Pilot pharmacologic randomized controlled
trial for psychogenic nonepileptic seizures
W.C. LaFrance, Jr., MD,
MPH
G.I. Keitner, MD
G.D. Papandonatos,
PhD
A.S. Blum, MD, PhD
J.T. Machan, PhD
C.E. Ryan, PhD
I.W. Miller, PhD
ABSTRACT
Objective: There have been few treatment trials for psychogenic nonepileptic seizures (PNES).
Some psychotherapies have been shown to improve PNES and comorbid symptom outcomes. We
evaluated a pharmacologic intervention to test the hypothesis that sertraline would reduce PNES.
Methods: We conducted a pilot, double-blind, randomized, placebo-controlled trial in an academic
medical hospital with epilepsy center outpatients. Subjects aged 18 to 65 years diagnosed with
video-EEG–confirmed PNES were treated with flexible-dose sertraline or placebo over 12 weeks.
Seizure calendars and symptom scales were charted prospectively. Secondary outcome measures included psychiatric symptom scales and psychosocial variables.
Results: Thirty-eight subjects enrolled, and 26 (68%) completed the trial. Thirty-three subjects
Address correspondence and
reprint requests to Dr. W. Curt
LaFrance, Jr., Rhode Island
Hospital, 593 Eddy St., Potter 3,
Providence, RI 02903
william_lafrance_jr@brown.edu
with nonzero nonepileptic seizure rates at baseline were included in intent-to-treat analysis of the
primary outcome. Subjects assigned to the sertraline arm experienced a 45% reduction in seizure
rates from baseline to final visit (p ⫽ 0.03) vs an 8% increase in placebo (p ⫽ 0.78). Secondary
outcome scales revealed no significant between-group differences in change scores from baseline to final visit, after adjustment for differences at baseline.
Conclusions: PNES were reduced in patients treated with a serotonin selective reuptake inhibitor,
whereas those treated with placebo slightly increased. This study provides feasibility data for a
larger-scale study.
Level of evidence: This study provides Class II evidence that flexible-dose sertraline up to a maximum dose of 200 mg is associated with a nonsignificant reduction in PNES rate compared with a
placebo control arm (risk ratio 0.51, 95% confidence interval 0.25–1.05, p ⫽ 0.29), adjusting for
differences at baseline. Neurology® 2010;75:1166–1173
GLOSSARY
AED ⫽ antiepileptic drug; CI ⫽ confidence interval; DSM-IV ⫽ Diagnostic and Statistical Manual of Mental Disorders, 4th
edition; ES ⫽ epileptic seizures; ITT ⫽ intent to treat; PNES ⫽ psychogenic nonepileptic seizures; PTSD ⫽ posttraumatic
stress disorder; QOL ⫽ quality of life; RCT ⫽ randomized controlled trial; RIH ⫽ Rhode Island Hospital; RR ⫽ risk ratio; SSRI ⫽
serotonin selective reuptake inhibitor; vEEG ⫽ video-EEG.
Reports of pharmacologic therapy for psychogenic nonepileptic seizures (PNES) were first
published at the turn of the 20th century1 and have reappeared in later case reports2; however,
no definitive randomized controlled trials (RCTs) have been completed to date.3-6 Some medically unexplained symptoms (presumed psychogenic) have been shown to be responsive to
pharmacologic interventions.7-11 In addition to their established efficacy for treating depression
and anxiety,12 serotonin selective reuptake inhibitors (SSRIs) have shown promise in trials for
conversion or somatoform disorders11,13 and some personality disorders.14 These frequently
occurring comorbidities in patients with PNES15 make SSRIs particularly attractive as a potential treatment for patients with PNES.
e-Pub ahead of print on August 25, 2010, at www.neurology.org.
From the Department of Neurology and Comprehensive Epilepsy Program (W.C.L., A.S.B.), Rhode Island Hospital, Brown Medical School;
Department of Psychiatry and Human Behavior (W.C.L., G.I.K., C.E.R., I.W.M.), Brown Medical School; Department of Community Health
(G.D.P.), Brown University; and Research Department (J.T.M.), Rhode Island Hospital, Departments of Orthopaedics & Surgery, Brown University,
Providence, RI.
