Depression in Epilepsy: Etiology, Phenomenology,

Eprlepsia,

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Department o

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Summary: A history of depression or depressive symptom- atology has been reported in up to two-thirds of patients with medically intractable epilepsy, whereas community studies have demonstrated affective disorder only in a quarter of these patients. Depression has been reported peri- and interictally. However, differentiation may be difficult in patients with fre- quent seizures. Most authors have found no correlation between depression and epilepsy variables. However, complex partial seizures, especially of temporal lobe origin, appear to be etio- logic factors, particularly in men with left-sided foci. Depres- sion is also more common in patients treated with polytherapy especially with barbiturates, phenytoin, and vigabatrin. Depres-

sion has also been described de novo after temporal lobectomy. Psychosocial factors also play a part, but underlying risk factors (e.g., genetic, endocrine and metabolic) may explain the in- creased rates of depression in people with epilepsy compared to those with other neurologic and chronic medical conditions.

The association between epilepsy and depression has been known since antiquity. In the Hippocratic corpus, written around 400 B.c., it is stated:

melancholics ordinarily become epileptics, and epileptics melancholics: what determines the preference is the direc- tion the malady takes; if it bears upon the body, epilepsy, if upon the intelligence, melancholy ( 1).

The importance of recognizing depression in people with epilepsy is not only to enable appropriate treatment to be considered but also to identify patients at risk for suicide. The reported incidence of suicide and deliberate self harm varies considerably from series to series but is be- lieved to be at least four to five times that of the general population (2,3), and patients with temporal lobe epi- lepsy (TLE) are at increased risk by a factor of up to 25 (23). Robertson (4) reviewed 17 studies detailing

Address correspondence and reprint requests to Prof. M. M.

Robertson at Department of Psychiatry and Behavioural Sciences, Uni-

versitv College London Medical School. 48 Riding House Street. Lon- .

don WIN SLA, U.K.

and Treatment

Michelle V. Lambert and *Mary M. Robertson

po

ical Medici

of Psychiatry and Behavioural Sciences, University College London Medical School, London, United Kingdom

ne (Neurops

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The depression appears to be endogenous. Patients tend to ex- hibit fewer neurotic traits and more psychotic symptoms such as paranoia, delusions, and persecutory auditory hallucinations. Treatment approaches include psychotherapy, rationalization of antiepileptic drug medication, antidepressant treatment, and ECT. The tricyclic and related antidepressants appear to be epileptogenic, especially in people at high risk (personal or family history of seizures, abnormal pretreatment EEG, brain damage, alcohol or substance abuse/withdrawal and concurrent use of CNS-active medication). Seizures tend to occur early in treatment or after dose increments, especially if rapidly titrated. There is little evidence that the newer antidepressants, e.g., selective serotonin reuptake inhibitors, moclobemide, venlafax- ine, or nefazodone are more epileptogenic than placebo. Key Words: Depression-Epilepsy-Antiepileptic drugs- Selective serotonin reuptake inhibitors.

cause of death in patients with epilepsy and found that the average incidence of suicide was nine- to tenfold that of the general population ( 13.2% compared with 1.4%). Two reports have also shown a 5-7% increase in self- poisoning in these patients (5,6).Suicide has been re- ported in patients with severe epilepsy, epilepsy with other handicaps, and those seen in specialist clinics (4) but may also follow an improvement in seizure control (7).Increased suicide rates have also been reported after temporal lobe surgery even if the outcome was success- ful (8,9).Harris and Barraclough (3)performed a meta- analysis of follow-up studies to assess suicide rate in psychiatric and neuropsychiatric conditions. They found the highest suicide rate for patients with surgically treated TLE who had an increased risk by a factor of 80, with a standardized mortality rate (SMR) of 8,750. Risk factors for completed suicide have been found to include Drevious historv of deliberate self-harm, familv historv of suicide, stressful life events, poor morale, stigma, and psychiatric disorders and

depression, psychosis, and personality disorder (3,4).

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One study in the general population found that half of those who committed suicide did so within 24 h after a medical consultation, many ingesting their prescribed drugs, and almost half had communicated their suicidal intent (10). Therefore, physicians should specifically consider and inquire about suicidal ideation and intent in

was the most common ictal emotion. Ictal depression appears to be more common in patients with TLE (15).in whom rates of over 10% have been reported ( 16,17). No association with laterality of seizure focus has been found (15-17).

patients with epilepsy who may be at risk for attempting

suicide. stimuli. It can occur in isolation (SPS) or within seconds

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Depression in patients with epilepsy has been reported to minutes before the development of a complex partial

peri- and inter-ictally. However, in patients with frequent seizures, differentiation may be difficult.

(CPS) andlor secondarily generalized seizure. The sever-

Prodromal moods

or irritability o

of depression

hours to days before a seizure and are often relieved by

the convulsion

the 19th century psychiatrist Grule:

ly described

by

)observed d liams (15

( 11). This w

as eloquent

history of ictal depression who committed suicide during a cluster of CPSs. Complex (formed) hallucinations may accompany the depressive feelings. Williams ( 15) and Weil (16)reported an association between olfactory hal- lucinations and ictal depression. Interestingly, several workers have found ictal depression to be of prolonged duration, often persisting into the postictal period, which may represent underlying subclinical seizure activity (1516).

. . . physician and attendants do hope for a seizure in these often very difficult patients, which comes like a salvation for everybody: the patient is much more bearable for weeks thereafter ( 12).

Blanchet and Frommer (13) performed a prospective study examining prodromal mood changes. They found that most patients reported more depression on the days immediately preceding their seizure than on interictal days, along with improvement of mood after seizures. The phenomenology of these low moods was not docu- mented. The authors suggest several explanations for the prodromal mood changes. The low mood may be a symptom of subclinical seizure activity or of physiologic or biologic processes involved in initiation of both the lowered mood and the seizure. In some patients, how- ever, a negative, depressed or dysphoric mood in com- bination with negative life events may increase the like- lihood of seizures.

A more recent study (14) evaluated 148 adult patients

with epilepsy of whom 128 had partial seizures. Pre-

monitory symptoms were defined as behavioral phenom-

ena that preceded seizures by at least 30 min. A third of

the patients with partial seizures reported premonitory

symptoms (usually before secondarily generalized sei-

zures) compared with none of the patients with primarily

generalized epilepsy (PGE).Half of the symptoms were

emotional in nature and consisted of feelings of irritabil-

ity, depression, fear, elation, and anger. The symptoms

lasted between 10 min and 3 days, and the intensity

TREATMENT OF PRE- AND ICTAL DEPRESSION

Although prodromal and ictal depression does not usu- ally require treatment per se, improvement in seizure frequency (see below) should reduce the occurrence of these forms of depression. These depressive pre- and peri-ictal feelings may be regarded by some patients as an “early warning system.” Patients may have time to alert people that they require assistance and may also have time to move to a place of safety. Medication such as fast-acting benzodiazepines may abort or prevent the development of the attack as may behavioral methods such as stress management, biofeedback, or aroma- therapy (21-23).

POSTICTAL DEPRESSION

Blumer (24) described three patients who developed depression lasting hours to days immediately after sei- zures. However, these patients also experienced episodes of interictal depression, and Blumer noted that it was rare to find a patient who suffered postictal depression alone.

ccur

reported a patient who attempted suicide during such an episode. Mendez and Doss (20) reported a patient with a

Ictal depression, classically, is of sudden onset and occxurs out of cwontext i.e., not revlated to envuironmental

ts hopelessness and despair ( 1 1). Lim et al. ( 18) described

PREICTAL DEPRESSION a patient with nonconvulsive status epilepticus present- ing as a case of psychotic depression, and Betts (19)

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ICTAL DEPRESSION CPSs in 18 patients with medically intractable depres- sion. Postictal flattened or depressed affect occurred Depression can occur as part of the ictus itself. Wil- more commonly after CPSs originating in right temporal

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of a series of 2,000 patients with epilepsy, although fear not appear to be consistent with those of an earlier single

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Epilepsia, Vol. 4

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seizure, SPS) in approximately 1% bilateral limbic dysfunction. However, these findings do

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INTERICTAL DEPRESSION

Epidemiology

Interictal depression is believed to be much more com- mon than peri-ictal depression. However, the prevalence is not known. Most studies have been criticized for using nonrepresentative hospital samples, for being retrospec- tive, or for using questionnaires rather than clinical judg- ment to diagnose depression. Interpretation is further complicated by the fact that some studies have reported

depressive symptomatology whereas others reported de- pressive illness.

The major studies investigating depression in PWE are shown in Table 1 and should be compared with the prevalence of depression in the general population of 1-3% for men and 2-9% for women (45). In general, depression is more common andor more severe in pa- tients with epilepsy than in patients with other neurologic and chronic medical conditions (29,46,47). The rate of depression appears to be lowest in community studies, increasing in patients attending hospital outpatient cen-

ters, and is highest in patients with medically intractable epilepsy being evaluated for epilepsy surgery (34,48,49), although in some centers patients with severe psychiatric disorders are excluded from the epilepsy surgery pro- gram.

Some investigators have not found such high rates of depression in people with epilepsy. Fiordelli et al. (50) found that only 6% of patients with cryptogenic epilepsy in Milan had a DSM-111-R depressive disorder (depres- sive disorder NOS or dysthymia) compared with 5% of controls. However the study group could be considered atypical because only 90% of the patients had “active” epilepsy (i.e., had experienced seizures within the previ- ous 2 years) and only 28% had partial seizures of pre- sumed temporal lobe origin, reflecting the exclusion of patients with documented brain lesions.

Etiology

Various causative factors have been proposed for the development of depression in people with epilepsy (Table 2). The etiology is most likely to be multifacto- rial, with several different factors playing a part in each individual patient.

A family history of depression has been reported in some studies. Robertson et al. (54) found that more than half of 66 patients with both epilepsy and depression had a family history of psychiatric illness, usually depres- sion. Others, however, have found no association (31,37, 39). Only one study has compared the incidence of psy- chiatric disorders in first-degree relatives of patients with acquired epilepsy (26 probands) with relatives of patients with genetic epilepsy, (juvenile myoclonic epilepsy, JME) (60). Depression was the most common psychiatric disorder in both probands and relatives and almost twice as many patients with JME had first-degree relatives with mental illness. The findings of this small study

DEPRESSIONzINEPILEyPSYxwvS2u3zyt

case report (26) of a patient who developed postictal depression after left-sided CPSs and hypomania after right-sided seizures.

Gender

Blumer (24) has postulated that postictal depression is

a consequence of the inhibitory mechanisms involved in

the termination of seizures. He suggested that procon-

vulsant antidepressant medication (see below) in lower also found men to be over-represented in depressed pa- doses than usually prescribed, along with optimal control tients (31,46,53) and patients who deliberately harmed of the epilepsy would be the treatment of choice and themselves (6).

