression, compared to a 30% placebo response (Charney, 1998). Refractory depression in people with epilepsy appears to be less common than in patients with idiopathic depression. It was noted that only about 15% of people with epilepsy manifesting idiopathic dysthymic disorders where refractory to TCAs (Blumer, 1988). In patients with epilepsy it is suggested to follow the proposal "start low, go slow", to avoid provoking seizures, but also adding the phrase "make sure you get there".
Drug trials often claim success even if patients have significant residual symptoms. It is therefore important to attempt to maximize the medication dosage with a goal of remission, not only symptom reduction. If the TCAs are used, it is recommended to monitor the serum levels to avoid overdose and a greater risk of seizure provocation (Preskorn, 1992). Overdoses of SSRIs and SNRIs have also been associated with elevated seizure rates (Barry, 2001).
Increased risk of seizures
Antidepressants, particularly the tricyclic antidepressants (TCAs), are associated with increased risk of seizures, particularly in higher doses, which could be another motive for hesitating to start treatment. However, animal models and research into the effects of antidepressants in overdose are the major sources of data, showing proconvulsive effects being a very neglected area of research.
The SSRIs in general have a low seizure propensity, are usually well tolerated in overdose and have favourable adverse effect profile, making them suitable as first line treatments for depression in patients with epilepsy. Also antidepressants that act at multiple receptors (mirtazapine, venlafaxine may be appropriate drug options.
It is important to consider interactions with AEDs, especially those which are metabolised in the liver by cytochrome P450 hepatic system, causing enzyme inhibition, such as carbamazapine, phenytoin and phenobarbital.
Some SSRIs do not interact with common AEDs, for example sertraline, escitalopram and citalopram (Andersen, 1991; Barry, 2003).
AEDs with no or few interactions are i.e. levetiracetam, lamotrigine and gabapentin. Antidepressants that are especially associated with seizure provocation and should be used with caution in susceptible patients are clomipramine, maprotilene, bupropion and amoxipine.
AED with psychotropic properties
Several AEDs have psychotropic properties and some of the most widely used mood stabilizers in bipolar affective disorders are AEDs like valproate, carbamazapine, lamotrigine, gabapentin and topiramate (Post, 1996; Calabrese, 1996; Suppes, 2002) and some studies suggest efficacy also in depression in patients with epilepsy (Kalogjera-Sackellares, 2002; Edwards, 2000). On the other hand some AEDs reveal depression in their profile of reported side effects, including topiramate, tiagabine and vigabatrin (Trimble, 1998). Withdrawal reactions, involving affective symptoms, have been noted with phenytoin, carbamazapine and valproate during inpatient evaluation (Ketter, 1994).
Other useful treatment options
As psychosocial factors can play a fundamental role in the expression of depression in people with epilepsy, cognitive, behavioural and interpersonal therapies may be extremely useful interventions either as concurrent, sequential or crossover treatments with drug therapy (Fava, 1998, Segal, 2002). Unfortunately there is little research done to refer to evidence-based medicine.
Electro-convulsive therapy (ECT) is another modality for the treatment of particularly refractory depression, but also in an emergency when safety of the patient is at risk. The criteria for the use of ECT are the same for patients with epilepsy as for patients with idiopathic depression and can be administered safely in patients with epilepsy (Regenold, 1998; Kaufman, 1996).
Vagus nerve stimulation (VNS) has become an acceptable treatment for patients with mainly refractory seizures. It is claimed VNS is a relatively safe and well-tolerated treatment that has facilitated a 50% seizure reduction in 50% of patients. Although the mechanism of VNS is unknown, its effects on mood have stimulated considerable interest. Improved mood and alertness has been noted in some of the patients treated with this method, regardless of seizure amelioration (Rush, 2000; Schmidt, 2001).
VNS has also been studied in treatment- resistant depression and was well tolerated and has demonstrated a response rate of up to 40 % in the acute phase and an apparent continued improvement for two years (Morris, 1999; Marangell, 2002). Recent research has also focused on other techniques such as transcranial magnetic stimulation for epilepsy and neuropsychiatric disorders (Harden, 2000; Elger, 2000).
Patients with epilepsy are at increased risk for depression. Neurobiological, iatrogenic and psychosocial factors may contribute to this increase. The physician must take into account the possible positive and negative effects of AEDs and ADs varying, the use of safer ADs in appropriate dosages, the potential for drug interactions and the importance of adequate maintenance of therapy. The recognition of the mood disorder and prompt treatment when indicated is important for the well-being of this category of patients.
1. Lewis A. Melancholia: a historical review. J Ment Sci 1934;80:1-42
2. Perrine K, Hermann BP, Meador KJ, Vickrey BG, Cramer JA, Hays RD, Devinsky O. The relationship of neuropsychological functioning to quality of life in epilepsy. Arch Neurol. 1995 Oct;52(10):997-1003.
