SEARCH

SEARCH BY CITATION

Keywords:

  • Major depressive disorder;
  • Bipolar disorder;
  • Dysthymia;
  • Anxiety disorder;
  • Quality of life in epilepsy;
  • Temporal lobe epilepsy;
  • Frontal lobe epilepsy

Abstract

  1. Top of page
  2. Abstract
  3. Prevalence and Clinical Manifestations
  4. The Impact of MD on the Life of PWE
  5. The Bidirectional Relation Between MD and Epilepsy
  6. Treatment Considerations
  7. References

SummaryMood disorders (MD) are a frequent comorbidity of epilepsy with a negative impact on quality of life. The higher prevalence of MD in people with epilepsy (PWE) is most likely a reflection of a bidirectional relation between the two conditions, and common pathogenic mechanisms. Treatment of MD in PWE is safe with selective serotonin reuptake inhibitor (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), but nonpsychiatrists need to know when to refer these patients to a psychiatrist for further evaluation and treatment.


Prevalence and Clinical Manifestations

  1. Top of page
  2. Abstract
  3. Prevalence and Clinical Manifestations
  4. The Impact of MD on the Life of PWE
  5. The Bidirectional Relation Between MD and Epilepsy
  6. Treatment Considerations
  7. References

 Mood disorders (MD) are the most frequent psychiatric comorbidity in patients with epilepsy (PWE), with a prevalence of 20–50%; the higher prevalence rates have been typically identified in patients with poorly controlled epilepsy (Kanner, 2003). Mood disorders are a heterogeneous family of conditions with several clinical expressions each with a different course and therapeutic requirements. They can mimic the primary MD, but in a significant percentage of patients, they present with clinical manifestations that do not meet any of the diagnostic criteria of the primary MD listed in the Diagnostic and Statistical Manual of Mental Disorders. In the early twentieth century, Kraepelin (1903) and then Bleuler described a MD in PWE consisting of a pleomorphic pattern of symptoms that included affective symptoms with prominent irritability intermixed with euphoric mood, fear, and symptoms of anxiety, as well as anergia, pain and insomnia. Gastaut confirmed these observations. Blumer coined the term “interictal dysphoric disorder” to refer to this type of depression in epilepsy and described its chronic course with recurrent symptom-free periods that responded well to low doses of antidepressant medication (Blumer and Zielinski, 1988).

Major depressive episode (MDE) is the most frequent type of MD recognized by clinicians with diagnostic screening instruments available. Yet, recognition of a MDE is not sufficient, as they can occur as part of several types of MD, including major depressive disorder (e.g., recurrent MDEs), bipolar disorder, double depression (dysthymia and recurrent MDEs) and have been described in the midst of an interictal dysphoric disorder in PWE. Why should neurologists care? The different types of MD have a different course and different therapeutic requirements. For example, in major depressive disorders the use of chronic antidepressant therapy is the treatment of choice. In bipolar disorders, antidepressant may worsen the course by facilitating the switch to a manic or hypomanic episode and the development of a rapid cycling bipolar disorder which may be pharmacoresistant form. Thus, in these patients, antidepressant medication should be used with extreme caution and only in combination with mood stabilizing agents.

Often, MD occur concurrently with symptoms of anxiety and/or full blown anxiety disorders with such comorbidity increasing the suicide risk which in PWE is already higher than in the general population. A review of 11 studies found the overall suicidal rate in PWE to be five times higher than in the general population and 25 times expected in patients with complex partial seizures of temporal lobe origin (Harris & Barraclough, 1997). Jones et al. found that the lifetime average suicidal rate was 12% in PWE compared to 1.1–1.2% in the general population.

Finally, depressive episodes can occur during the peri-ictal period only, that is, preceding and/or following the occurrence of epileptic seizures. Postictal symptoms of depression are relatively common. For example in a study of 100 consecutive patients with refractory epilepsy, 43% reported a median of five symptoms following more than 50% of their seizures and having a median duration of 24 h (Kanner et al., 2004). These symptoms are not prevented by antidepressant medication.

The Impact of MD on the Life of PWE

  1. Top of page
  2. Abstract
  3. Prevalence and Clinical Manifestations
  4. The Impact of MD on the Life of PWE
  5. The Bidirectional Relation Between MD and Epilepsy
  6. Treatment Considerations
  7. References

Five studies of patients with pharmacoresistant epilepsy consistently demonstrated depression to be the most powerful predictor for each domain of health-related quality of life, even after controlling for seizure frequency, severity, and other psychosocial variables. In addition, people whose depression was untreated used significantly more health resources of all types, independently of seizure type, and time since the last seizure. Furthermore, people with mild to moderate depression had two-fold and people with severe depression, four-fold higher frequency of medical visits than nondepressed people. Also, the presence and severity of depression was found to be a predictor of worse disability scores, independently of duration of the seizure disorder (Cramer et al., 2004).