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Few studies have addressed this variable. However, Altshuler et al. (51) found the highest Beck Depression Inventory (BDI) scores in male patients with TLE, and Strauss et al. (52) found that men with left-sided foci were more vulnwerable to depressvion. Other authors have

Conversely,

(but nonsignificant) number of women to have psychiat- ric morbidity as measured using the present state exami- nation (PSE), and more women with epilepsy and de- pression have been reported by others (543.5). Still oth- ers, however, have not found gender to be a significant etiologic factor (35,39).

Although the results of the various studies are not congruent, the majority of studies that have addressed gender have found men to be most at risk. This is par- ticularly significant because studies of people with de- pression without epilepsy have demonstrated an in- creased prevalence in women.

Sinistrality

This factor has not been intensively explored. Some studies have observed that more left-handed people with epilepsy tended to have psychiatric morbidity, especially depression (51). However, other studies have found no such association (37). The expression of left-handedness may indicate early brain injury.

Neurologic

Depression may be associated with a neurologic con- dition that is also responsible for the epilepsy, e.g., mul- tiple sclerosis, cerebrovascular disorder, dementia, and head injury (56,.57), and may be more common in pa- tients with a structural lesion (28,58). However, some studies have not found a structural brain lesion to be associated with depression in patients with epilepsy (31,59).

Genetic/environmental

Standage and Fen

ton (29) foun

d a higher

might be explained by either genetic or environmental

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hypotheses, and further studies are needed.

Epitepsru, Vol. 40, Suppl.

10,1

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999

M. V. LAMBERT zyxwvutzsyrqxwpov

S24

Reference Currie et al. (27)

Taylor (28)

Standage and Fenton (29) Roy (301

Mender et al. (31)

Brown et al. (32)

Edeh and Toone (33)

Edeb et al. (34)

Victoroff et al. (35) Gureje (36)

Indaco et al. (37)

Victoroff (38)

Robertson et al. (39)

Manchanda et al. (40)

Jacoby et al. (41)

Baker et al. (42) Ring et al. (43)

Blumer et al. (44)

AND M.

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Medically intractable epilepsy

Hospital sample, PWE

Hospital sample, PWE Community study PWE

Hospital sample, PWE

PWE >16 years hospl community sample

PWE

Community sample

Hospital sample

Medically intractable epilepsy

Hospital sample, PWE Nigeria

Hospital sample, PWE

Medically intractable CPS

Hospital sample, PWE

Medically intractable epilepsy

Community sample All PWE

Seizure-free

Frequent seizures (>]/month)

100

27

42 175

28

88

88

62 26 47

204

96

60

18

300 (231 TLE)

696 350 168

Semi-structured interview (PR)

PSE (PR)

HDRS (PR) HDRS (PR) BPRS (PR)

SPI (PR)

CIS (PR)

CIS (PR)

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TABLE 1. Epidemiologic studies o j depression in people with epilepsy

Population

Hospital sample, TLE 666

M. ROBERTS

Number Measure Findings

111 R (PR)

DSM CIS (PR)

HDRS (PR)

BDI (SR)

ZDI

SCID (PR), DSM-111-R

HDRS (PR) NDI (PR)

BDI (SR)

LPD (SR)

STAI (SR) SSRQ (SR) WPSI (SR) DSM-III-R (PR)

6

37.3% psychiatric cases 53%: neurosis

29%: psychosis

7%: PD

50%: depression (DSM-Ill-R)

Lifetime prevalence of 88.3%: any psychiatric disorder

70%: axis I diagnosis 58.3%: depression 31.7%: anxiety

10%: psychosis

5%: bipolar disorder

18.3%: axis II diagnosis (PD)

27%: depressed

DSM-111-R

47.3%: psychiatric case 29.3%: axis I diagnosis 10.7%: anxiety

3%: mood disorder 4.3%: SLPE

18%: axis I1 diagnosis

25%: anxious

9%: depressed

13%: anxious

4%: depressed

44%: anxious

21%: depressed

Perceived seizure severity, predicted anxiety

and depression

52%: psychiatric disorder

21%: depression

18%: anxiety

57%: interictai dysphoric disorder 67%: interictal dysphoric disorder

~~

TL, temporal lobe; PD, personality disorder; TLE, temporal lobe epilepsy; PWE, people with epilepsy; SLPE, schizophrenia-like psychosis of epilepsy; CNS, central nervous system; Hosp, hospital; MSE, mental state examination; SLPE, chronic psychosis; CPS, complex partial seizure; FLE, frontal lobe epilepsy; PR, physician rated; SR, self-rated; HDRS, Hamilton Depression Rating Scale; PSE, present state examination; BPRS, Brief Psychiatric Rating Scale; SPI, Standardised Psychiatric Interview; CIS, Clinical Interview Schedule; DSM IIIR, Diagnostic and Statistical Manual, Edition 111, revised; BDI, Beck Depression Inventory; ZDI, Zung Depression Inventory; SCID, Structured Clinical Interview for DSM-111-R NDI, Newcastle Depression Inventory; LPD, Levine-Pilowsky Depression Questionnaire; STAI, Spielberger State- Trait Anxiety Inventory; SSRQ, Social Readjustment Rating Questionnaire; WPSI, Washington Psychosocial Seizure Inventory.

Epilepsia,Vd.4z0,Suppl.z10y,1999yxwxwvvuutstrsqrpqopnomn

Community sample PWE 696 [as in Jacoby et al. (41)]

Medically intractable 60 epilepsy

Medically intractable TLE 44

Medically intractable FLE

6

ON

Interview

review (PR) 7% aggressive, 6% obsessive)

and case no

te 44%: ab

s, 11%

87%: any psychiatric disorder

48%: “psychopathy”

30%: neurosis (17% depressed, 7% anxious.

4% obsessional)

22% past psychiatric history (60% depression,

75% depressed mood, 50% anxiety)

54.7% depressed (65% CPS; 42% other seizures) 55%: depression

4 times more PWE had been hospitalized than control

g p with similar socioeconomic and disability levels 26.7%: subjectively depressed

31.1%: objectively depressed

22.2%: subjectively anxious

11.1%: objectively anxious

47.7%: psychiatric cases

21.6%: depressive neurosis

14.8%: anxiety neurosis

47.7%: psychiatric cases

40.3%: psychiatric cases (9.7% anxiety neurosis,

2%: history o

normal MSE

(19% anxiou

depressed,

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19.4% depressive neurosis)

65.4%: psychiatric cases (26.9% anxiety neurosis,

26.9% depressive neurosis)

f depression 38%: currently depressed

TABLE 2. Etiology

ofdepression i

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epilepsy

Age at onset of epilepsy

Duration of epilepsy

Seizure type

Number of different seizure types

Localization of focus (LRE vs. PGE; TLE vs. extra-TLE) Lateralization of focus

Seizure frequency

Seizure severity

Seizure control. “forced normalization” Secondary generalization of seizure

Iatrogenic

Type of AED

Number of AED

Serum level of AED

Secondary effects of AED, e.g., hormonal, serum folate

deficiency

Effect of epilepsy surgery

Psychosocial Stigma

Discrimination

Locus of control

Fear of seizures Attributional style Adjustment to epilepsy Parental overprotection Social support Socioeconomic status

PWE, people with epilepsy; HI, head injury; MS, multiple sclerosis; CVA, cerebrovascular accident; SOL, space-occupying lesion; LRE, localization-relatedepilepsy; PGE, primary generalized epilepsy; TLE, temporal lobe epilepsy; AED, antiepileptic drug.

Intelligence

Thompson and Oxley (61) noted that the mean IQ of 92 patients with medically intractable seizures being ad- mitted to a specialist hospital was 83.6. However in the majority of cases this had not been detected at school, which may have contributed to the conduct and emo- tional disturbances observed in these patients.

Lund (62) assessed 302 patients with learning disabil- ity and found that twice the percentage of patients with concomitant epilepsy had a psychiatric disorder (includ- ing behavioral problems and autism) compared with pa- tients without epilepsy. Psychiatric disorder was more common in those who had experienced seizures in the preceding year (52% compared with 36% with a history

of epilepsy) and was inversely proportional to IQ. Stef- fenberg et al. (63) assessed 98 children and adolescents with learning disability and epilepsy and found a psychi- atric disorder (mainly autistic disorder and an autistic- like condition) in over 90% of the patients in whom a psychiatric condition could be categorized. Surprisingly, the two other major studies of patients with learning disability failed to find an increased rate of psychiatric illness in those with epilepsy (64,65). This may reflect the difficulty in diagnosing psychiatric co-morbidity in

e

A wide variety of metabolic and hormonal changes are reported during ictal activity (66). Enhanced turnover of norepinephrine has been reported in chemically induced seizures, and a wide range of changes in tryptophan and 5-hydroxy indoleacetic acid (5-HIAA) have been docu- mented during both electrically and chemically induced seizures. Norepinephrine, tryptophan, and 5-HIAA have all been implicated in theories regarding the develop- ment of depression. Endocrine changes, such as in- creases in prolactin and vasopressin, are seen after spon- taneous generalized seizures and after both unmodified and modified ECT, suggesting that they are not a con- sequence of the peripheral events of a generalized sei- zure but arise from the electrical seizure activity. In con- trast, increases in plasma growth hormone, adrenocorti- cotropic hormone (ACTH), and cortisol are less after modified ECT compared with unmodified ECT. After

generalized seizures, marked activation of the autonomic nervous system has.been reported, with increases in epi- nephrine and norepinephrine. After prolonged seizures, blood glucose increases, which may promote insulin re- lease, resulting in secondary hypoglycemia (66).

The above changes are a reflection of enhanced neu- ronal and sympathetic activity. Concomitant behavioral changes are believed to result from enhanced excitation and synchronicity in some excitatory systems and from enhanced inhibition affecting other pathways or struc- tures. However, more refined in vivo measurements of neurochemical changes will be required to fully correlate them with behavioral changes (66).

EPILEPSY FACTORS

Age of onsetJdurationof epilepsy

Although some studies have found an association be- tween late-onset epilepsy and depression (67), most have found no relationship with either age of onset (29- 31,34,35,39,46,47,51,59) or duration of epilepsy (29,30, 37,39,5139).

Seizure type

Many studies have found depression to be more com- mon in patients with CPS (27,30,31,36,37.54,69). Oth- ers, however, demonstrated that the number of seizure types was correlated with greater risk for psychiatric dis- order (50,70).

Neurologic (e.g., HI, MS, CVA, SOL)

Gender

IQ

Genetic/environmental factors Endocrine/metabolic factors Epilepsy factors

Endocrine/metabolic factors

n people with

trs from profound disability, a problem encountered in a

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DEPRESSION IN EPILEPSY

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Several studies have found depression to be more common in patients with TLE (27,32,36,58,71-74). Oth- ers, however have not confirmed the excess psychiatric morbidity in these patients with TLE (29,75,76). Edeh and Toone (33) did not find higher psychiatric morbidity

Epilepsia.Vol. 40,Suppl.

