Affective Disorders
Andres M. Kanner
Dietrich Blumer
Introduction
Mood disorders are the most common comorbid psychiatric disorders associated with epilepsy, but their real incidence and prevalence have yet to be established. Some of the primary reasons for the lack of definitive epidemiologic data include the diversity in methodologies and sample populations across studies, the underreporting of symptoms of depression by patients and families, and the underrecognition by clinicians. Population-based studies, however, have clearly shown that the prevalence of depression in people with epilepsy (PWE) is significantly higher than in healthy controls, as well as in people with chronic medical disorders.59,62,96,104,144
There is an ongoing debate as to whether depression in PWE differs from that in people with primary mood disorders.105 Proponents of both schools of thought are probably correct, as a significant percentage of PWE can experience any of the various forms of primary mood disorders (i.e., major depressive disorder, dysthymic disorder, bipolar disorder, cyclothymic disorder) indistinguishable from those described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).57 By the same token, several authors have identified atypical clinical manifestations of mood disorders in a significant proportion of PWE that fail to meet any of the diagnostic criteria suggested in the DSM-III, DSM-III-R, and DSM-IV.19,105,110,134 Kraepelin and Bleuler were the first to recognize a “unique” clinical presentation of mood disorders in PWE consisting of recurrent episodes of “dysphoric symptoms”18,115; Gastaut expanded on Kraepelin’s initial observations and Blumer coined the term interictal dysphoric disorder.19,74,75 The purpose of this chapter is to provide a comprehensive review of mood disorders in epilepsy. The aim of this chapter is to provide a general review of the different aspects of affective disorder in PWE with special attention to epidemiologic and clinical data, the underlying pathogenic mechanisms with special attention to the existence of common pathogenic mechanisms that may be operant in depression and epilepsy, and the basic principles in their treatment. The chapter concludes with a brief discussion of interictal dysphoric disorder.
Epidemiologic Data
Lifetime prevalences for major depressive episodes in the general population have been reported to range between 3.7% and 6.7%, for dysthymic and minor depressive disorders between 2.1% and 3.8%, and for manic episodes 0.6% and 1.1%.111 Recent population-based studies identified significantly higher prevalence rates of depression in PWE. For example, the Canadian Community Health Survey evaluated the existence of mental health problems in a large sample of the population (n = 36,984).200 A total of 253 subjects were found to have epilepsy (corresponding to a prevalence rate of epilepsy of 0.6%). The investigators used the Composite International Diagnostic Interview (Short Form) to identify a history of depression and found a lifetime prevalence of depression of 22.2% (95% confidence interval [CI], 14.0% to 30.4%) compared with 12.2% in the general population, with higher rates of major depression in younger, but not older (>64 years), age groups. Furthermore, lifetime suicidal ideation was higher in PWE (25.0% [95% CI, 16.6 to 33.3]) than in the general population (13.3% [95% CI, 12.8 to 13.9]). In a separate population-based study, Ettinger et al. investigated the presence of symptoms of depression among 775 PWE, 395 people with asthma, and 362 healthy controls identified from a cohort of 85,358 adults aged 18 years and older using the Centers of Epidemiologic Studies-Depression (CES-D) Instrument.62 PWE experienced symptoms of depression with a significantly greater frequency (36.5%) and severity than people with asthma (27.8%) and healthy controls (11.8%). Of note, 38.5% of PWE whose score on the CES-D suggested the presence of a depressive disorder and 43.7% of people with asthma and depression were never previously evaluated for depression. The same group of investigators compared the lifetime prevalence rates of bipolar symptoms and past diagnoses of bipolar I and II disorder with the Mood Disorder Questionnaire (MDQ) among subjects who identified themselves as having epilepsy and those with migraine, asthma, or diabetes mellitus or a healthy comparison group.63 Bipolar symptoms, evident in 12.2% of epilepsy patients, were 1.6 to 2.2 times more common in subjects with epilepsy than with migraine, asthma, or diabetes mellitus, and 6.6 times more likely to occur than in the healthy comparison group. A total of 49.7% of patients with epilepsy who screened positive for bipolar symptoms were diagnosed with bipolar disorder by a physician, nearly twice the rate seen in other disorders. However, 26.3% of MDQ-positive epilepsy subjects carried a diagnosis of unipolar depression, and 25.8% had neither a uni- nor bipolar depression diagnosis.