Study funding: Supported by the NIH/NINDS 5K23 NS045902.
Disclosure: Author disclosures are provided at the end of the article.
Presented in part as a poster at the 2009 American Academy of Neurology, Seattle, WA.
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Copyright © 2010 by AAN Enterprises, Inc.
Acknowledging the heterogeneity in the
PNES population and the observed benefit of
SSRIs in other somatoform disorders, we
proposed a pharmacologic treatment with
therapeutic breadth that addresses both comorbidities and PNES directly. Based on the high
frequency of Axis I and II serotonergic-mediated
symptoms in PNES (i.e., depression,16 anxiety
and impulsivity17), we initially hypothesized that
treating the comorbidities in patients with
PNES would reduce PNES. SSRIs are a reasonable choice to safely treat these conditions. Of
the SSRIs, sertraline (Zoloft®; Pfizer, New
York, NY) has the broadest US Food and Drug
Administration indications and the fewest drugdrug interactions, a concern because many such
patients with seizures also use antiepileptic drugs
(AEDs). An open-label trial of flexible-dose sertraline in 8 patients with PNES for proof of concept was conducted preceding the current pilot
RCT.13
The primary hypothesis of this pilot RCT
was to assess the magnitude of seizure frequency reduction by treatment to inform a
power analysis for a full-scale RCT. Secondary hypotheses were to identify potential predictors of treatment response.
METHODS Standard protocol approvals, registrations, and patient consents. We received approval from the
Rhode Island Hospital (RIH) Institutional Review Board, received written informed consent from all patients participating
in the study at enrollment, and provided the ClinicalTrials.gov
identifier: NCT00159965.
Patients and procedures. Patients were referred to the RIH
neuropsychiatry/behavioral neurology clinic between July 2002
and June 2008, after being diagnosed with PNES. PNES diagnosis was established by capturing at least 1 of the patient’s typical PNES on video-EEG (vEEG). The standard 10 –20 electrode
system was used and was recorded by cable, 16-channel telemetry, combined EEG and video recording. EKG was monitored.
Data were collected in a standard fashion that included interictal
samples and all recorded episodes. The combined vEEG recordings were reviewed by a board-certified epileptologist (A.S.B.).
The diagnosis of PNES was defined as stereotypic, motor
manifestations (including the initiation or cessation of motor
activity/staring), with or without change in level of consciousness, on vEEG with no recognizable buildup of rhythmic epileptiform (ictal) activity immediately before, during, or after the
event. Patients, and family members, if present, were given the
diagnosis in the RIH comprehensive epilepsy center in a standard format explaining the differences between epilepsy and
PNES and their divergent treatments. Patients who were potential study candidates underwent neuropsychiatric examination
and clinical screening by a board-certified neurologist and psychiatrist (W.C.L.).
Inclusion criteria were age between 18 and 65 years and
vEEG diagnosis of PNES. Patients had to have experienced at
least 1 event in the month before enrolling. Patients with only
subjective sensory seizures without apparent loss of consciousness or behavioral arrest were excluded. Patients with mixed epileptic seizures (ES) and PNES who could clearly distinguish
between their events were included (n ⫽ 2). Other exclusion
criteria included using monoamine oxidase inhibitors or pimozide within 30 days before study, receiving optimized sertraline
currently (ⱖ100 mg daily for 3 weeks), presence of current
psychosis, suicidality, or DSM-IV substance dependence diagnosis, inability to complete written surveys, pending litigation, or
disability application. Participants currently taking an antidepressant were allowed to enroll, but all medication dosages were
held constant during the trial. Participants currently receiving
psychotherapy were allowed to enroll; however, those beginning
new therapy were excluded.