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10, I

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S26 zyxwM. Vz. LAMvByERT ANuDxM. M. RwOtBERTsSONvzruyqtxpsworqnv

in patients with TLE compared with non-temporal lobe focal epilepsy, but found that focal epilepsy, regardless of site of focus, had more interictal psychopathology than PGE. A study by Hermann et al. (77) found in- creased perseverative responding on the Wisconsin Card Sorting Test and dysphoric mood state in patients with left TLE, suggesting that frontal lobe dysfunction may be an additional factor in the genesis of depression in pa- tients with TLE. Bromfield et al. (78) confirmed this hypothesis by reporting a bilateral reduction in inferior frontal lobe glucose metabolism, in depressed patients with CPS.

suggest that a left-sided origin predisposes for depression (92). A theory has been proposed that the nondominant hemisphere subserves negative feelings, whereas the dominant subserves positive emotional states (93,86). It has been hypothesized that the “release” of the contra- lateral hemisphere after ipsilateral seizure inactivation results in the affective changes (26). Mendez et al. (31) suggested several explanations: (a) the depression is sec- ondary to a focal lesion in the left hemisphere; (b) the depression is caused by continuous subclinical electro- physiologic alterations affecting limbic areas; and (c) depression reflects the interictal perifocal area of “sur- round inhibition” and ipsilateral hypometabolism, ob- served with positron emission tomography (PET) studies (35,38,96-98). Schmitz et al. (99) however, noted that patients with left-sided epilepsy and higher scores on the BDI were found to have more contralateral temporal and bilateral frontal hypoperfusion (measured with SPECT). The authors observed that the hypoperfusion may repre- sent the widespread perfusion changes involving the lim- bic frontal regions seen in people with TLE, which may be related to functional deafferentation, interictal inhibi- tory activity, or postictal depletion of substrates (78,99).

Stevens (76) has criticized studies implicating TLE/

CPS, suggesting the reason for the excess of TLE in

PWE suffering from psychiatric disorders, merely repre-

sents the fact that TLE is the most common type of

epilepsy in adults. Furthermore, other studies have found

no association with seizure type (29,46,79,80) or focus

(54). Manchanda et al. (81) assessed 30 patients with

TLE, 25 with non-temporal lobe focal epilepsy, and 19

with multifocal onset/generalized epilepsy, referred to a

teaching hospital epilepsy investigation unit. Over half

had a DSM-111-R psychiatric disorder, but no significant differencesinpsychiatricmorbiditywereobservedwTheinconsistencviesinfindinugsmayinptartbeesx-r among the different foci. Only 4.25% of the entire group plained by the difficulty in reliably lateralizing the sei-

Lateralization of seizure focus

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were diagnosed as having a “mood” disorder (6% with zure focus using scalp EEG electrodes (100).However, TLE, 4% with non-temporal focal epilepsy, and none another explanation for the preponderance of left-sided

with generalized epilepsy).

fo

ci in patients with

rized from the findings of Bear and Fedio (101), who noted that patients with right sided-foci tended to deny or minimize their negative behavior, whereas those with a left-sided focus tended to be more self-critical. Thus, patients with left-sided ictal onset would be more likely to rate themselves as more depressed with self-report measures. To produce more objective ratings, it is sug-

zyxwvutsr

Flor-Henry (82) was the first to suggest a relationship

between laterality of seizure focus and psychosis. He

postulated that depression was associated with nondomi-

nant (right) temporal lobe lesions. However, this conclu-

sion was based on the evaluation of nine patients, of

whom four had a right-sided, two a left-sided, and three gested that physician-rated scales should be used in com- a bilateral focus. Since then, many studies have ad- bination with self-report measures.

dressed the issue of laterality.

Some studies have found that right-sided foci are as- Seizure frequencylseverity and control: the role of

sociated with depression (31;

ed normalization

nonsignifica

nt associatio

n) forc

and several have found that lateralization was not a sig- Several studies have reported a decrease in seizure

nificant etiologic factor (37,59,80,84,85). Most studies, however, have found that although psychiatric disorder in general, especially hypomania (26,86), tends to be associated with right-sided foci, depression appears to be more common in those with left-sided foci (31,35,47,51- 54,78,87-91). Victoroff et al. (38) found that left-sided ictal onset and hypometabolism were associated with a history of and current depression in patients with CPS. However, patients with right-sided hypometabolism also had a history of major depression, suggesting that left- sided ictal onset and degree of hypometabolism were independent risk factors for development of depression.

In summary, although there are studies associating de- pression with either left- or right-sided foci, the majority

frequency before the onset of the depressive illness (29, 72,82,102). Mendez et al. (47) found that patients with epilepsy and depression had significantly fewer general- ized seizures than those without depression. These au- thors postulated that nonreactive depression may occur when AED therapy prevents generalization from an epi- leptic focus. Others, however, have not found an associa- tion (31,3734) and still others have even documented an association with an increase in seizure frequency (70,103). Recent quality of life studies have found fre- quent seizures to be associated with increased anxiety, depression, and stigma (41,104), as is perceived seizure severity (42). Trostle et al. (49) reported fewer psycho- social problems (assessed using the Washington Psycho-

Epilepsia, Vol. 40, Suppl. 10, 1999

epilepsy and

depression ca

n be the

o-

DEPRESSIONzINEPILEyPSYxwvS2u7zty

social Seizure Inventory, WPSI) in patients who were not receiving AEDs and had been seizure-free during the preceding year. Those who were seizure-free on AEDs had intermediate scores. Patients who continued to ex- perience seizures despite AEDs had the most severe psy-

chosocial problems. Severity of seizures was associated with the seventy of self-reported psychosocial problems.

IATROGENIC DEPRESSION

Antiepileptic medications

Polypharmacy has been shown to be associated with

depression in patients with epilepsy (47,50), and Shor-

von and Reynolds (105) reported an improvement in alertness,concentration,drive,mood,andsociabilityaf-andcaseseries(131)havezfoundLTGytobeefficacxiousw ter reduction of polytherapy to monotherapy. in bipolar affective disorder.

Certain AEDs have been found to be psychotropic, Topiramate has been shown to be an effective second- and others are associated with behavioral changes and line AED, and depression appears to occur no more com-

depression. Phenobarbital (PB) has been associated with monly than with placebo

depression in adults (55,106). Brent et al. (107) found a found to have minimal side effects, not significantly dif-

higher prevalence of both depression (40% vs. 4%) and suicidal ideation (47% vs. 4%) in adolescents and chil- dren taking PB compared with carbamazepine (CBZ). Dodrill (108) reviewed 90 studies in which the behav- ioral effects of phenytoin (PHT), barbiturates, CBZ, or valproic acid (VPA) were assessed in patients with epi- lepsy and normal volunteers. Barbiturates were most clearly associated with negative behavioral changes, in-

cluding depression. In more than half the studies, posi- tive behavioral changes were associated with CBZ (decreased anxiety and depression) and VPA (improved mood and increased happiness). Phenytoin produced positive and negative effects in similar numbers of re- ports. A recent double-blind prospective study compared the efficacy and toxicity of PHT, primidone (PRM), PB, and CBZ. At 1 year, behavioral toxicity scores were highest for those on PHT and lowest for CBZ (109). Dalby (110) reported a psychotropic effect in approxi- mately half the patients treated with CBZ, which has

also been shown to be associated with less depression than PRM (73) and PHT (111). CBZ is also efficacious as an antidepressant in patients without epilepsy and is prophylactic in the control of manic-depressive illness (112-114), as is VPA (112,114-116).

Fewer studies have been performed with the newer anticonvulsants. Vigabatrin (VGB) is an irreversible in- hibitor of y-aminobutyric acid (GABA)-transaminase and thus increases levels of the inhibitory neurotransmit- ter GABA. This drug appears to be particularly associ- ated with depression, developing in up to 10% of patients (117). The depression typically occurs within a few weeks after the drug is introduced or after dose incre- ments. A past history of psychiatric disturbance has been found to be a major risk factor (1IS).

Efficacy data (1 19) have shown lamotrigine (LTG) to

een

ferent from placebo (133) and also has the advantage of not inducing liver enzymes (132). Case reports also sug- gest it may be efficacious in bipolar disorder (134,135). The most recent AED to be licensed as adjunctive therapy in the United Kingdom is tiagabine (TGB), which acts by blocking the uptake of GABA into neurons and glia. Concern has been expressed, however, that TGB may be associated with the development of depres- sion because, like VGB, it increases the cerebral level of GABA. Intravenous GABA can produce dysphoria and anxiety in both normal volunteers and patients with bi- polar affective disorder (136). Early reports have docu- mented asthenia, nervousness, and depression to be ad- verse events (137-1 39), although a recent monotherapy study reported adverse mood changes only with rapidly

titrated high-dose TGB (140). It is therefore too soon to make recommendations about TGB, but at present cau- tion is advised in prescribing it for patients with a history of psychiatric disorder.

Caution must be exercised in withdrawing AEDs, es- pecially benzodiazepines and barbiturates, because both depression and anxiety have been reported after discon- tinuation of anticonvulsants (141,142).

For further discussion of depression and AEDs, see Schmitz, this issue.

Metabolic effects of AEDs

Tryptophan

be at least as effective in producing seizure freedom as CBZ, while being better tolerated (fewer adverse effects and withdrawals from the study). Several studies have shown improvements in well-being with LTG add-on therapy (120-124). Lamotrigine has also been found to

zyxwvu

produce increased happiness and mastery (perceived in-

ternal control) than placebo, which was not dependent on change in seizure frequency or severity (125). Mono- therapy studies have shown that LTG produced improve- ments in all the Side Effect and Life Satisfaction

(SEALS) Inventory scores (cognition, dysphoria, temper, tiredness, and worry) compared with CBZ (126,127) and improvement in the SEALS score for dysphoria com- pared with PHT (126,128). Recent case reports (129,130)

(132). Gaba

Pratt et al. (143) reported that PB and PHT reduced plasma free tryptophan, whereas CBZ increased levels compared with normal volunteers and untreated patients with epilepsy. Plasma free tryptophan influences seroto- nin turnover. Therefore, the authors postulated that this may be the mechanism that produces the psychotropic effect of CBZ and the depressant effects of PB and PHT.

Epilepsia, Vol.

40, Suppl. 1

0. I999

xw

pentin has b

zyzy

zyxw

Folate deficiency

c disorders o

zvyuxwtvsvruqutptsozrnq

qy AED therapy causes a decrease in serum, red blood due to a seizure-suppressing inhibitory mechanism.

S28

zyxw

M. V

. LAM

B

ERT AN

D

M. M. R

O

BER

TSON

ing LTG has found no reduction in folate (149). Folate Many investigators have found the

side of temp

oral deficiency has been associated with psychiatric morbid- lobe surgery to be predictive of postoperative depression.

ity (predominantly depression) in patients both with (144,145,147) and without epilepsy (150-152). Vitamin B,, deficiency has also been documented in patients with epilepsy, especially those with psychiatric disturbance. It is believed to be secondary to the antifolate action of the AEDs (147) and may be exacerbated by the administra- tion of oral folic acid supplements (153). Folates appear to have a major role in methylation in the nervous system (154). Methylfolate donates its methyl group to homo- cysteine to form methionine (which is catalyzed by B,,), which then passes the methyl group to S-adenosyl- methionine (SAMe). SAMe is the sole methyl donor in the brain in many methylation reactions involving neu- rotransmitters and monoamines, which are believed to be implicated in the etiology of affective disorder. SAMe has been found to have antidepressant properties and raises 5-HIAA and HVA (by products of monoamine metabolism) in the CSF. There has been little published research on the effect of administering folate supple-

ments to patients with epilepsy. This is partly because of

concerns about the proconvulsant properties of folic acid

(153,155). However, there have been reports of an im-

provement in drive, speed of cerebration, alertness, con-

centration, and well-being in patients with documented

folate deficiency after oral folic acid supplements (es- bectomy, especially if there is only partial improvement pecially if supplemented with vitamin B,,), although in in their seizures (9,59,159,161,162). Despite this, little half of these patients the seizure control deteriorated research has examined this surprising and important as-

zyxw

DEPRESSION AFTER EPILEPSY SURGERY

There have been several studies, many several decades old, assessing postoperative depression. These are sum- marized below.