3. Lehrner J, Kalchmayr R, Serles W, Olbrich A, Pataraia E, Aull S, Bacher J, Leutmezer F, Groppel G, Deecke L, Baumgartner C. Health-related quality of life (HRQOL), activity of daily living (ADL) and depressive mood disorder in temporal lobe epilepsy patients. Seizure. 1999 Apr;8(2):88-92.
4. Annegers JF, Dubinsky S, Coan SP, Newmark ME, Roht L. The incidence of epilepsy and unprovoked seizures in multiethnic, urban health maintenance organizations. Epilepsia. 1999 Apr;40(4):502-6.
5. Akiskal HS, Bourgeois ML, Angst J, Post R, Moller H, Hirschfeld R. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord. 2000 Sep;59 Suppl 1:S5-S30.
6. Jacoby A, Baker GA, Steen N, Potts P, Chadwick DW. The clinical course of epilepsy and its psychosocial correlates: findings from a U.K. Community study.
Epilepsia. 1996 Feb;37(2):148-61.
7. Ettinger A, Gibson P, Craymer J, Dean P, Blum D, Reed M. Prevalence of depression in persons with epilepsy, and associated finding from epilepsy impact project (abstract). Epilepsia 2002;43(suppl 7):120
8. Hermann BP, Seidenberg M, Bell B. Psychiatric comorbidity in chronic epilepsy: identification, consequences, and treatment of major depression.
Epilepsia. 2000;41 Suppl 2:S31-41.
9. Edeh J, Toone B. Relationship between interictal psychopathology and the type of epilepsy. Results of a survey in general practice. Br J Psychiatry. 1987 Jul;151:95-101.
10. Victoroff JI, Benson F, Grafton ST, Engel J Jr, Mazziotta JC. Depression in complex partial seizures. Electroencephalography and cerebral metabolic correlates. Arch Neurol. 1994 Feb;51(2):155-63.
11. Robertson MM, Channon S, Baker J. Depressive symptomatology in a general hospital sample of outpatients with temporal lobe epilepsy: a controlled study.
Epilepsia. 1994 Jul-Aug;35(4):771-7.
12. Indaco A, Carrieri PB, Nappi C, Gentile S, Striano S. Interictal depression in epilepsy. Epilepsy Res. 1992 Jun;12(1):45-50.
13. Wiegartz P, Seidenberg M, Woodard A, Gidal B, Hermann B. Co-morbid psychiatric disorder in chronic epilepsy: recognition and etiology of depression.
Neurology. 1999;53(5 Suppl 2):S3-8..
14. Reynolds EH. Interictal psychiatric disorders. Neurochemical aspects.
Adv Neurol. 1991;55:47-58.
15. Kanner AM, Nieto JC. Depressive disorders in epilepsy. Neurology. 1999;53(5 Suppl 2):S26-32.
16. Barraclough BM. The suicide rate of epilepsy. Acta Psychiatr Scand. 1987 Oct;76(4):339-45.
18. Lambert MV, Robertson MM. Depression in epilepsy: etiology, phenomenology, and treatment. Epilepsia. 1999;40 Suppl 10:S21-47.
19. American Psychiatric Association. Practical guideline for treatment of patients with major depressive disorder (revision). Am J Psychiatry, 2000:1284-98
20. Manchanda R, Schaefer B, McLachlan RS, Blume WT. Relationship of Site of Seizure Focus to Psychiatric Morbidity. J Epilepsy 1995; 8: 23-8
21. Hermann BP, Seidenberg M, Bell B, Woodard A, Rutecki P, Sheth R. Comorbid Psychiatric Symptoms in Temporal Lobe Epilepsy: Association with Chronicity of Epilepsy and Impact on Quality of Life. Epilepsy Behav. 2000 Jun;1(3):184-190.
22. Betts TA.A follow-up study of a cohort of patients with epilepsy admitted to psychiatric care in a English city. In Harris P, Mawdsley C, editors. Epilepsy proceedings of the Hans Berger Centenary symposium. Edinburgh: Churchill Livingstone, 1974: 326-38
23. Barry JJ. The recognition and management of mood disorders as a comorbidity of epilepsy. Epilepsia. 2003;44 Suppl 4:30-40.
24. Hermann BP, Seidenberg M, Haltiner A, Wyler AR Mood state in unilateral temporal lobe epilepsy. Biol Psychiatry. 1991 Dec 15;30(12):1205-18.
25. Bench CJ, Frackowiak RS, Dolan RJ. Changes in regional cerebral blood flow on recovery from depression. Psychol Med. 1995 Mar;25(2):247-61.
26. Coyle JC, Schwenk TL, Fechner-Bates.Nondetection of depression by primary care physician reconsidered.Gen Hosp Psychiatry 1995;17:3-12
27. Hirschfeld RM, Keller MB, Panico S, Arons BS, Barlow D, Davidoff F, Endicott J, Froom J, Goldstein M, Gorman JM, Marek RG, Maurer TA, Meyer R, Phillips K, Ross J, Schwenk TL, Sharfstein SS, Thase ME, Wyatt RJ. The National Depressive and Manic-Depressive Association consensus statement on the undertreatment of depression. JAMA. 1997 Jan 22-29;277(4):333-40.