After enrolling, patients documented their pre-enrollment
PNES frequency for 2 weeks before enrollment and rated their
psychosocial functioning and symptoms. Baseline measures from
the 38 patients in this study were used in a larger cross-sectional
study of quality of life (QOL) in PNES.18 As part of the initial
examination establishing PNES and the comorbid diagnoses,
participants were also administered the Structured Clinical Interview for DSM-IV Axis I Disorders and Structured Interview
for DSM-IV Personality Disorders by trained research interviewers. Additional historic and medical data were collected from
chart review, patient query, and self-report surveys. Self-report
and clinician symptoms scales were prospectively administered
biweekly during the visits, with patients reporting symptoms for
the 2 prior weeks.
Study design. Patients were treated in a double-blind, randomized, placebo-controlled trial. Patients were randomly assigned in blocks of 10, by a computer-generated schedule, in a
1:1 ratio to either the placebo or the sertraline group. Both patient and physician were blinded to treatment group. Allocation
was concealed by having the RIH pharmacy generate and maintain the randomization schedule. Pharmacy prepared similarappearing capsules of 25-, 50-, or 100-mg dosages of the
medications. The blind was not broken until after the entire
study was completed. Patients were followed up prospectively for
2 weeks without treatment to establish a baseline for measures.
Beginning day 15, patients were started on either 25 mg sertraline or 25 mg placebo equivalent. The flexible-dosage design was
that sertraline or placebo dose was increased in biweekly intervals
to 50 mg, and then by 50-mg increments to a maximum of 200
mg daily, unless increase was limited by side effects. Subjects
were seen in six 30-minute, biweekly sessions, according to a
pharmacologic trial protocol19 by a clinician with more than 10
years of experience in neurologic and psychiatric pharmacotherapy (W.C.L.). The session consisted of delineating subjects’
PNES frequency and side effects, and adjusting medication dose.
Missed appointments were made up during the same or following week.
Measures. Beginning at enrollment, patients recorded their
PNES prospectively using a daily seizure calendar, which was
aggregated into biweekly intervals. Collateral information from
family informants was encouraged because some patients with
ES and PNES may be unaware of their events. Secondary outcome measures are listed in table 1. A trained rater, blinded to
treatment group, assessed symptom and psychosocial functioning scales. The Oxford Handicap Scale and Clinician Global
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September 28, 2010
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Table 1
Questionnaires used for secondary
outcome measures
Subjective depression symptoms: Beck Depression
Inventory II28
Objective depression symptoms: Modified Hamilton Rating
Scale for Depression29
Anxiety/posttraumatic stress disorder symptoms: Davidson
Trauma Scale30
Dissociative symptoms: Dissociative Experiences Scale31
Impulsivity: Barrett Impulsivity Scale32
Family functioning: Family Assessment Device33,34
Somatic symptoms: Symptom Checklist-9035
Patient symptoms and social functioning: Global
Assessment of Functioning36
Disability: Oxford Handicapped Scale37
Psychosocial functioning: Longitudinal Interval Follow-up
Evaluation–Range of Impaired Functioning Tool38
Coping techniques: Ways of Coping39
Quality of life: Quality of Life in Epilepsy-3140
Improvement Scale were assessed by a clinician blinded to treatment group.
Statistical methods. Data were analyzed using SAS for Windows 9.1.3 (SAS Institute, Inc., Cary, NC). Continuity-adjusted
2 was used to compare treatment groups on baseline categorical
variables. Between-group differences in continuous variables at
baseline were evaluated using the Student t test. Seizure counts
were modeled using Poisson regression. The Poisson is a distribution on the positive integers appropriate for describing seizure
counts; its sole parameter describes both its central tendency and
its variance. The Poisson distribution can be approximated by
the normal distribution when the event rate or sample size is
high; therefore, count data can be modeled adequately using
normal linear regression. However, for small sample sizes, Poisson regression is preferred. Mean seizure rate at final as the outcome and mean seizure count at baseline as an offset were used to
estimate the within-group change in relative frequency of seizures through the course of the study. The resulting rate ratio
was used as a measure of the treatment effect across the 2 study
conditions. Patients with zero seizures in the baseline period
were removed from this analysis because percentage improvement from baseline to follow-up could not be calculated for such
subjects. A scale parameter was also included to adjust standard
errors for overdispersion (variance greater than the mean). Analysis of covariance in which change scores from baseline to final
visit were compared across study arms, after adjustment for differences at baseline, was used to estimate within-group changes
on continuous secondary outcomes. Under an intent-to-treat
(ITT) approach, subjects with missing data at the end of the
study had their retrospectively reported baseline values carried
forward to visit 6.