Most authors have found that complete freedom from seizures is necessary for a postoperative reduction in depression (44,59,156-161). Blumer et al. (44) have sug-

qp

(145,153).

pec

Epilepsia, Vol. 40, Suppl. 10, 1999

gested that

the psychiatri

f epile

Therefore, the postoperative lessening of excitatory ac- tivity and relative predominance of inhibition may pre- dispose to the emergence of dysphoric, affective, and psychotic disorders. If there is a recurrence of seizures, renewed seizure-suppressing activity may also produce psychiatric morbidity. Patients not rendered seizure-free (even with >75% improvement of seizures) do not ap- pear to have any change in levels of depression, behav- ioral, or emotional adjustment (9,59,157,160,162,163). Patients only experiencing SPS postoperatively also

cell, and CSF folate levels in 11-15% of patients with

epilepsy compared with normal controls (144,145), al-

though earlier studies assessing outpatients taking barbi-

turates and/or phenytoin documented low folate in half to

three-quarters of patients (146,147). Reynolds et al.

(147) also reported megaloblastic hemopoiesis in 38% of

the patients whose sternal marrow was examined, which

reversed with oral folic acid therapy. Although reduced

folate has been documented with most AEDs, it is more

marked in patients receiving polytherapy (144,145,147) anditappearstobemorecommonwiththeliveren-continuetoexperiencedepression(16z4),perhapsybe-x zyme-inducing AEDs (145). Most studies assessing VPA cause the continued premonitory symptoms may act as a

have found little effect unless the patient was also taking reminder of their seizures and cause alarm that the aura enzyme inducers (145,148), and the single study assess- may herald a generalized seizure.

However, the various studies have produced contradic- tory findings. Fenwick et al. (165) assessed 96 patients after temporal lobectomy. A quarter had postoperative depressive symptoms, of which 72% had undergone a right-sided and 28% a left-sided operation. Other authors have also reported more mood changes after right-sided surgery (166).

Depression has been reported occurring de novo after temporal lobectomy (28,44,167-169) and amygdalohip- pocampectomy (166). Parashos et al. (170) reported the development of bipolar affective disorder and depres- sioddysthymia after anterior temporal lobectomy. Post- operative MRI scans revealed ipsilateral degeneration of the thalamus and putamen in both patients.

Postoperative depression tends to be more common in the first 2 months after surgery (44,17 1,172) and is often transient (171). Ring et al. (43) observed that at 6 weeks after surgery 27% had developed de novo symptoms of anxiety and 23% of depression, and 45% of patients had increased emotional lability. At 3 months after surgery, emotional lability and anxiety symptoms had diminished but depression tended to persist.

Many studies have shown a deterioration in the psy- chivatric and soucial status oftpatientssafter temrporal lo-

t of epileps

y surgery. E

toperative

from seizures can be associated with depression and be- havioral problems (159,163,170). Ferguson and Rayport (173) discussed this in 1965, suggesting that it was the abrupt (surgical) removal of a psychiatrically significant experience, the seizure, rather than the removal of tem- poral lobe tissue that was of major psychological impor- tance. They postulated that the postoperative seizure-free state permits assessment of the extent to which the sei- zure disorder has been incorporated into the adaptive

ven pos

psy may

b

freedom

e

patterns of the patient. They proposed that epilepsy may afford some patients psychological benefits. The illness may shield them from any hostile feelings friends and relatives may have toward the patient. In the series re- portedbyBladin(163),6%ofpatientsfoundadjustingto life without seizures so difficult that the situation re- sulted in divorce. The patient may use epilepsy as an “excuse”for failures in personal, social, and occupational areas. It may even allow inappropriate behavior to be

such as job loss, lack of friends, or relationship difficul- ties, to their epilepsy. This pessimistic attributional style has been associated with the development of depression (180).

DEPRESSIONzINEPILEyPSYxwvS29uzyt

ever, have not found any change (improvement epilepsy unit for assessment. Over half of the group re- or deterioration) in psychiatric status postoperatively, re- ported psychosocial problems in several areas. Moderate

%,

gardless of outcome with respect to seizure control (58). to severe employment difficulties were reported in 71

Taylor (28) and Rausch (176) have determined pre- and the majority of those who had been employed had dictors of a postoperative improvement in psychosocial performed only unskilled work. Seizure control did not

functioning:

1. Excellent seizure control.

2. No or mild preoperative psychopathology.

3. Good family support.

4. Good preoperative relationships at work and with

friends.

5. Age at surgery <30 years.

6. Good schooling and higher preoperative IQ.

PSYCHOSOCIAL FACTORS

Epilepsy is associated with repeated but unpredictable

episodes of loss of consciousness or alteration in behav-

ior, often resulting in embarrassment and loss of dignity

(54). This unpredictability and uncontrollability has been

compared with Seligman’s concept of “learned helpless-

ness,” which occurs when patients are exposed to ad-

verse experizences on a ranydom basis (17×7-179). Her-wWhitmanv(56)showedthautincreasedstressfullifeevents, mann (178) proposed that this may predispose to depres- poor adjustment to seizures, and financial stress were sion, and this has been developed into the concept of predictive of increased depression. However, such psy- locw of control. Preoperative depression has been cor- chosocial factors may have been the consequence of de-

related with

events not being attributable to the patient’s own efforts Roth et al. (103) assessed the physical exercise pat-

an external locu

s of control (a

perception of

pression r

ather than the

cause of it.

but rather to the effects of fate) (59). More recently, the concept of attributional style has been viewed as a marker of learned helplessness. A pessimistic attribu- tional style is characterized by the attribution of causality for positive events to “external, unstable and specific causes” and negative or adverse events to “internal, stable and global causes,” an example of which is epi- lepsy. Patients with epilepsy and a pessimistic attribu- tional style may therefore attribute global difficulties,

terns along with depression levels (measured using the BDI) in 133 outpatients attending an epilepsy center. Only 30% of the group were classified as “active” (par- ticipating in at least 20 min of exercise at a minimum of three times a week), and half the patients reported no exercise at all. Thirty-two percent of active patients were depressed compared with 59% of the nonactive patients. This finding was independent of variables such as age, gender, seizure frequency, or stressful life experiences.

Many studies have reported a deterioration in quality of life in patients with epilepsy (181,182), which may adversely affect mood ( 1 83). Rodin et al. ( I 84) reported that more than half of their sample of patients had a psychological or social problem with behavioral mani- festations. Similar findings were reported by Dodrill et al. (185), who assessed 315 patients with epilepsy from a wide range of social and educational backgrounds, suf- fering from different seizure types with varying age of onset, using the WPSI. They found emotional, interper- sonal, vocational, and financial concerns in over half the patients. Thompson and Oxley (61) assessed socioeco-

accepted. After the operation, the family may expect a

radical change in personality and may become critical of

the patient’s behavior and weaknesses. This may cause

the patient to become depressed and even to wish that

surgery had never been performed. Somatization and the

development of non-epileptic attack disorder (NEAD)

may occur. Preoperative counseling and postoperative rehabilitationmayhelppatientsandtheirfamiliesadjustnomicdifficultiesin92patientswithsevere,medicazllyy to life without seizures (174,175). Some authors, how- intractable epilepsy who were admitted to a specialist

zyxwvut

necessarily correlate with ability to find work because

other factors, such as social skills, emotional stability,

poor motivation, low self-esteem, and feelings of depen-

dency and helplessness, also contributed. In general, dis- satisfaction was related to the undemanding nature of the work, although a perceived need to “prove themselves” to colleagues and employers was also reported. The au- thors stressed that employment did not merely provide an income but also provided a daily occupation, which in turn would enhance self-esteem. Employment rehabilita- tion needs to focus on providing skills to cope with fear of seizures and job stress along with job finding and interview techniques. Three-quarters of the sample were dissatisfied with their social life, 68% had no personal friends, and 34% had never formed a “true friendship.” Only 16% were in a steady relationship, despite the fact that 71% were over the age of 20 years. Hermann and

Epilepsia, Vol. 4

tsr

zyzxywx

0, Suppl.

10, 1999

S30 zyxMw. Vz. LAMByERT AvNDxM. M.uROwBERTSONtzvsyurxtqswrpqvo

mily membe

Stigma

Goffman (194) defined stigma as any “attribute that is deeply discrediting” and believed that whether an indi- vidual was stigmatized by a trait depended on the atti- tudes of those perceiving the trait. For an attribute to be perceived as stigmatizing, the individual should have limited the disclosure of the attribute to few others and the individual should perceive that, if that attribute were more widely known, significant redefinition of self, ac- companied by various restrictions and regulation of con- duct, would follow (191,194). The stigmatizing nature of epilepsy has caused the psychosocial problems to out- weigh the clinical problems of seizure control. This is demonstrated by the fact that although only around 20% of patients with epilepsy develop chronic, intractable epi- lepsy, the majority continue to live with the label “epi- leptic” (195). Much of the literature assessing stigma in people with epilepsy was written in the 196Os, but un- fortunately stigma still affects these patients to the pre- sent day. Epilepsy has long been associated with disrepu- tability, satanic possession, and evil ( 1 96), violence (197-199). Myths, misconceptions, prejudice, and super- stitions are still associated with epilepsy (61). In some states in America, people with epilepsy were not eligible for federal civil service positions until 1959 and prohi- bitions against marriage were in place until 1965 (200). It remains difficult for people with a history of seizures to obtain life, holiday, and car insurance (201). A recent

personal (MVL) visit to China in 1998 revealed that

“epileptics” were banned from using a chair lift, as were

people with psychiatric conditions. Schneider and Con-

rad (191) interviewed 80 people with epilepsy about their

experiences of “coming out of the closet” with respect to

admitting the details of their “medical condition” to oth-

ers. Several patients reported that the lay public did not

understand what epilepsy was, in that many people still

regarded epilepsy to incorporate elements of madness

and evil. Some patients “test” society’s reaction to their zy epilepsy by selectively informing close associates of

their condition. Their confidants’ reactions tend to influ- ence future disclosure. Many patients were willing to share information about their epilepsy with close friends

The inactive patients were more likely to be afraid of

looking stupid or unattractive during exercise and were

more afraid that a seizure would be precipitated by ex-

ercise (or had previously experienced a seizure during

exercise) than the active group. Fifteen percent of the

inactive group had been advised to avoid most types of

exercise by their physician. From this study, it is not

possible to deztermine whyether exercixse reduces dwepres- a respvonse to contuinued seizurestrather than the cause of sion or whether depressed individuals exercise less. them. Families need to be encouraged to learn appropri- However, research has demonstrated that exercise re- ate reactions to seizures and ways to promoting indepen- duces depression in patients both without (186-1 88) and dent living skills, to prevent their lives revolving around

with epilepsy

was responsible for the lower rates of depression in the active group.