The impact of seizure control on the prevalence of depression has been investigated in four population-based studies. Using the Hospital Depression and Anxiety Symptoms scale, Jacoby et al.96 reported that of 168 patients with recurrent seizures, 21% met criteria for clinical depression. Using the same instrument, O’Donoghue et al.144 showed that among 155 PWE identified through two large primary care practices in the United Kingdom, 33% with recurrent seizures and 6% of those in remission had depression. Edeh and Toone59 used the Clinical Interview Schedule to demonstrate a depressive disorder in 22% of 88 epilepsy patients identified from general practices in the United Kingdom.
Clearly, the prevalence rates of depression are significantly higher in studies done in tertiary centers. For example, Victoroff et al. assessed the lifetime prevalence of psychiatric disorders meeting DSM-III-R diagnostic criteria by administering the Structured Clinical Interview for DSM-III-R—Patient Version (SCID-P) to 60 patients with medically intractable complex partial seizures.207 The standard interview was enlarged by explorations of the relationship between psychiatric complaints and course of the epilepsy, of brief periods of depression and elation, and of atypical personality features that had been reported among patients with temporal lobe epilepsy (TLE). Of
the 60 patients, 42 (70%) had histories of one or more DSM-III-R axis I diagnoses and 35 (58%) had histories of major depressive episodes or other depressive disorders.
the 60 patients, 42 (70%) had histories of one or more DSM-III-R axis I diagnoses and 35 (58%) had histories of major depressive episodes or other depressive disorders.
Current diagnoses of depression can also be identified more frequently among patients followed in tertiary centers. In a recently completed study of 199 consecutive outpatients from five epilepsy centers,103 the presence of an axis I diagnosis was identified according to DSM-IV criteria with the Structured Clinical Interview for DSM-IV diagnosis (SCID) and the Mini International Psychiatric Interview (MINI). Sixty-seven patients (34%) met a DSM-IV criterion of a mood and/or anxiety disorder: 37 (19%) met criteria for major depression, of whom 17 (8.5%) had a mixed major depression and anxiety disorder. Only four patients (2%) met criteria for dysthymic disorder and 27 (13.6%) for an anxiety disorder.
The relation between depression and epilepsy has traditionally been thought to be unidirectional, given the higher incidence and prevalence of depression in PWE and the recognition of several epilepsy-related pathogenic mechanisms, including (a) a reactive process to psychosocial stressors associated with a life with epilepsy, (b) neurophysiologic and neurochemical changes related to the seizure activity, and (c) iatrogenic pharmacologic and surgical factors. Yet, the higher prevalence rates of depression in PWE were based on cross-sectional studies, which do not necessarily establish causality between the two disorders. In fact, three recent population-based studies have questioned this long-held assumption of a unidirectional relation and suggested the existence of a “bidirectional” relation between depression and epilepsy, whereby the presence of a mood disorder can also be associated with an increased risk of developing epilepsy.20,89,90 Of note, these investigators were not the first ones to suggest the existence of such bidirectional relationship; indeed, 26 centuries ago, Hippocrates 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.”124 Such bidirectional relationship may in fact reflect the existence of common pathogenic mechanisms shared by epilepsy and depression, which facilitate the development of one disorder in the presence of the other (see below).
Clinical Presentations
Symptoms of mood disorders in epilepsy are classified according to their temporal relation to seizure occurrence into peri-ictal and interictal symptoms. Peri-ictal symptoms include symptoms that precede (preictal), follow (postictal), or are the expression of a seizure (ictal), while interictal symptoms occur independently of seizures. Often, patients may experience symptoms of depression during both peri-ictal and interictal periods.