28. Charney DS, Berman RM, Miller HL.Treatment of depression. In: Schatzberg AF, Nemeroff CB, eds. Textbook of psychopharmacology. 2nd ed. Washington, DC: American Psychiatric Press, 1998:705-31
29. Blumer D, Wakhlu S, Davies K, Hermann B. Psychiatric outcome of temporal lobectomy for epilepsy: incidence and treatment of psychiatric complications.
Epilepsia. 1998 May;39(5):478-86.
30. Preskorn SH, Fast GA. Tricyclic antidepressant-induced seizures and plasma drug concentration. J Clin Psychiatry. 1992 May;53(5):160-2.
31. Barry JJ, Lembke A, Huynh N.Affective disorders in epilepsy.In: Ettinger A, Kanner A, eds. Psychiatric issues in epilepsy: a practical guide to diagnosis and treatment. Philadelphia: Lippincott, Williams & Wilkins, 2001:45-71
32. Andersen BB, Mikkelsen M, Vesterager A, Dam M, Kristensen HB, Pedersen B, Lund J, Mengel H. No influence of the antidepressant paroxetine on carbamazepine, valproate and phenytoin. Epilepsy Res. 1991 Nov-Dec;10(2-3):201-4.
33. Post RM, Ketter TA, Denicoff K, Pazzaglia PJ, Leverich GS, Marangell LB, Callahan AM, George MS, Frye MA. The place of anticonvulsant therapy in bipolar illness. Psychopharmacology (Berl). 1996 Nov;128(2):115-29.
34. Suppes T. Review of the use of topiramate for treatment of bipolar disorders.
J Clin Psychopharmacol. 2002 Dec;22(6):599-609.
35. Kalogjera-Sackellares D, Sackellares JC. Improvement in depression associated with partial epilepsy in patients treated with lamotrigine.
Epilepsy Behav. 2002 Dec;3(6):510-516.
36. Trimble MR. New antiepileptic drugs and psychopathology.
Neuropsychobiology. 1998 Oct;38(3):149-51.
37. Ketter TA, Malow BA, Flamini R, White SR, Post RM, Theodore WH. Anticonvulsant withdrawal-emergent psychopathology.
Neurology. 1994 Jan;44(1):55-61.
38. Segal Z, Vincent P, Levitt A. Efficacy of combined, sequential and crossover psychotherapy and pharmacotherapy in improving outcomes in depression.
J Psychiatry Neurosci. 2002 Jul;27(4):281-90.
39. Kaufman KR, Saucedo C, Schaeffer J, Levesque M, Scannell T, Glouberman M. Electroconvulsive therapy (ECT) for intractable depression following epilepsy neurosurgery. Seizure. 1996 Dec;5(4):307-12.
40. Regenold WT, Weintraub D, Taller A. Electroconvulsive therapy for epilepsy and major depression. Am J Geriatr Psychiatry 1998 Spring;6(2):180-3.
41. Schmidt D.Vagus nerve stimulation for the treatment of epilepsy.Epilepsy Behav 2001;2:S1-5
42. Marangell LB, Rush AJ, George MS, Sackeim HA, Johnson CR, Husain MM, Nahas Z, Lisanby SH. Vagus nerve stimulation (VNS) for major depressive episodes: one year outcomes. Biol Psychiatry. 2002 Feb 15;51(4):280-7.
43. Harden CL, Pulver MC, Ravdin LD, Nikolov B, Halper JP, Labar DR. A Pilot Study of Mood in Epilepsy Patients Treated with Vagus Nerve Stimulation.
Epilepsy Behav. 2000 Apr;1(2):93-99.
44. Rush AJ, George MS, Sackheim HA, Marangell LB, Husain MM, Giller C, Nahas Z, Haines S, Simpson RK Jr, Goodman RA. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry 2000 Feb 15;47(4):276-86
45. Morris, GL, Mueller,WM, The Vagus Nerve Stimulation Study Group. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. Neurology 1999;53:1731
46. Elger G, Hoppe C, Falkai P, Rush AJ, Elger CE. Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Res. 2000 Dec;42(2-3):203-10.
47. Edwards KR, Sackellares JC, Vuong A, Hammer AE, Barrett PS. Lamotrigine Monotherapy Improves Depressive Symptoms in Epilepsy: A Double-Blind Comparison with Valproate. Epilepsy Behav. 2001 Feb;2(1):28-36.
48. Kanner AM, Barry JJ. The impact of mood disorders in neurological diseases: should neurologists be concerned? Epilepsy Behav. 2003 Oct;4 Suppl 3:3-13.
Published on CNSforum 19 May 2004