Children with epilepsy

A child with epilepsy needs to find ways of adapting to the diagnosis while developing strategies for dealing with self-identity, family overprotection/guilt, and the environment. Some children may use their seizures as a way of controlling the family environment and this, in turn, may result in the later development of nonepileptic seizures.

Parental expectations of their child with epilepsy, along with family and social rejection, have been found to have deleterious effects on the psychological devel- opment of the child (190). Feelings of shame, expressed as secrecy and fear of exposure, have been reported to be learned from parents. The more a parent conveys a defi- nition of epilepsy as something “bad,” the more likely the child will see it as something to be concealed. Parents who see their child’s epilepsy as “just like any other medical condition” will encourage their children to have a more neutral view, with a more open “information control strategy,” and will limit the use of epilepsy as a “crutch” or “excuse” (191). Unfortunately, parents who do treat their child with epilepsy normally, allowing them to lead an active life, may feel guilty if their child is injured during a seizure while taking part in typical childhood pursuits, such as climbing trees or riding a bicycle. Overprotective parents, on the other hand, may produce reactions of rebellion or passivity from their child. Physicians and friends also have been reported to encourage concealment as a strategy for dealing with epilepsy (191). Long and Moore (192) compared 19 chil- dren with epilepsy with their closest-in-age sibling. They found that parents expected their child with epilepsy to have more emotional problems and to be more unpre- dictable and highly strung. The parents were more domi- nant, restrictive, and strict with their child with epilepsy, 32% believed the child should be supervised at all times, 28% prohibited swimming, 21% cycling, and 16% team games. Children with epilepsy were found to have lower self-esteem than their siblings, were more socially iso- lated, and underachieved at school, especially with re-

Epilepsia, Vol. 40, Suppl. 10, 1999

(1 89). Ther

efore, it is l

ikely that ex

ercise the fa

y (61).

spect to reading. These findings appear to affect both psychosocial development and seizure control. Hauck (193) reported that 61% of children of “autocratic” par- ents continued to have seizures despite 3 years of ad- equate AEDs, whereas 61% of children of “nonauto- cratic” parents were seizure-free. However, it is possible that the overprotectiveness of the autocratic parents was

r with epileps

srq

DEPRESSION IN EPILEPSY S31 zy

but not with prospecztive emplyoyers or thxose involvewd in Fear ovf seizuresutsrqp the issuing of drivers’ licenses. Scambler and Hopkins Mittan (206,207) first reported that patients with epi-

(202) reported that over two-thirds of patients did not lepsy tend to express fears about dying or severely in-

inform their partners about their seizures until after the juring themselves during seizures, and concerns about

marriage, and only

provision of epilepsy support groups has been an impor- atric illness and cognitive decline. Although some of

5% inform

tant step in providing support for patients with epilepsy and comparing experiences of the effects of “coming out of the closet”. Ryan et al. (203) assessed 445 people with epilepsy from a variety of socioeconomic levels and em- ployment histories and with a wide range of seizure vari- ables. They found that stigma was not universally per- ceived and was not related to frequency and severity of seizures. Eighty-one percent felt that they had been treated fairly by employers and 70% felt neither unrea- sonably limited nor treated differently because of sei- zures. However, 22% reported that they had been dis-

missed from at least one of their previous four jobs for an epilepsy-relatedreason. Perceived stigma was dependent on perceived employment discrimination, perceived sei- zure-imposed limitations, years of education and, to a minimal extent, on the age and sex of the individual. Similarly, Jacoby et al. (195) found that only 14% of 607 patients in remission experienced stigma. However, pa- tients who scored positively for stigma also had lower scores for self-esteem and mastery and had been seizure- free for less time. Those who scored negatively for stigma tended to be over SO years of age. Although only

2% recalled an occasion in which they had been treated unfairly at work and only 3% believed that their epilepsy was the reason for their current lack of employment, 32% believed that their epilepsy had made it more difficult to obtain a job (195).

Recently, “felt” stigma has been differentiated from “enacted” stigma (195,204,205). Enacted stigma refers to episodes of discrimination, whereas felt stigma refers to the shame associated with being “epileptic” and the fear of enacted stigma. Felt stigma was much more prevalent than enacted stigma and was the product of stigma coaching, usually by parents. It preceded rather than re- sulted from periods of enacted stigma and was the major source of unease, self-doubt, and disruption (205). Scam- bler and Hopkins (205) also reported that patients be- lieved that when they were told their diagnosis, they

An essential prerequisite for treatment of depression in people with epilepsy is making the correct diagnosis. Studies have found that hospital medical and nursing staff fail to detect affective disorder in 3672% of cases

ed their e

mployers.

The the lon

these fears may be realistic, many are the consequence of lack of knowledge and misperceptions of the actual risks associated with epilepsy. Patients who exhibit a high number of fears and concerns tend to have more emo- tional and behavioral difficulties, including lack of con- fidence, depression, and anxiety. Goldstein et al. (208) assessed fear of seizures in 96 patients with various de- grees of seizure control. They found that concern about emotional functioning, followed by concerns about avoiding seizure-inducing stimuli, were the most fre- quently endorsed items. They also found that these concerns were related to behavioral and emotional ad-

justment regardless of demographic and neuroseizure variables. These authors conclude that modifying mal- adaptive cognitions and beliefs may help correct misper- ceptions and irrational fears and, in so doing, improve behavioral and emotional adjustment. They advocate the use of cognitive-behavioral therapy for this purpose. Others, however, have found no relationship between depression and psychosocial factors such as socioeco- nomic status (37), education ( 3 7 5 l ) , and employment status (51).

In summary, most authors have found no correlation between depression and epilepsy variables such as age of onset, the presence of an intracranial lesion or seizure frequency (31). However, CPSs and TLE, especially of left-sided origin in men, have been associated with de- pression (56) and severity of depression has been found to correlate with duration of epilepsy (54). Although psy- chosocial factors may play a part, depression appears to occur more in patients with epilepsy than in patients with other neurologic disorders (31,46,47) or chronic medical conditions (74), suggesting that an organic mood disor- der rather than a reaction to a chronic disability is the major etiologic factor.

DIAGNOSIS OF INTERICTAL DEPRESSION

perceived stigma and affective disorder, especially per- cases (210). One reason for this may be making the as-

became transformed from “normal” people to “epilep-

tics” and they believed that they had a stigmatizing con-

dition, despite the fact that few could recall any inci- dencesofactualstigmaordiscriminationagainstthem.(209),andthatgeneralpractitionerscozrrectlydiagnyosex Arnston (204) reported a positive relationship between depression at the first consultation only in 50% of the

ceived helplessness, depression, anxiety, and somatic sumption

symptoms, and a negative relationship with self-esteem “You’d be depressed too, if you had. .

and life satisfaction. Similarly, Jacoby (195) reported an the depressive disorder is not diagnosed, the patient will association between stigma and the subjects’ affective continue to suffer from two disabilities, at least one of

state.

atable (21

1).

zyxwv zy

which (the

depression)

e fully tre

xw

g-term con

sequences o

f epile

psy such

as psychi-

rmal reac utsrtion to illnqp

that depressio

n is a no

should b

Epilepsra, Vol. 4

. .” Howeve

0, Suppl. 1

0, 1999

ess:

r, if

S32 zyxwM. V. LAMBEvRT AND Mu. M. ROBERtTSONszryqxpwov

Betts (212) has differentiated between a depressive reaction (or reactive depression) and a depressive illness (or endogenous depression). Depressive feelings usually respond to circumstance and tend to be understandable as a reaction to an event. Betts describes a “grief reaction” that may affect the patient and family when the diagnosis of epilepsy is given. First, there may be a period of denial followed by struggle (during which guilt and anger may be experienced) and then depressive feelings as they come to terms with the diagnosis. This depressive reac- tion should be regarded as normal. Patients and their family should be encouraged to work through it until acceptance and resignation occur (212).

Depressive illness can be diagnosed using the fnter- national Classification of Disease criteria (ICD10). De- pressed mood, reduced energy, and loss of interest and enjoyment are the main symptoms, two of which should be present for at least 2 weeks, for a diagnosis of mild or moderate depression, and all three for severe depression. In addition, two of the following symptoms should be present for mild, three for moderate, and four for severe depression: reduced concentration and attention, reduced self-esteedself-confidence, ideas of guilt and unworthi- ness, pessimistic views of the future, ideas or acts of self-harm or suicide, disturbed sleep, and diminished ap- petite (213). One can also diagnose depression according to DSM-IV criteria (214), which also have strict stipu- lations.

dysthymic, with irritability and humourlessness. Betts (212) also reports that depression in patients with epi- lepsy tends to be endogenous with sudden onset, fluctu- ating markedly until it suddenly ends.

Robertson et al. (54) assessed 66 patients with epi- lepsy referred to a neuropsychiatric department at a ter- tiary refemal center who fulfilled the Research Diagnos- tic Criteria (RDC) for major depressive disorder (215). The Hamilton Depression Rating Scale (HDRS) (216), the BDI (217), and the Levine-Pilowsky Depression Questionnaire (LPD) (218) showed them to be “moder- ately depressed.” The majority (60%)were classified as having an endogenous depression using the Newcastle Diagnostic Scale (NDI) (219) and the LPD. High hostil- ity scores were obtained especially for the intropunitive measures of self-criticism and guilt.

Blumer et al. (220) noted that some patients with epi- lepsy experienced episodic depressive episodes lasting up to 12 h, occurring on average five times a month, along with periods of euphoria lasting up to 4 h, on average three times a month. They further investigated these symptoms in 75 patients with epilepsy undergoing neurodiagnostic monitoring (221) and found 44% to have an interictal dysphoric disorder. The syndrome comprised eight symptoms, of which most patients ex- perienced five: depressive moods (intense to the point of suicidal despair), accompanied by anergia, pain, insom- nia, anxiety, phobic fears, intermittent paroxysmal irri- tability (to the point of explosive anger or rage), and euphoric moods (consisting of a “sudden, endogenous

The low mood tends to be pervasive and long-lasting.

Classically, patients wake early feeling unrefreshed, with

low mood that may improve as the day progresses (di- sense of blissful euphoria in the absence of elated hy- urnal mood variation). Despite these guidelines, diagno- peractivity”). Blumer stressed that patients with a large sis can be difficult and Betts (212) has also stressed that number of the above symptoms may be at increased risk drug intoxication (especially with PHT), can resemble for sudden unexpected suicide attempts and the develop-

zyxwvvuutstrs

depression.