Peri-ictal Symptoms
Peri-ictal depressive symptoms and episodes are the least well studied with respect to their actual prevalence and are usually ignored by clinicians. Their occurrence has never been factored into any study investigating the prevalence of depressive symptoms/disorders in PWE despite the fact that their existence has been known to neurologists and psychiatrists for a long time.
Ictal Symptoms
It has been estimated that psychiatric symptoms occur in 25% of “auras”; 15% of these involve affect or mood changes.54,209,212 For example, ictal symptoms of depression ranked second after symptoms of anxiety/fear, which are the most common type of ictal affect in one study. Ictal symptoms of depression are of short duration typically, are stereotypical, occur out of context, and are associated with other ictal phenomena. The most frequent symptoms include feelings of anhedonia, guilt, and suicidal ideation.
Preictal Symptoms
Preictal symptoms or episodes typically present as a dysphoric mood preceding a seizure by several hours to days. The best evidence is presented in the study by Blanchet and Frommer, who investigated mood changes in the course of 56 days in 27 PWE who were asked to rate their mood on a daily basis.17 Mood ratings pointed to a dysphoric state 3 days prior to a seizure in 22 patients. This change in mood was more accentuated during the 24 hours preceding the seizure.
Postictal Symptoms
Postictal symptoms have been recognized for a very long time, but have been poorly studied in a systematic manner. Their detection can often be elusive as they do not occur necessarily on the same day as the seizure. Rather, symptom-free periods of up to 5 days can exist between the seizure occurrence and onset of psychiatric symptoms. The prevalence of postictal psychiatric symptoms was investigated in a study done at the Rush Epilepsy Center in Chicago in 100 consecutive patients with refractory epilepsy.107 Only symptoms that occurred following more than 50% of seizures in the previous 3 months were included. In this study, the postictal period was defined as the 72 hours that followed a seizure. Symptoms that occurred during both interictal and postictal periods were also identified and compared in their severity during these periods. Since neurovegetative symptoms and fatigue are common postictal symptoms as well as symptoms of depression, they were analyzed separately so as not to inflate falsely the prevalence of postictal symptoms of depression (PSD).
Among the 100 patients, 43 experienced a mean of 4.8 ± 2.4 PSD (range 2 to 9; median = 5). The median duration of two thirds of symptoms was 24 hours. Twenty-five had a history of a mood disorder and 11 of an anxiety disorder. Table 1 shows the PSD and their respective median duration.
There was a significant association between a history of depression and the occurrence of the following PSD: Hopelessness, suicidal ideation, self-deprecation, and guilt. Furthermore, there was a significantly greater number of PSD in the presence of a history of depression and anxiety disorders.
Thirteen of these patients experienced a minimum of seven PSD lasting 24 hours or longer. Postictal suicidal ideation was identified in 13 patients. Eight patients experienced passive and active suicidal thoughts, while five only reported passive suicidal ideation. Ten of these 13 patients (77%) had a past history of either major depression or bipolar disorder, and this association was highly significant. Furthermore, the presence of postictal suicidal ideation was also significantly associated with a history of psychiatric hospitalization.
Among these 43 patients, PSD occurred together with postictal symptoms of anxiety (PSA) in 27 patients (63%) and seven other patients reported as well postictal psychotic symptoms. Table 1 shows the types of PSA and their median duration. Furthermore, 37 patients reported interictal symptoms of depression that worsened in severity during the postictal period in 30 patients.
Table 1 Prevalence and Median Duration of Postictal Symptoms of Depression and Anxiety | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Postictal hypomanic symptoms (PHM) included excessive energy and racing thoughts, which were identified in 22 patients: 15 patients reported racing thoughts and nine reported increased energy, but only two reported both symptoms (see Table 1). The occurrence of PHM only correlated significantly with that of postictal psychotic symptoms. In contrast to PSD, a psychiatric history was not a risk factor of PHM.
Clearly, the occurrence of PSD is relatively high among patients with refractory epilepsy. Yet, in none of the studies on the prevalence of depression in epilepsy published so far has any investigator discriminated between an interictal, preictal, or postictal occurrence. The impact that PSD may have in “shaping” the psychiatric clinical phenomena of depression in PWE has yet to be established. Yet, it is likely that preictal symptoms and PSD may account for the frequent “atypical” characteristic of depressive disorders.