The Bidirectional Relation Between MD and Epilepsy

  1. Top of page
  2. Abstract
  3. Prevalence and Clinical Manifestations
  4. The Impact of MD on the Life of PWE
  5. The Bidirectional Relation Between MD and Epilepsy
  6. Treatment Considerations
  7. References

Hippocrates observed that people with depression were likely to develop epilepsy and vice-versa. Three population-based case-controlled studies confirmed these observations (Hesdorffer et al., 2000) and noted that people with depression had three to seven times higher risk of developing epilepsy and one study found that a prior history of suicidality was associated with a five-fold greater risk of developing epilepsy. The existence of such relationship does not imply causality but rather suggests common pathogenic mechanisms.

Common pathogenic mechanisms in MD and epilepsy include abnormalities of common neurotransmitter systems, including serotonin (5HT), norepinephrine (NE), dopamine (DA), glutamate and gamma-amino-butyric acid (GABA). Deficits in 5HT transmission in human depression are thought to be partially related to a paucity of serotonergic innervation in terminal areas suggested by low 5HT levels in brain, plasma, and platelets and a deficit in serotonin transporter binding sites in postmortem human brain (Nestler et al., 2002). A deficit in the density or affinity of postsynaptic 5HT1A receptors has been identified in the hippocampus and amygdala of untreated depressed patients who committed suicide. In addition, impaired serotonergic transmission has been associated to defects in the dorsal raphe nuclei of suicide victims with major depressive disorders consisting of an excessive density of serotonergic somatodendritic impulse suppressing 5HT1A autoreceptors. Furthermore, 5HT, NE, and DA in MD are the transmitter systems targeted by psychotropic drugs in the management of MD (Charney et al., 1998).

The role of 5HT and NE in epilepsy has been recognized in animal models and in humans with temporal lobe epilepsy (TLE). The role of 5HT and NE has been described in genetic epilepsy prone rats (GEPR) with its two strains, GEPR-3 and GEPR-9. These animals have a predisposition to sound-induced generalized tonic–clonic seizures and, particularly in GEPR-9s, a marked acceleration of kindling (Jobe et al., 1999). Both have innate serotonergic and noradrenergic pre- and postsynaptic transmission deficits. Noradrenergic deficiencies in GEPRs appear to result from deficient arborization of neurons arising from the locus coeruleus, coupled with excessive presynaptic suppression of NE release in the terminal fields and lack of postsynaptic compensatory up-regulation. There also is evidence of deficits in serotonergic arborization in the GEPR's brain as well as deficient postsynaptic 5HT1A-receptor density in the hippocampus. Increments of either NE or 5-HT transmission can prevent seizure occurrence while reduction has the opposite effect. For example, drugs that interfere with the release or synthesis of NE or 5-HT exacerbate seizures in the GEPRs, including NE storage vesicle inactivators. Conversely, drugs that enhance serotonergic transmission, such as the selective serotonin reuptake inhibitor (SSRI) sertraline, result in a dose-dependent seizure frequency reduction in the GEPR that correlates to the extracellular serotonergic thalamic concentration. The 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP) has anticonvulsant effects in GEPRs when combined with the SSRI, fluoxetine.

The role of monoamines in epilepsy in humans has been identified with the use of positron emission tomography (PET) studies in patients with TLE that targeted the 5HT1A receptor. A reduced 5HT1A receptor binding was found in mesial temporal structures ipsilateral to the seizure focus in patients with and without hippocampal atrophy. In addition a 20% binding reduction was found in the raphe and a 34% lower binding in the ipsilateral thalamic region to the seizure focus (Toczek et al., 2003). In a separate PET study aimed at quantifying 5HT1A receptor binding in 14 patients with TLE, decreased binding was identified in the epileptogenic hippocampus, amygdala, anterior cingulate, and lateral temporal neocortex ipsilateral to the seizure focus, as well as in the contralateral hippocampi and in the raphe nuclei. Clearly, a decrease in 5HT1A binding can be identified in both patients with TLE and primary major depressive disorder.

In addition changes in common structures have been identified including atrophy of temporal- and frontal-lobes in patients with primary major depressive and bipolar disorders and in PWE. These changes have been identified with high-resolution MRI and volumetric measurements of the amygdala, hippocampus, entorhinal cortex, temporal lateral neocortex, as well as of the prefrontal, orbito-frontal, and mesial-frontal cortex, and to a lesser degree, of the thalamic nuclei and basal ganglia (Sheline, 2003). It is not surprising that PWE whose seizure foci are in temporal and frontal lobes have a higher prevalence of MD.