Mendez et al. (31) compared 20 hospitalized de- pressed patients with epilepsy with 20 patients suffering from depression alone. They found that more than half of the depressed patients presented with an agitated, psy- chotic depression with impulsive suicidal behavior. Both groups had a similar number of prior suicide attempts and shared the following characteristics of depression: anhedonia, tearfulness, psychomotor retardation, reduced energy and libido, along with appetite and sleep distur- bances. Patients with epilepsy and depression had sig- nificantly fewer “neurotic” traits such as anxiety, guilt, rumination, hopelessness, low self-esteem, and somati- zation. However, these patients had significantly more “psychotic” symptoms such as paranoia, delusions, and

qrp symptoms, not merely the depressive ones, tend to re-

PHENOMENOLOGY OF INTERICTAL DEPRESSION

persecutory

major depression, patients with epilepsy tended to be treated medically unless prolonged, and therefore atypi-

Epilepsia,Vol. 4

auditory

hallucinations. Between episodes of

zy

xwvutsrqponm

0, Suppl. 10

, 1999

t of an in

rictal psycho

is. He

noted t

te

s

hat

all th

men

spond rapidly to low-dose antidepressants.

e

TREATMENT OF INTERICTAL DEPRESSION

Psychological treatment

Supportive therapy provided by trained therapists, so-

cial workers, or epilepsy nurse specialists should be of-

fered to all newly diagnosed patients and their families

(174). This would provide an opportunity to educate the

patients and their families about epilepsy, to determine

their emotional reactions to the condition, and to correct

false beliefs. Ziegler (222) suggested the approach of

optimistic fatalism, explaining that they have epilepsy,

which may or may not get better, and suggesting that

they focus on “how to make the best of it.” zy

Depressive reactions should be treated with supportive therapy, counseling (174), and rehabilitation (175). Betts (212) has stressed that these reactions should not be

cal, because such episodes may become protracted if treated with antidepressants or tranquilizers. More severe reactions may require specialized psychotherapy, such as cognitive-behavioral therapy (223). An intervention pro- cedure to alter attributional style toward optimism has been developed for patients with epilepsy which may ameliorate depression (224). Psychotherapy can also be used to improve coping skills, and this has been shown to improve mild depressive illness and anxiety and to re-

duce seizure frequency (21). Ferguson and Rayport (173) advocate rehabilitation following epilepsy surgery, to en- able the patients to live without the help of an illness that had been both a “weapon and a shield”.

Patient support groups introduce patients to fellow

overcome feelings of hopelessness, rejection and isola- tion. Becd et al. (225) showed in an uncontrolled trial that self-help group intervention can significantly modify depression and dysthymia in outpatients with epilepsy.

Adjustment of AEDs

The seizure and epilepsy syndrome should be reevalu- ated and treated with the most appropriate AED, prefer- ably as monotherapy. Valproate, CBZ, and LTG should be considered as first-line AEDs and, whenever possible, barbiturates, PHT, and VGB should be avoided. How- ever, priority should be given to attaining optimal control because remission of seizures has been found to be ac- companied by an improvement in psychosocial function- ing (226).

Antidepressant treatments

General considerations

Approximately 60-70% of acute major depressive epi- sodes will respond to antidepressant treatment (227), and early treatment intervention has been shown to reduce the duration of the episode by almost 50% (228). How-

ever, antidepressant treatment is often prescribed in sub- therapeutic amounts, Tyrer (229) found that a quarter of patients referred by general practitioners to a psychiatric outpatient clinic were receiving inadequate doses, and this has also been reported in teaching hospitals (230). After complete remission of symptoms, antidepressant therapy should be continued for at least 4 months to reduce the chance of relapse (231).

Choice of antidepressant

In the United Kingdom, there are currently almost 30 drugs licensed for treatment of depression (Table 3). The choice of agent for patients with epilepsy depends on the most prominent symptoms of depression in each patient (e.g., insomnia, anxiety, psychomotor retardation, sexual dysfunction, and suicidal ideation), efficacy, interactions with concomitant medication, side-effect profile, and particularly the epileptogenic potential.

Maprotiline Mianserin Trazodone Viloxazine

Mo

(e.g., mature cheese, pate, pickled fish, beer, red wine, yeast extracts) and over-the-counter cold cures containing sympathomimetic amines, can precipitate a hypertensive crisis, the “cheese reaction” (232).

Isocarboxacid Phenelzine Tranylcypromine

Newer antidepressants zyxw Reversible inhibitor of monoamine oxidase A (RIMA):

Moclobeiaide. Safe without dietary restrictions in major studies (233) but patients should avoid eating large quantities

of tyramine-rich foods ( e g , >

50 g of stro

should take the medication after meals Selective serotonin re-uptake inhibitors (SSRIs)

Fluvoxamine Fluoxetine Sertraline Paroxetine Citalopram

Serotonin reuptake inhibitor (and serotonin type 2 receptor blocker)

Nefazodone

Serotonin norepinephrine reuptake inhibitor

Venlafaxine

Norepinephrine reuptake inhibitor

Reboxetine

Noradrenergic and specific serotonergic antidepressant (NaSSA)

Mirtazapine

Efficacy

Davis and Glassman (234) reviewed 44 controlled tri- als comparing imipramine, a tricyclic antidepressant (TCA), with placebo, and found that 65% of those on imipramine improved compared with 30% on placebo. It is widely believed that the newer antidepressants do not significantly differ with respect to efficacy compared with the TCAs (235-237), although there is some evi- dence that venlafaxine may have a more rapid onset of action (238).

DEPRESSION zIN EPILEyPSY zxywxvs3wu3 ztyv

TABLE 3. Antidepressants currently available in the United Kingdom

Older antidepressants

Tricyclics (TCAs): Anticholinergic and antimuscarinic side

effects, such as drowsiness, dry mouth, blurred vision, constipation and urinary retention are common. Hypotension, dizziness, syncope, and confusion common in the elderly

Amitriptyline

Amoxapine

Clomipramine

Desipramine

Dothiepin

Doxepin

Imipramine

Lofepramine

Nortriptyline

Protriptyline

Trimipramine

sufferers who can provide emotional support and helpzyxwvu Related antidepressants

noamine oxida

se (MAO) inhib

oods

There has only been one double-blind, placebo- controlled study of antidepressants in patients with epi- lepsy (239), which compared amitriptyline with nomi-

itors: Tyramine rich f

Epilepsia, Vol. 4

ng cheese) an

d

zyxw

0. Suppl. 10

, 1999

s34zyxM.wV.LAMBERT ANvD M.M. ROuBERTSONztysxrqwpv

fensine in 42 patients. At 6 weeks all patients had im-

proved, with no significant differences between the

active drugs and placebo. Between weeks 6 and 12, ami- triptylinewascomparedwithnomifensine,withnopla-P450lA2,2D6,and3A4isoenzymes(264),incliniczaly cebo control, and at 12 weeks, nomifensine was found to practice it is unlikely that it would inhibit the metabolism

be superior. of coadministered AEDs (265).

Most of the above reports are single case studies, and

Interactions in clinical practice the greatest risk of toxicity would

In theory, monoamine oxidase (MAO) inhibitors withfluoxetineorfluvoxamineincombinationwithPHT

should not be co-administered with CBZ because this may precipitate a hypertensive crisis (240). However, studies have reported no adverse interactions with phen- elzine, tranylcypromine (241), or moclobemide (242). There has been a case report (243) of the toxic serotonin syndrome (TSS), consisting of uncontrollable shivering, agitation, incoordination, restlessness in feet when sit- ting, involuntary contractions progressing to myoclonic- like leg movements, hyperreflexia, and a frightened hy- perarousal state believed to be secondary to the concomi- tant use of fluoxetine in a patient receiving CBZ for an affective disorder.

The majority of antidepressants are either metabolized by or inhibit, to various degrees, one or more of the cytochrome P450 isoenzymes in the liver, the clinical relevance of which has been reviewed by Nemeroff (244).Itisestimatedthat5-10% ofthewhitepopulation lack the isoenzyme P450 2D6 (slow metabolizers) and are at risk for developing toxic plasma concentrations at normal “therapeutic” doses of drugs metabolized by this liver enzyme, which include several TCAs, fluoxetine, paroxetine, and venlafaxine (244). A simple assay is available, however, to screen for those at risk (245).

Clinically relevant interactions for patients with epi- lepsy that involve the cytochrome P450 system are mainly associated with concomitant use of antidepres- sants with PHT and CBZ (Table 7). The metabolism of PHT is believed to be catalyzed by the P4502C isoen- zymes (244,246). It is estimated that 3-5% of the white population are poor metabolizers of P450 2C19 (244). Imipramine (246), fluoxetine, fluvoxamine, and sertra- line (244) are believed to inhibit these eznzymes. Case reports have demonstrated raised PHT levels with fluox- etine (247-250), and sertraline (251). However, other studies have failed to find raised PHT levels with sertra- line (252) or paroxetine (253). CBZ is metabolized by the P450 3A isoenzymes (244,246), which are believed to be inhibited by fluoxetine, fluvoxamine, sertraline, and nefazodone (244). A normal volunteer study dem- onstrated elevated CBZ levels after concomitant medi- cation with fluoxetine (254), and adverse events have been reported, with raised plasma concentrations of CBZ, with fluoxetine (255,256), fluvoxamine (257,258), sertraline (259), and nefazodone (260). Raised levels have also been reported with viloxazine (261). However, the mechanism for this has not been identified (246).

be

or CBZ, whereas sertraline, paroxetine, and citalopram have little effect and therefore should not produce clini- cally significant interactions (244,266,267).

The anticonvulsants PB, PRM, PHT, and CBZ are potent liver enzyme inducers (268), which can result in reduced plasma levels and therefore reduced efficacy of antidepressants metabolized by the same isoenzymes. Clinically significant interactions have been reported with TCAs (269) and paroxetine (270).

Safety: adverse effects at therapeutic levels

Sedation. Most of the older antidepressants, espe- cially the TCAs, mianserin, and trazodone (271,272),pro- duce sedative side effects (Table 7). This may be par- ticularly troublesome to patients taking AEDs known to cause sedation, such as barbiturates and benzodiaz- epines, and one report (273) suggests that sedative anti- depressants are more epileptogenic. Sedative antidepres- sants may be given to patients with co-existent anxiety or agitation but they may result in daytime drowsiness and impaired psychomotor function. In patients with sleep disturbance, drugs known to improve sleep architecture, such as moclobemide (274), nefazodone (275), or mirtazapine (276), should be considered. Hindmarch et al. (272) showed that lofepramine, moclobemide, and the SSRIs were associated with equal or even less psycho-

motor slowi

Epilepsia,Vol. 4

, 1999

Other studies have failed to find raised CBZ levels with paroxetine (253), sertraline (252), fluoxetine, or fluvox- amine (263). Although mirtazapine is a weak inhibitor of

ng than pla

zy (<15

cebo. Mirtaz

tamine-blocking properties, especially at low doses mg/day) and therefore is associated with sedation in 19%

TABLE

4. Factors a

sk of

Patient related

History of previous seizures

Family history of a seizure disorder

Abnormal pre-treatment EEG

Brain damage, head injury

Dementia

Learning disability

History of electroconvulsive treatment (ECT) AlcohoUsubstance abusdwithdrawal

Reduced renamepatic drug elimination capacity

ssociated wit

apine has str

zyxwv

antidepressant induced seizures

Risk factors

h increased ri

zyxwvu

Drug related

High dose/plasma level of antidepressant or metabolites Overdose of antidepressant

Rapid dose escalation

Concurrent use of drugs that lower seizure threshold

Concurrent use of drugs that inhibit metabolism of antidepressant

zyxwvutsrqponm

0, Suppl. 10

ong his-

and drowsiness in 23% of patients, which is maximal in the first week but gradually reduces by weeks 3-4. How- ever, at higher doses ( 1 5 4 5 mg/day), mirtazapine in- creases norepinephrine, which produces arousal and thus tends to counteract some of the sedation (264). Vigilance and driving performance have also been reported to be impaired early in the course of treatment with mirtazap- ine, but tend to improve over the first few weeks (277). One study in normal volunteers found mirtazapine to

antidepressant, or changing medication before consider- ing introducing a counteracting agent, such as yohim- bine.