Interictal Depressive Disorders
Interictal depressive disorders have been the most commonly recognized. As stated above, there is an ongoing debate as to whether depressive disorders differ between people with and without epilepsy. In fact, some investigators have found that in up to 50% of PWE suffering from a depressive disorder, the depressive disorder failed to meet a DSM-III or -IV diagnostic criteria for one of the listed mood disorders.134
The following categories are included in the DSM-IV: Major Depressive Disorder, Dysthymic Disorder, Minor Depression, Bipolar Disorder, and Depressive Disorder Not Otherwise Specified or secondary to a medical condition or substance.57 The difference between major depressive disorders and dysthymic disorder is based largely on severity, persistence, and chronicity. According to DSM-IV criteria, symptoms in both disorders may include combinations of depressed mood, anhedonia, worthlessness, guilt, decreased concentration ability, recurrent thoughts of death, and neurovegetative symptoms (i.e., weight loss or gain, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue). In patients with a major depressive episode, at least 2 weeks of either a depressed mood or anhedonia must accompany four of these symptoms. In contrast, dysthymic disorder is a more chronic but less intense process with symptoms persistent for more days than not for at least 2 years. Minor depression is a category that is similar to major depressive episode in duration but encompasses at least two but less than five of the depressive symptoms noted above.
Bipolar disorders are of two types, depending on the occurrence of manic (type I) or hypomanic (type II) episodes in addition to major depressive episodes. The DSM-IV diagnosis for manic episodes includes the requirement of a distinct period of abnormally and persistently elevated mood lasting at least 1 week and of sufficient severity to cause marked impairment in social functioning. The diagnosis for a hypomanic episode includes the requirement of a distinct period of persistently elevated mood lasting throughout at least 4 days and observable as a disturbance by others. The diagnosis of a cyclothymic disorder requires the presence of numerous hypomanic and minor depressive episodes for at least 2 years.
Concurrent Psychiatric Symptoms in Depressive Disorders in Epilepsy
Investigators have reported a frequent co-occurrence of mood and anxiety disorders in patients with and without epilepsy, with comorbid rates ranging between 50% and 80% in patients with primary mood disorders. The existence of comorbid anxiety symptoms or disorders has a significant impact on the quality of life of depressed patients and their recognition is of the essence as they significantly increase the suicidal risk of depressed patients.29 Thus, any evaluation of mood disorders for clinical or research purposes are incomplete in the absence of an investigation of comorbid symptoms of depression and vice versa.
Similar observations have been made in PWE. In a study of 199 patients with epilepsy from five epilepsy centers, 73% of patients with a history of depression met also DSM-IV criteria for an anxiety disorder.103 Furthermore, several investigators dating back to Kraepelin, Bleuler, Gastaut, and more recently Blumer and Kanner have made a point of emphasizing the pleomorphic nature of the symptomatology in depressive disorders in PWE, which in addition to symptoms of anxiety include irritability, increased energy, and physical symptoms.18,19,74,75,110,115 To a significant degree, these authors attributed the atypical manifestations of depression in epilepsy to these symptoms. This point is discussed in greater detail in the section on Interictal Dysphoric Disorder.
Nonetheless, recent studies have shown that these additional symptoms can be identified in PWE suffering from depressive disorders that also meet DSM-IV diagnostic criteria. In the study by Jones et al. cited above,103 a DSM-IV diagnosis of a mood and/or anxiety disorders was established with the MINI and SCID in 199 consecutive outpatients from five epilepsy centers. These patients completed a 46-item self-rating instrument the Mood and Anxiety Symptoms in Epilepsy (MASE), which includes symptoms from eight domains (depression, anxiety, irritability, self-consciousness, physical symptoms, disturbances in socialization, suicidal ideation, and increased energy) on two occasions, 2 weeks apart. Sixty-seven patients met criteria for a DSM-IV axis I diagnosis: Each one of the 37 patients that met criteria for major depression reported symptoms of irritability and anxiety; 36 experienced physical symptoms, primarily fatigue; and 31 reported periods of increased energy. Clearly, these data show that depression in epilepsy in its “typical” manifestations not only consists of symptoms of depression, but is more often than not accompanied by symptoms of anxiety and irritability and, paradoxically, symptoms of increased energy. Whether this pleomorphic semiology is specific to depression in PWE or may be present in other neurologic disorders has yet to be established.