Ninety of the 128 patients who were assessed for eligibility were excluded. Seventy-three did
not meet inclusion criteria, and 17 were eligible but
declined participation or were geographically unable
to participate and did not enroll. Reasons for exclusions included using an optimized SSRI (n ⫽ 29),
inability to differentiate events (n ⫽ 11), infrequent
RESULTS
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September 28, 2010
events (n ⫽ 9), no vEEG (n ⫽ 8), age (n ⫽ 7), and
other exclusions (n ⫽ 9) (figure).
Sociodemographic data, comorbidities, and clinical factors were similar in both placebo and sertraline
groups. Patients in the placebo arm reported slightly
higher unemployment, anxiety and Axis II diagnoses,
AED use, and a family history of seizures. Patients in
the treatment group reported slightly higher frequency of mood diagnoses, trauma history, prior
treatment with antidepressants or with psychotherapy, and seizures; however, none of the differences
between the 2 groups were significant (table 2). Similarly, baseline measures in the placebo group revealed higher baseline mean self-reported depression
scores, impulsive symptoms, and overall symptoms,
whereas the treatment group reported higher baseline
mean trauma symptoms and dissociative symptoms;
none of these differences were significant (table 3).
Of the 38 participants who enrolled, 26 subjects
provided end-of-study data (68% study completion
rate) (table 3). Sixteen of the 19 who received active
drug tolerated a dose of at least 100 mg, with 10
patients tolerating up to the maximum of 200 mg
daily. There were no severe adverse events. Thirtythree subjects were included in the ITT analyses for
the primary outcome. Subjects excluded from the
Poisson regression models consisted of 5 patients
with a retrospectively reported biweekly baseline rate
of zero seizures, because the outcome of interest (relative change in PNES rates from baseline to end of
study) could not be calculated for such subjects.
Primary analysis: Treatment effect on seizure frequency. Relative change in seizure rates. There was no
difference between treatment groups (risk ratio [RR]
0.51, 95% confidence interval [CI] 0.25–1.05, p ⫽
0.29). However, further analyses were conducted using an overdispersed Poisson regression model to
estimate relative change in biweekly seizure rates from
baseline to study end, separately, by treatment group.
These analyses indicated that patients in the sertraline arm manifested a 45% decline in biweekly seizure rates over the 12-week course of the
intervention from 22.24 to 12.18 (ratio 0.55, 95%
CI 0.32– 0.93, p ⫽ 0.03). In contrast, control subjects experienced an 8% increase in biweekly seizure
rates from 13.38 to 14.38 (ratio 1.08, 95% CI 0.65–
1.77, p ⫽ 0.78). Using the ratio of these 2 ratios
(RR) as a summary measure of treatment effectiveness, our study provides suggestive evidence that
pharmacologic treatment reduced seizure rates in the
sertraline arm relative to a placebo control arm, adjusting for differences in seizure rates at baseline. Table 4 presents the raw mean and median seizure
counts for all visits before exit. Cross-sectional Poisson regressions revealed no between-condition differ-
Figure
CONSORT flowchart: Psychogenic nonepileptic seizures pilot pharmacologic randomized
controlled trial
CONSORT ⫽ Consolidated Standards of Reporting Trials; ITT ⫽ intent-to-treat.
ences significant at ␣ ⫽ 0.05 at any of the
intermediate time points.
Fifty percent change in seizure rates. Among subjects
with nonzero retrospectively reported baseline seizure
rates, 8 of 17 patients in the sertraline arm reported a
50% or greater reduction in the seizure frequency by
their final session, compared with 3 of 16 patients in the
placebo arm (ITT rates of 47.1% vs 18.8%, p ⫽ 0.18),
resulting in a number needed to treat of 3.53. Of these
responders, 6 patients in the sertraline group reported
complete cessation, vs a single patient in the placebo
group (ITT rates of 35.3% vs 6.3%, p ⫽ 0.08).