Epileptogenic potential. Seizures were first reported in people taking antidepressants in 1959, one year after the launch of the TCA imipramine (301). Since then, many studies and case reports have documented seizures with most non-MA0 inhibitor antidepressants. Many cli- nicians are therefore reluctant to prescribe much-needed medication to depressed patients with epilepsy or those at risk for seizures. However, many of the reports have been criticized for being retrospective, not clearly defin-

memory disturbance (281). Depression has also been shown to adversely affect memory and other cognitive functions (282). The older TCAs, especially amitripty- line, along with mianserin and trazodone, have been found to produce cognitive impairment and therefore should be avoided. The SSRIs (283) and mirtazapine (278)have not been shown to impair memory processes.

Sexual function. Sexual dysfunction (both impaired desire and performance) has been reported in both men and women with epilepsy (284-287). Diminished sexual satisfaction is often reported in outpatients suffering from depression (288). The reported incidence of sexual dysfunction associated with antidepressant treatment varies widely among studies and can affect libido, arousal, and orgasm (289). Balon et al. (290) found sex-

ual dysfunction in 43.3% and painful orgasm in 18% of male patients treated with antidepressants. They did not find that dysfunction was linked to any particular anti- depressant. TCAs, mianserin, M A 0 inhibitors, venlafax- ine, SSRIs (289) and reboxetine (data on file; Pharmacia and Upjohn, 1997) have all been found to cause dysfunc- tion (Table 7). Priapism, however, was mainly associated with trazodone (291). Sexual side effects appear to be highest with clomipramine, (over 90% in one study) and the SSRIs (292). Sexual dysfunction has been reported in 8-75% with fluoxetine (292), mainly anorgasmia, al- though retrograde ejaculation has also been reported with this drug (289). Sexual dysfunction appears to occur less commonly with the more selective serotonin inhibitor citalopram. However failure of ejaculation has been re- ported in 3.3% (293). Sexual dysfunction appears to oc- cur no more often with mirtazapine (294-297), nefaz- odone, or moclobemide than with placebo (289,298) (the latter has even been associated with an improvement in sexual functioning in some studies) (299). Assalian and Margolese (300) discussed the treatment of sexual dys- function associated with antidepressants. They advocate waiting for tolerance to develop, reducing the dose of

Some authors have suggested that various risk factors

may predispose to the precipitation of drug-induced sei-

zures and that these may be either patient- or drug-

related; see Table 4 (302,306,307). The patient-related predisposing factors have been documented in over half

the patients who experienced seizures when taking the

TCAs and buproprion (304,308).Another report has sug-

gested that patients at risk for developing seizures during psychotropic drug treatment can be identified by having

an enhanced amplitude of the early cortical somatosen-

sory evoked potentials (SSEPs) after median nerve stimulation (309). Other authors, however, have found

that antidepressant-induced seizures are predominantly

related to dose or plasma level (310,311). Preskorn and

Fast (3 11) also noted that they could not find any reports

of TCA-induced seizures at therapeutic plasma concen-

trations and concluded that patients who experienced convulsions at therapeutic doses of antidepressants were

likely to be slow metabolizers of the drugs. Seizures are

more likely to occur during the first week of antidepres-

sant treatment or after an increase in dose, especially

after rapid dose escalation (302). zy

DEPRESSIONzINEPILEyPSYxwvs3.5zuty

have similar adverse effects on psychomotor and cogni-

tive effects as amitriptyline, and more mental slowness,

along with reduced tapping rate and flicker fusion fre-

quency, than diazepam (278). Clinical trials have shown ing a “seizure,” and including patients who have over- that citalopram (279) and venlafaxine (280) are not as- dosed on the antidepressant, taken other proconvulsant sociated with significantly higher sedation than with pla- medication, or who are at high risk for drug-induced

zyxwvutsrqpon

cebo.

Memory. Patients with epilepsy often complain of The incidence of seizures occurring with therapeutic

).

doses of antidepressants varies from 0.1 to 4% (302). This needs to be compared to the annual incidence of first seizures in the general population, estimated at 0.073-0.086% (303).

Bupropion, a monocyclic antidepressant, was with- drawn in the United Kingdom in 1986 because of its proconvulsant properties but is still available in the United States. Patients taking >450 mg/day have been reported to have a seizure incidence of 0.35-0.44% (304). It has also been shown to cause agitation, insom- nia and nausea. A recent review (305) has suggested that the sustained release preparation (available since late 1996) may be less epileptogenic than the immediate re- lease version. Despite this, its use in patients with epi- lepsy is not recommended.

seizures (se

e below

Other investigators have not found an increased inci-

Epilepsia, Vol.4

zyzyxw

0,Su

1

ppl. IO,

9

99

S36 M. V. LAMBERT AND zM. M. ROyBERTSONxzwyxvwut

Newer antidepressants

Of the older antidepressants, trazodone is believed to zures (325,328). Gigli et al. (329) administered 20-40 have little epileptogenic potential, either at therapeutic mg of fluoxetine to nine nondepressed patients with epi-

(317) or toxic (318) doses, and most reported cases of

TABLE 5. Data sheet recommendations for antidepressant use in patients with epilepsy

Antidepressant

Amitriptyline Amoxapine Clomipramine

Desipramine Dothiepin Doxepin Imipramine

Lofepramine Nortriptyline Protriptyline Trimipramine Maprotiline

Mianserin Trazodone Viloxazine Isocarboxacid Phenelzine Tranylcypromine Moclobemide Fluvoxamine Fluoxetine

Sertraline

Paroxetine Citalopram Nefazodone Venlafaine Reboxetine Mirtazapine

zyxwv SIP, extreme caution in PWE or predisposing

nm

SIP

SIP

eizures.

Data sheet recommendation

convulsions have occurred in patients taking concorni- tant medication (317).

dence of seizures related to antidepressant medication

and some have even demonstrated improved control.

Ojemann et al. (312) retrospectively studied the effect of

at least 2-month treatment with doxepin on seizure fre-

quency in 19 patients with known epilepsy. Fifteen pa-

tients experienced a reduction in seizure frequency

(greater than 50% reduction in over half) and two re-

ported no change. Two patients experienced increased

seizures. However, they suffered from both partial and

generalized tonic-clonic seizures and, in each case, one

of the seizure types reduced in frequency on doxepin.

Robertson and Trimble (239) found no increase in sei-

zure frequency with concomitant treatment with amitrip-

tyline or nomifensine compared with placebo. Although

the bicyclic viloxazine has been associated with convul-

sions (313), other reports have shown it to have anticon-

vulsant potential in both animal studies (314) and clinical

use (261,315). Fromm et al. (316) reported improvement inabsenceandmyoclonic-astaticseizureswithimipra-zwithoyrshortlyafxteranotherdwrugknowntolovwertheu mine. seizure threshold (322-327) or in patients at risk of sei-

Irreversible MA0 inhibitors are generally considered to have less proconvulsant potential than the TCAs. The potential for drug interactions and the dietary restrictions (see Table 3), however, limits their use.

Reviews of the literature indicate that the older anti- depressants with the highest epileptogenic potential are the TCAs, especially amoxapine and clomipramine, along with bupropion (not available in the United King- dom), maprotiline, and mianserin (56,302,3 19). The data sheet recommendations for the use of antidepressants in people with epilepsy are shown in the Tables.

There have been reports of seizures with the SSRIs. However, these have mainly been single case studies (320,321) and often occur when the SSRI is administered

awal, all

return

factors for epilepsy

SP. for oatients with low convulsion threshold (322,330), and all the SSRIs have been associated with

I.

SIP, avoid if possible if history of epilepsy SP

SIP, extreme caution in PWE or predisposing

factors

SIP

SIP, as dothiepin

SP

SP, as dothiepin

C/I, known/suspected epilepsy or low convulsion

threshold

SIP, as dothiepin

SIP

SIP

SIP

SIP, great caution in PWE

SIP

None

SIP, discontinue if develop seizures

C/I, avoid if unstable epilepsy, carefully monitor

controlled epilepsy

Discontinue if seizures develop

SIP, avoid if unstable epilepsy, carefully monitor

inappropriate secretion of antidiuretic hormone (331- 340). Hyponatremia has been documented in 25% of elderly patients taking SSRIs (341) and diuretic co- medication may increase the risk (342,343). This should be considered when antidepressants are co-administered with another drug associated with hyponatremia, such as CBZ (344).

The newer antidepressants have also been shown to have either no effect or even anticonvulsant properties. In animal experiments, fluoxetine has been shown to enhance the anticonvulsant effects of PHT and CBZ (345). Fluoxetine produced complete seizure control in six and 30% reduction in 11 of 17 patients suffering from partial and/or secondarily generalized seizures (346). Fluoxetine administered to patients with learning disabil- ity, epilepsy, and aggressive behavior did not alter the frequency of seizures (347) and no significant procon- vulsant effect was reported in a major clinical trial of this drug (348). Fluvoxamine did not produce any change in seizure frequency nor EEG in 35 patients with epilepsy

controlled epilepsy

SIP, discontinue if seizures develop

None

SIP

SIP, discontinue if seizures develop

SP (349). Paroxetine has also been shown not to affect sei-

five of who

zyxwvutsrqpon

SIP

zure frequency or the EEG (253,270,350), and preclini-

zy

cal studies and clinical trials have not found sertraline to lepsy. be more epileptogenic than placebo (351). Preclinical

SP, special precaution; C/I, contraindicated; PWE, people with epi-

Epitepsia,Vd.40,Suppl. 10,1999

m had sym

At the

lepsy,

lower dose, one improved, six remained unchanged, and twuo experietncedsincreaserd seizqures. Sevpen patienots were treated with the higher dose, and of these five remained unchanged and two worsened. After fluoxetine with-

zyxwvutsrq

dr

ed to th

e base

There have been several reports of antidepressant-

induced seizures in patients found to have hyponatremia

ptomatic epilepsy.

line frequ

ency of s

DEPRESSIONzINEPILEyPSYxwvs3u7zty

normal volunteer studies did not find citalopram to have

a significant effect on the EEG ( 3 5 2 ) , and controlled

clinical trials have not shown it to precipitate seizures

(293).Blumer (353) recently advocated the use of SSRIs

in combination with TCAs for intractable depression in

patients with epilepsy, reporting a 68% good or excellent

response. Increased seizure frequency was noted only in

patients taking 200 mg TCA daily. Therefore, the author recommendedprescribingamaximumof150mg/day.Inzamitriyptyline(360x).Therefore,wfluvoxamineandvparox-u summary, most studies have revealed convulsions to oc- etine have a higher number of reported convulsions with

cur in up to 0.2% of patients taking SSRIs (354). respect to their market share than the other SSRIs, as Major clinical trials have also not found a significant does venlafaxine (360).

epileptogenic effect for venlafaxine (355), moclobemide

(356), or nefazodone (357) compared with placebo. In antidepressants and seizures and concluded that antide-

clinical studies, seizures were reported in 0.2% of pa- tients treated with reboxetine (data on file, Pharmacia and Upjohn, 1997) but may have been accounted for by other factors, including co-administration of other pro- convulsant medication. Only one patient of a possible 2,796 (0.035%) has been reported to experience a seizure while taking 80 mg of mirtazapine (the usual therapeutic dose being 15-45 mg/day). She had previously experi- enced seizures while taking clomipramine (358).