Atypical Expressions of Depression in Epilepsy
As stated above, depressive disorders in PWE often fail to meet any of the DSM-III, -III-R, or -IV criteria. For example, using DSM-III-R criteria, Mendez et al. had to classify almost 50% of depressive disorders as atypical depression.134 Wiegartz et al. found that the depressive episodes of 25% of PWE were also classified as atypical depression not otherwise specified.211 The interictal dysphoric disorder is the classic example of the atypical expression of depression in PWE and is reviewed at the end of this chapter.
In a study of the semiology of depressive episodes severe enough to merit pharmacotherapy in 97 consecutive patients with refractory epilepsy, only 28 (29%) met DSM-IV criteria for major depressive disorder.110 The remaining 69 patients (71%) failed to meet criteria for any of the DSM-IV categories. These 69 patients presented a clinical picture consisting of anhedonia (with or without hopelessness), fatigue, anxiety, irritability, poor frustration tolerance, and mood lability with bouts of crying. Some patients also reported changes in appetite and sleep patterns and problems with concentration. Most symptoms presented with a waxing and waning course, with repeated interspersed symptom-free periods of 1 to several days’ duration. Their semiology resembled the most a dysthymic disorder, but the recurrence of symptom-free periods intermittently precluded DSM criteria for this condition. We therefore referred to this form of depression as dysthymic-like disorder of epilepsy (DLDE).
In 33 of these 69 patients, the predominant and most disabling symptom was anhedonia, while in the remaining 36 patients irritability and poor frustration tolerance were the most disabling symptoms. Of note, patients with DLDE in whom anhedonia was the predominant symptom (vs. irritability) were significantly more likely to have experienced a prior history of major depressive episodes (45.5% vs. 19.5%). Whether DLDE is a variant of the interictal dysphoric disorder has yet to be established in systematic studies (see below).
Subclinical or subsyndromic forms of depression are another presentation of atypical depression, both in primary mood disorders and in depressive disorders of PWE. In the study of 199 consecutive PWE cited above,103,109 132 patients (64%) failed to meet any DSM-IV axis I diagnosis according to the SCID and MINI; yet, using the self-rating instruments Beck Depression Inventory (BDI) or the CES-D, 32 patients (16% of the entire cohort) were also found to have been experiencing symptoms of depression of mild to moderate severity. Furthermore, symptoms of anxiety were identified in 31 of these 32 patients with the MASE, symptoms of irritability in 32, physical symptoms in 24, and symptoms of increased energy in 18.
Suicidality as an Expression of Depression in Epilepsy
The suicide rate in PWE is five times higher than the expected rate in the general population. However, among patients with TLE the suicide rate can be 25 times higher.77 For example, Robertson reviewed 17 studies pertaining to mortality in epilepsy and found that suicide was ten times more frequent than in the general population.166 Rafnsson et al. recently reported the results of a population-based incidence cohort study in PWE from Iceland in which suicide had the highest standard mortality rate (5.8) of all causes of death,158 and it was 3.5 in a Swedish study carried out among 9,000 previously hospitalized PWE.142 The topic of suicidality in PWE is reviewed in detail in Chapter 211 in this book.
Impact on Quality of Life
Depression has been found to yield a significant negative impact on the quality of life of PWE. For example, in a study of 56 consecutive patients with TLE, Lehrner et al.123 found depression to be the most powerful predictor for each domain of health-related quality of life. Even after controlling for seizure frequency and severity and other psychosocial variables, there remained a significant association between depression and ratings indicative of poor quality of life. In another study of 257 patients with epilepsy, Perrine et al.150 found that the mood factor had the highest correlations with scales of the Quality of Life in Epilepsy (QOLIE-89) and was the strongest predictor of quality of life in regression analyses, as the mood factor was responsible for 46% of the variance in overall quality of life.