Among patients with nonzero baseline rates who
provided information at study end, sertraline sub-
jects with Axis II disorders (n ⫽ 5) reported higher
baseline biweekly seizure rates than those without
Axis II diagnoses (n ⫽ 9). In the placebo group, there
were no significant differences in baseline seizure
rates between patients with (n ⫽ 11) and without
(n ⫽ 3) Axis II disorders.
Secondary outcomes. Mean scores on secondary
outcome scales assessing depression, anxiety, impulsivity, somatic symptoms, QOL scores, and
psychosocial functioning did not reveal betweenarm differences in change scores from baseline to
final session, after adjustment for differences at
baseline (all p ⬎.05) (table 3).
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1169
Table 2
Patient baseline characteristics for PNES pharmacologic pilot
randomized, placebo-controlled trial (N ⴝ 38)a,b
Placebo (nⴝ19)
Sertraline (n ⴝ19)
Mean (SD)
Mean (SD)
n (%)
n (%)
Sociodemographic factors (self-reported)
Age, y
34.4 (12.6)
Age at PNES onset, y
28.4 (15.2)
Female sex
38 (13.9)
33.5 (16.2)
13 (68.4)
Education, y
12.7 (2)
Unemployed currently
16 (84.2)
13.9 (2.5)
14 (73.7)
11 (57.9)
Receiving disability currently
7 (36.8)
6 (31.6)
Married currently
8 (42.1)
10 (52.6)
Driving currently
5 (26.3)
7 (38.9)
Mood disordersc
10 (52.6)
13 (68.4)
Anxiety disordersc
17 (89.5)
16 (84.2)
Axis II disorder
12 (63.2)
8 (42.1)
5 (26.3)
5 (26.3)
8 (42.1)
5 (26.3)
History of trauma/abuse
14 (73.7)
17 (89.5)
Previous psychotherapy
10 (52.6)
12 (63.2)
Treated with psychotropic medications
(past and current)
15 (79)
17 (89.5)
Clinical diagnosisc (made by MD and SCID)
Impulsivity (cluster B personality
or traits)
Somatoform disordersc
(other than PNES)
Clinical factors (from history at baseline)
Benzodiazepines
6 (31.6)
5 (26.3)
Antidepressants
7 (36.8)
12 (63.2)
Antipsychotics
1 (5.3)
Using AEDs at baseline
2 (10.5)
12 (63.2)
6 (31.6)
Average total number of lifetime AEDs
2.8 (3)
2 (2.1)
Average time from PNES onset
to diagnosis, y
4.6 (6.3)
3.7 (5.8)
Seizure frequency (2 wk before
enrollment)
11.3 (12.1)
19.9 (43.5)
Abnormal neurologic examination
result at enrollment
13 (68.4)
11 (57.9)
Abnormal MRI of the brain (past
or at enrollment)
10 (52.6)
6 (31.6)
Interictal epileptiform activity
7 (36.8)
4 (21.1)
Slowing only abnormality
2 (10.5)
4 (21.1)
11 (57.9)
5 (27.8)
7 (36.8)
8 (42.1)
30-min EEG tracing
Biological family history of seizures
History of head injury
Abbreviations: AED ⫽ antiepileptic drug; PNES ⫽ psychogenic nonepileptic seizures;
SCID ⫽ Structured Clinical Interview for DSM-IV Axis I Disorders.
a
Patient medical history obtained by interview and record review.
b
All between-group comparisons p ⬎ 0.05 (not significant).
c
Not mutually exclusive.
In this pilot RCT, we assessed SSRI
treatment to reduce seizure frequency in PNES. The
trial was not powered for establishing treatment efficacy; rather, it was conducted to establish an effect
DISCUSSION
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September 28, 2010
size for a pharmacologic intervention and to demonstrate feasibility of conducting a future multicenter
RCT for PNES. Given the small, pilot nature of this
trial, it is not surprising that no significant differences were found in seizure rates between sertraline
and placebo groups. Nonetheless, patients in the sertraline arm manifested a significant 45% decline in
biweekly seizure rates vs control subjects, who experienced a nonsignificant 8% increase, suggesting that
subjects assigned to the sertraline arm received some
benefit relative to placebo. This pilot trial can neither
substantiate nor refute the utility of SSRI treatment
in patients with PNES.