Table 5 shows the data sheet recommendations with respect to epilepsy (240). Table 6 shows the number of suspected drug reaction reports of “Convulsions and Epi- lepsy” associated with the Selective Serotonin Reuptake Inhibitors (SSRIs) and associated antidepressants. It is important to note that the receipt of a reaction by the Committee on Safety of MedicinesMedicines Control Agency (CSMMCA) does not necessarily mean that it has been caused by the drug as many factors have to be taken into account in assessing causal relationships in- cluding, temporal association, the possible contribution

of concomitant medication and the underlying disease. Many factors also influence the number of reports re- ceived and in most situations there is considerable “un- der-reporting’’ of reactions. It has been estimated from various surveys, (359) that only 10-15% of serious ad- verse reactions are reported (CSM-Personal communi- cation, July 1999). McConnell and Duncan (360) have discussed the difficulties encountered in evaluating CSM

Drug name

Moclohemide Fluvoxamine Fluoxetine Sertraline Paroxetine Citalopram Nefazodone Venlafaxine

zyxwvutsrq

TABLE 6. Convulsions reported to CSM

No. of reports of ‘Status epilepticus’ (fatalities)

No.of reports of exacerhationhg gravation of seizures

No. of

all other reports of ‘Convulsions and epilepsy’

Total no. of reports (fatalities) (fatalities) received

zyx 8 (0) 7285

4 (0) 695

0 (0) 949 1 ( 0 ) 2228

wvutsrqp

3 (0) 523 2 (0) 2447

epines or other antidepressants), no deaths or seizures

14(

7013

1963

were reported, even in the “frail elderly,” and the most

6 (0)

common outcome was sedation. There has been recent concern that citalopram may be more dangerous than other SSRIs in overdose (371). However, most of the patients had also ingested other drugs. Several workers

0)

data. Factors influencing reporting patterns include how recently a drug has been introduced, media coverage, and whether the adverse reaction was expected. The market share of a given drug (which reflects the extent of usage) needs to be taken into account. Between 1991 and 1995, only six antidepressants accounted for over half the pre- scriptions dispensed in the United Kingdom, the most common being dothiepin, followed by fluoxetine and

Dai

pressant drugs have both convulsant and anticonvulsant properties, the anticonvulsant properties predominating at low doses and the convulsant at higher blood levels. These authors commented that antidepressant drugs are like several AEDs in that they can both prevent and cause seizures.

Safety in overdose

Frommer et al. (362) reviewed TCA overdoses in 2,536 patients from 26 studies and found a seizure inci- dence of 8.4%. Other studies have reported lower inci- dences and have noted that the epileptogenic potential varies among the antidepressants. Seizures have been reported in 3-8% of overdoses with TCAs (318,363). However, higher rates of 13% have been reported with dothiepin (364). Maprotiline, amoxapine, and citalopram appear to be particularly associated with seizures fol- lowing overdoses, with rates ranging from 12-77% for maprotiline (3 18,365,366), 24-36% with amoxapine (318,367) and in 18% taking 0.6-1.9 g and 47% taking I .9-5.2 g of citalopram (368).

Cassidy and Henry (369) calculated a “fatal toxicity

index,” deaths by acute poisoning per million NHS pre-

scriptions, and calculated that desipramine, tranylcypro-

mine, dothiepin, amitriptyline, nortriptyline, maprotiline,

doxepin, and imipramine were the most dangerous anti-

depressants. Swinkels and de Jonghe (237) stated that a

drug was “safe” when 14 times the therapeutic daily dose

(i.e., 2-week supply) was greater than the lethal dose.

Using this method, the SSRIs, moclobemide, rnianserin

and trazodone can be regarded as safe, and the TCAs as

less safe. Montgomery (294) summarized the 10 cases of

overdose that have been reported with mirtazapine. De-

spite in some cases more than a month’s supply being

ley and Nari

toku (361) r

eviewed the litera

ture on

ingested (always with co-medication, usually benzodiaz-

Epilepsia, Vol. 40. Suppl. 10. 1999

S38

M. V. LAMBERT

AND M.

M. ROBER

TSON

Antidepressant

Interactions with AEDs

Mianserin

Trazodone

Viloxazine ++

NC A/M N C AIM + – + NC AIM

Isocarboxacid Phenelzine Tranylcypromine Moclobemide Fluvoxamine Fluoxetine Sertraline Paroxetine Citalopram Nefazodone Venlafaine Reboxetine Mirtazapine

1BP – Stimulant ++ – + Cheese reaction, 1BP

zy

— vuts

TABLE

of adverse ev

depressants in pati

psy

zyxzywxvzwyuvxuwtsv

ztysxrw psychomotor retardation dysfunction potential from OD Other side effects

7. Summary

Sedation memory Sexual Epileptogenic Risk

+ ++

+t +

– 2/52 Supply

++ —

++ ++ ++ + ++ ++ +

– Stimulant ++ – + Cheese reaction,

– Stimulant

– Improves sleep – Anxiety, insomnia – Anxiety, insomnia – Anxiety, insomnia +

xw ++

++ – – –

++

– 2/52 Supply

Cheese reaction, 5 BP

ents with anti

ents with epile

zyx AIM

Amitriptyline + ++ + + ++Seizures NC AIM

Amoxapine +

+ + + + + +

+ + ++ ++Seizures NC

Clomipramine

Desipramine

Dothiepin

Doxepin

Imipramine

Lofepramine

Nortriptyline + + + Protriptyline + – Stimulant +

++ ++ ++ +Seizures NC AIM

+ + ++ + ++ + ++

+ ++Seizures NC AIM ++ ++ Seizures NC AIM – ++Seizures NC AIM ++Seizures A/C A/M + Seizures NC AIM -/+ ++Seizures NC AIM N C AIM Trimipramine + ++ + + +Seizures NC AIM

+low dose ++high dose -/+

+ +Seizures

zyxwvzy

Maprotiline + ++ + ++ ++Seizures NC

-/+ + Seizures

+ +Improves sleep, impairs driving – – – Anxiety, insomnia ++ – – +

+

vomiting

AEDs, antidepressants; OD, overdose; CA, contraindicated; AIC, anticholinergic; AIM, antimuscarinic; 1BP, hypotension; ?, increased; – 2/52 supply, no fatalities when 2 week supply ingested; +, more than (>) placebo: ++, >> placebo; -, same as placebo; -I+, differing reports, some < and some same as placebo.

have questioned the cause of death and have stressed the importance of limiting the total number of tablets dis- pensed (372,373).

In summary, all the antidepressants appear to be ef- fective for treatment of depression in patients with epi- lepsy. All have variable rates of adverse events, which are shown in Table 7. The studies have used different methods for assessing and diagnosing adverse effects. Therefore, they cannot be directly compared and sum- mated. Thus, in Table 7, “++” refers to an adverse event being definitely present, “+” refers to an adverse expe- rience occurring more than with placebo, and “-“means no documented increase in the side effect compared with placebo. Choice of antidepressant depends on the char-

acteristics and requirements of the individual patient. For example, activation may be preferred in patients with psychomotor retardation and slight sedation in patients with agitation or anxiety.

Lithium

Lithium is frequently prescribed for the treatment and prophylaxis of bipolar affective disorder and is also li- censed for the prophylaxis of recurrent depression. Controversy exists as to the proconvulsant properties of lithium, despite small open studies failing to demon- strate adverse effects in patients with epilepsy (374,375). Several studies have reported seizures in patients treated with lithium at both toxic (376-379) and therapeutic

+

+

++ + ++ -/+ ++ – ++ +

on 7 Weight

CA

AIM

– 2/52 Supply

Nausea, dizziness – 2/52 S ~ p p l y Nausea, vomiting – 2/52 Supply Nausea, vomiting – 2/52 Supply Nausea, vomiting – 2/52 Supply Nausea, vomiting

rqzypxw + -/+ Nausea

Nausea,

– -I+ Dry mouth, nausea

-F -/+ Dry mouth, constipation

-S

t Appetit

edation

e Dry mouth

ut

serum levels (377,380-385). EEG changes have also been reported in patients (378,385,386) and in nor- mal volunteers (387). A recent article included pre- existing EEG abnormalities as a risk factor for the de-

lactic in the control of manic-depressive illness (112-

l precaution” in th

131) and gabapentin (134,135). Therefore, these AEDs should be used for the treatment of epilepsy in patients with co-existent bipolar disorder and additional therapy with lithium may be avoided.

Electroconvulsive therapy

ECT is not contraindicated in patients with epilepsy

and may be life-saving in those with severe or psychotic depression not responding to antidepressants (212). It has even been found to be safe after temporal lobectomy (172). There have been reports of spontaneous seizures in patients after ECT (389,390). However, major studies have found the incidence of spontaneous seizures fol- lowing ECT to be lower than the incidence of epilepsy in the general population (391,392). Hsiao et al. (393) re- ported the complications in 98 patients with epilepsy who received ECT and found an increase in seizure fre- quency in only one patient and the development of status epilepticus in two. Studies have also shown that the sei-

zure threshold tends to rise by an average of 80% (range 25-200%) during the course of treatment (394), therefore some workers consider ECT to be an effective anticon- vulsant (395,396). The efficacy of ECT may be reduced if AEDs decrease the intensity of the induced seizures

dose and gradually increased, and they should be con- tinued for at least 4 months after complete clinical re- covery. Other medication known to reduce the seizure threshold should be avoided. Patients and AED levels should be carefully monitored. If seizures develop, the patient should be changed to an antidepressant with lower risk. Patients with severe, uncontrolled epilepsy or who develop exacerbation of seizures may be best man-

aged as inpatients. ECT is not contraindicated in people with epilepsy and may be life-saving.

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zyxwvu

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