Likewise, in a group of 125 patients who had undergone temporal lobe surgery at least 12 months previously, Gilliam et al. showed that mood status was the most significant predictor of the patients’ assessment of their own health status.78 In another investigation, Gilliam examined the variables responsible for poor quality of life identified with the QOLIE-89 in 194 adult patients with refractory partial epilepsy80 and found that the only independent variables significantly related to poor quality-of-life scores were high levels of depression and neurotoxicity from antiepileptic drugs. Patients had a median 9.7 seizures/month (range 0.3 to 51), but the author saw no relationship between the type and/or the frequency of seizures and quality-of-life scores. Identical findings were replicated by Boylan et al. in a more recent study.28 Cramer et al. also found
that depression was significantly associated with poor quality-of-life scores on the QOLIE-89 independently of the type of seizures; these investigators found, however, that seizure freedom for the last 3 months increased (i.e., improved) the quality-of-life ratings.47 In the study of 199 patients described above, Kanner et al. found that the scores of the QOLIE-89 were significantly higher (i.e., better quality of life) among patients who had been seizure free for the last 6 months than those with persistent seizures.109 These patients, however, were significantly less likely to have experienced a depressive disorder. The presence of a comorbid anxiety disorder with depression has also been associated with worse ratings in the QOLIE-89. In the same study cited above, patients with mixed anxiety/major depression had significantly lower scores than patients with major depression alone and these were in turn lower than those with only anxiety disorder.
that depression was significantly associated with poor quality-of-life scores on the QOLIE-89 independently of the type of seizures; these investigators found, however, that seizure freedom for the last 3 months increased (i.e., improved) the quality-of-life ratings.47 In the study of 199 patients described above, Kanner et al. found that the scores of the QOLIE-89 were significantly higher (i.e., better quality of life) among patients who had been seizure free for the last 6 months than those with persistent seizures.109 These patients, however, were significantly less likely to have experienced a depressive disorder. The presence of a comorbid anxiety disorder with depression has also been associated with worse ratings in the QOLIE-89. In the same study cited above, patients with mixed anxiety/major depression had significantly lower scores than patients with major depression alone and these were in turn lower than those with only anxiety disorder.
Depression in PWE can also have a significant impact on health care costs associated with the management of the seizure disorder. For example, Cramer et al. investigated the impact of comorbid depression on health care utilization and health care coverage by PWE in U.S. communities using a postal survey questionnaire.46 They found that 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 a twofold and people with severe depression a fourfold 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 (Sheehan’s Disability Scale), independently of duration of the seizure disorder. These data highlight the impact of comorbid depression on health care utilization by people with epilepsy.
Pathogenic Mechanisms
Is There a Bidirectional Relationship between Depression and Epilepsy?
Three studies published in the last 15 years have raised the possibility of a bidirectional relation between depression and epilepsy.69,89,90 In the first study, Forsgren and Nystrom conducted a population-based case-control study of patients with newly diagnosed onset epilepsy in Sweden, and discovered that patients were seven times more likely to have reported a history of depression than were controls.69 Hesdorffer et al. conducted a second population-based case-control investigation of the prevalence of new onset epilepsy among adults aged 55 and older, and showed that compared to controls, patients were 3.7 more likely to have had a history of depression prior to their first seizure.89 The same authors conducted a population-based study in Iceland that included children and adults with newly diagnosed unprovoked seizures and/or epilepsy.90 They found that patients with a history of major depression (by DSM-IV criteria) were significantly more likely than controls (odds ratio [OR] 1.7) to suffer from unprovoked seizures and epilepsy. Furthermore, a history of suicidal ideation was associated with a significantly greater risk of developing epilepsy (OR 5.5) independent of a history of major depression. These data do not indicate causality between the two disorders, but rather suggest the existence of common pathogenic mechanisms operant in depression and epilepsy.