Treatment Considerations

  1. Top of page
  2. Abstract
  3. Prevalence and Clinical Manifestations
  4. The Impact of MD on the Life of PWE
  5. The Bidirectional Relation Between MD and Epilepsy
  6. Treatment Considerations
  7. References

Based on the anticonvulsant effects of serotonergic and noradrenergic agents demonstrated in animal models it would be reasonable to infer that the use of antidepressant drugs are safe in PWE, a concept that has been contrary to the common belief of many clinicians. A recent study suggests a “protective” effect of SSRI and serotonin- norepinephrine reuptake inhibitors (SNRI) in depressed patients: Alper et al. compared the incidence of seizures between depressed patients randomized to placebo and SSRIs (citalopram, fluoxetine, fluvoxamine), the SNRI venlafaxine and the α2 antagonist mirtazapine in the course of regulatory studies submitted to the Food and Drug Administration (Alper et al., 2007). The seizure frequency among patients randomized to placebo was 1501.5 seizures/100,000 years, while that of patients randomized to the antidepressants was 534.8 seizures/100,000 years. Clearly depressed patients have a higher incidence of seizures than the general population, especially in those randomized to placebo.

It is my opinion that the following type of MD should be referred to psychiatrists from the time they are identified: any major depressive disorder that fails to remit after two trials with antidepressant drugs, any bipolar disorder or a psychotic depressive episode and any MD complicated with suicidal ideation. For patients with MDE, dysthymic disorder or interictal dysphoric disorder, the first line of treatment should include an SSRI that has no pharmacokinetic interaction with AEDs, such as escitalopram or citalopram. If symptoms persist at maximal doses, a trial with an SNRI such as venlafaxine or duloxetine should be considered. Patients who fail to respond to a second trial should be referred to a psychiatrist, as they may be suffering from pharmacoresistant MD. Four antidepressants should not be used in PWE: clomipramine, maprotiline, amoxapine, and bupropion.

An important obstacle to the treatment of MD in PWE is failure of recognition by the treating physician. To minimize this problem, a six-item screening instrument, the neurological disorders depression inventory for epilepsy (NDDI-E), recently was validated to screen for MDE s in PWE (Gilliam et al., 2006). It takes only 3 min to complete with score of ≥14 suggestive of a major depressive episode mandating and a more in-depth evaluation. The NDDI-E minimizes the effects of confounding factors such as adverse events from antiepileptic drugs or associated cognitive problems.

Disclosure of Conflicts of Interest

The contributing author to this article have declared the following conflicts of interest: Dr. Kanner has acted as a paid consultant to Glaxo-Smith-Kline, UCB, Novartis, Valeant Pharmaceuticals, Abbott, Shyre Laboratories, Cyberonics and Ortho McNeill. He has received research funding from Glaxo-Smith-Kline and Novartis.

References

  1. Top of page
  2. Abstract
  3. Prevalence and Clinical Manifestations
  4. The Impact of MD on the Life of PWE
  5. The Bidirectional Relation Between MD and Epilepsy
  6. Treatment Considerations
  7. References
  • Alper K, Schwartz KA, Kolts RL, Khan A. (2007) Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) Summary Basis of Approval reports. Biol Psychiatry 62:345354.
  • Blumer D, Zielinski J. (1988) Pharmacologic treatment of psychiatric disorders associated with epilepsy. J Epilepsy 1:135150.
  • Charney DS, Berman RM, Miller HL. (1998) Treatment of depression. In: SchatzbergAF, NemeroffCB, eds. Textbook of Psychopharmacology, Second Edition. American Psychiatric Association Press; Washington , DC , pp. 705732.
  • Cramer JA, Blum D, Fanning K, Reed M; Epilepsy Impact Project Group. (2004) The impact of comorbid depression on health resource utilization in a community sample of people with epilepsy. Epilepsy Behav 5:337342.
  • Gilliam FG, Barry JJ, Hermann BP, Meador KJ, Vahle V, Kanner AM. (2006) Rapid detection of major depression in epilepsy: a multicentre study. Lancet Neurol 5: 399405.
  • Harris EC, Barraclough B. (1997) Suicide as an outcome for mental disorders: a meta-analysis. Br J Psychiatry 170:205228.
  • Hesdorffer DC, Hauser WA, Annegers JF, Cascino G. (2000) Major depression is a risk factor for seizures in older adults. Annals of Neurology 47:246249.
  • Jobe PC, Dailey JW, Wernicke JF. (1999) A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders. Crit Rev Neurobiol 13:317356.
  • Kanner AM. (2003) Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms and treatment. Biol Psychiatry 54:388398.
  • Kanner AM, Soto A, Gross-Kanner H. (2004) Prevalence and clinical characteristics of postictal psychiatric symptoms in partial epilepsy. Neurology 62:708713.
  • Kraepelin E. (1903) Psychiatrie. 7. Auflage. Liepzig : JA Barth.
  • Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, et al. (2002) Neurobiology of depression. Neuron 34(1):1325.
  • Sheline YI. (2003) Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry 54(3):338352.
  • Toczek MT, Carson RE, Lang L, Ma Y, Spanaki MV, Der MG, Fazilat S, Kopylev L, Herscovitch P, Eckelman WC, Theodore WH. (2003) PET imaging of 5-HT1A receptor binding in patients with temporal lobe epilepsy. Neurology 60:749756.