Common Pathogenic Mechanisms in Epilepsy and Depression
Two classes of pathogenic mechanisms are likely to be operant in both disorders: (a) abnormal secretion patterns of neurotransmitter systems including serotonin (5HT), norepinephrine (NE), dopamine (DA), γ-aminobutyric acid (GABA), and glutamate; and (b) structural and functional abnormalities of common neuroanatomic structures in limbic structures, particularly in temporal and frontal lobes.
Abnormal Secretion of Neurotransmitters
Data from experimental animal studies.
Abnormal serotonergic, noradrenergic, and dopaminergic transmission in the brain has been recognized as a pivotal pathogenic mechanism of mood disorders and has been the basis for the development of antidepressant pharmacologic treatments.191 By the same token, a decreased serotonergic and noradrenergic activity has been shown to facilitate the kindling of seizures, exacerbate seizure severity, and intensify seizure predisposition in some animal models of epilepsy as shown below.98 Compelling data are derived from studies with two strains of genetic epilepsy-prone rats (GEPR), GEPR-3 and GEPR-9, which are characterized by genetically determined predisposition to sound-induced generalized tonic–clonic seizures (GTCSs).44,50,98,99,100,205 Both strains of rats have innate pre- and postsynaptic noradrenergic and serotonergic transmission deficits, the former resulting from deficient arborization of neurons arising from the locus coeruleus coupled with excessive presynaptic suppression of stimulated NE release in the terminal fields and lack of postsynaptic compensatory up-regulation.44,50,98,99,100,205 GEPR-9 rats have a more pronounced NE transmission deficit and, in turn, exhibit more severe seizures than GEPR-3 rats.215 Abnormal serotonergic arborization has also been identified in the GEPR’s brain coupled with deficient postsynaptic serotonin1 A-receptor density in the hippocampus.49 Of note, GEPRs display similar endocrine abnormalities to those identified in patients with major depressive disorder (MDD), such as increased corticosterone serum levels, deficient secretion of growth hormone, and hypothyroidism.101
Increments of either NE and/or 5HT transmission with the selective serotonin reuptake inhibitor (SSRI) sertraline resulted in a dose-dependent seizure frequency reduction in the GEPR, which correlated with the extracellular thalamic serotonergic thalamic concentration.213,214 In addition, the 5-HT precursor 5-HTP has been shown to have anticonvulsant effects in GEPRs when combined with a monoamine oxidase inhibitor (MAOI),98 while SSRIs and MAOIs have been found to exert anticonvulsant effects in genetically prone epilepsy mice and baboons as well as in nongenetically prone cats, rabbits, and rhesus monkeys.133,152,153,213,217 Conversely, drugs that interfere with the release or synthesis of NE or 5HT exacerbate seizures in the GEPRs.98,138 These include NE storage vesicle inactivators reserpine or tetrabenazine, the NE false transmitter α-methyl-m-tryosine, the NE synthesis inhibitor α-methyl-Δ-tyrosine, and the 5-HT synthesis inhibitor Δ-chlorophenylalanine, all of which have also been found to facilitate seizure occurrence in humans.138,143,197
An anticonvulsant effect of serotonergic activity has been reported in other animal models of epilepsy. Lopez-Meraz et al. studied the impact of two 5HT1 A receptor agonists, 8-OH-DPAT and indorenate, in three animal models of epileptic seizures (clonic–tonic induced by pentylenetetrazol [PTZ], status epilepticus of limbic seizures induced by kainic acid [KA], and tonic–clonic seizures induced by amygdala kindling) in Wistar rats.127 They found that 8-OH-DPAT lowered the incidence of seizures and the mortality induced by PTZ, increased the latency and reduced the frequency of wet-dog shake and generalized seizures induced by KA and at high doses diminished the occurrence and delayed the establishment of status epilepticus. Indorenate increased the latency to the PTZ-induced seizures and decreased the percentage of rats that showed tonic extension and death, augmented the latency to wet-dog shake and generalized seizures, and diminished the number of generalized seizures.
The antiepileptic effect of 5HT1 A receptors has been associated with a membrane hyperpolarizing response associated
with increased potassium conductance in hippocampal kindled seizures in cats, and in intrahippocampal kainic acid–induced seizures in freely moving rats.13,148 Furthermore, antiepileptic drugs (AEDs) with established psychotropic effects (carbamazepine [CBZ], valproic acid [VPA], and lamotrigine [LTG]) have been found to cause an increase in 5HT.41,42,51,52,53,189,210,216 In fact, the anticonvulsant protection of CBZ can be blocked with 5HT-depleting drugs in GEPRs.216 Likewise, in a recent study, Clinckers et al. investigated the impact of oxcarbazepine (OXC) infusion on the extracellular hippocampal concentration of 5HT and DA in the focal pilocarpine model for limbic seizures.41 When OXC was administered together with verapamil or probenecid (so as to ensure its passage through the blood–brain barrier), complete seizure remission was obtained associated with an increase in 5HT and DA extracellular concentrations.42
with increased potassium conductance in hippocampal kindled seizures in cats, and in intrahippocampal kainic acid–induced seizures in freely moving rats.13,148 Furthermore, antiepileptic drugs (AEDs) with established psychotropic effects (carbamazepine [CBZ], valproic acid [VPA], and lamotrigine [LTG]) have been found to cause an increase in 5HT.41,42,51,52,53,189,210,216 In fact, the anticonvulsant protection of CBZ can be blocked with 5HT-depleting drugs in GEPRs.216 Likewise, in a recent study, Clinckers et al. investigated the impact of oxcarbazepine (OXC) infusion on the extracellular hippocampal concentration of 5HT and DA in the focal pilocarpine model for limbic seizures.41 When OXC was administered together with verapamil or probenecid (so as to ensure its passage through the blood–brain barrier), complete seizure remission was obtained associated with an increase in 5HT and DA extracellular concentrations.42
In addition, it has been suggested that the anticonvulsant effect of the vagal nerve stimulator (VNS) in the rat could be mediated by noradrenergic and serotonergic mechanisms, as deletion of noradrenergic and serotonergic neurons in the rat prevents or reduces significantly the anticonvulsant effect of VNS against electroshock- or pentylenetetrazol-induced seizures.35,139 Furthermore, the effect of VNS on the locus coeruleus and raphe may be responsible for its antidepressant effects identified in humans.3
Data from studies in humans.
Depression in PWE has been associated more frequently with seizure disorders of temporal and frontal lobe origin, with prevalence rates ranging from 19% to 65% in various patient series.6,74,75,95,104,163,207 In contrast to animal studies, the impact of pharmacologic augmentation or reduction in 5HT and NE transmission on seizures in humans has been rather sparse and mostly based on uncontrolled data. For example, depletion of monoamines with reserpine has been associated with an increase in frequency and severity of seizures in PWE,143,197 while the use of reserpine at doses of 2 to 10 mg/day was found to lower the electroshock seizure threshold and the severity of the resulting seizures in patients with schizophrenia.138 The tricyclic antidepressant imipramine, with reuptake inhibitory effects of NE and 5HT, was reported to suppress absence and myoclonic seizures in double-blind placebo-controlled studies.71,72,73 Open trials with the SSRIs fluoxetine and citalopram yielded an improvement in seizure frequency, but no controlled studies with this class of antidepressants have been performed as of yet.4,65
Functional Neuroimaging Studies in Epilepsy and Primary Depression.
The use of positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies has yielded significant data suggestive of abnormal 5HT activity in primary depressive disorders and in epilepsy, with particular involvement of 5HT1 A receptors. Deficits in 5HT transmission in human depression is thought to be partially related to a paucity of serotonergic innervation of its terminal areas suggested by a scarcity of 5HT levels in brain tissue, plasma, and platelets and with a deficit in serotonin transporter binding sites in postmortem human brain.8,30,32,33,38,39,120,121,122,129,140,145,146,151,167,192,195 Serotonin stores and transporter protein are important components of serotonin terminals so that a combined deficit is a plausible indicator of reduced axonal branching and synapse formation.
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