Analysis of secondary outcome measures including
psychiatric symptoms, QOL, family functioning, and
psychosocial functioning did not reveal significant differences between the treatment and placebo groups.
This finding differs markedly from that in a trial of cognitive behavioral therapy for PNES conducted in parallel with this study that showed not only reduced PNES
frequency, but also improved symptoms of depression
and anxiety, QOL scales, and family functioning.20 The
lack of significant improvement in secondary outcome
measures in this pilot pharmacologic trial provides indirect evidence that the pharmacologic trial may not have
been “contaminated” with psychotherapy, a potential
concern for pharmacologic trials.19
The population enrolled in our trial was reflective
of this disorder’s complexity, as noted in clinical
practice and reported in the literature. Sociodemographic characteristics of the 38 participants who enrolled and completed baseline measures are
consistent with current PNES literature. Neurologically, a number of patients with PNES 1) have neuroimaging abnormalities of uncertain relevance, 2)
have interictal EEG abnormalities despite no epileptiform abnormalities during their seizure, and 3)
have abnormal neurologic examination results despite the absence of a “focal lesion” causing their
events. Psychiatrically, patients with PNES are a heterogeneous population having at least 1 comorbid
condition, including depression, anxiety, posttraumatic stress disorder (PTSD), or a personality disorder.15 In this study, most of the participants had
more than 1 Axis I disorder accompanying their diagnosis of PNES. More than half had a mood, anxiety, or personality disorder. Given that SSRIs are the
treatment of choice for the comorbidities, and to maximize generalizability to PNES populations seen in hospitals and clinics, we included patients with anxiety,
mood, or personality disorder or a combination of the
disorders. If current psychiatric clinical trial exclusion
criteria were applied to “real-world” outpatients, the
majority of patients seen in practice, up to 90%, would
be excluded from RCTs, thus limiting generalizabil-
Table 3
Assessment ratings at baseline and exit in psychogenic nonepileptic seizures pharmacotherapy
pilot randomized controlled triala,b
Placebo
Cutoffc
Scale
Sertraline
Baseline (n ⴝ 19),
mean (SD)
Exit (n ⴝ 14),
mean (SD)
Baseline (n ⴝ 19),
mean (SD)
Exit (n ⴝ 12),
mean (SD)
Modified Hamilton Depression Scale
⬍7
16.8 (8.8)
13.3 (8.4)
17.8 (21.0)
11.6 (9.0)
Beck Depression Inventory II
⬍14
22.1 (13.9)
17.0 (13.3)
16.7 (13.0)
11.7 (11.5)
Davidson Trauma Scale
⬍17
48.1 (40.0)
43.4 (40.0)
52.5 (31.6)
40.3 (36.9)
Barrett Impulsivity Scale
⬍70
72.6 (17.8)
66.2 (15.9)
57.8 (16.5)
64.9 (13.2)
Dissociative Experiences Scale
⬍5
17.4 (11.0)
12.1 (12.2)
21.0 (19.7)
8.5 (13.2)
Symptom Checklist-90
⬍85
109.4 (70.9)
91.4 (77.2)
84.9 (73.3)
78.9 (67.2)
Global Assessment of Functioning*
⬎80
49.1 (7.1)
52.0 (7.9)
53.3 (10.3)
56.8 (11.0)
Oxford Handicap Scale
⬍2
3.4 (0.7)
2.6 (1.2)
3.1 (0.8)
2.3 (1.3)
Clinical Global Impressions–Improvement
1
—
3.5 (1.6)
—
2.9 (1.4)
Clinical Global Impressions–Severity
1
5.1 (0.6)
3.9 (0.9)
4.9 (0.8)
3.3 (1.6)
Quality of Life in Epilepsy-31*
⬎63
38.2 (19.0)
46.9 (24.0)
48.4 (20.7)
56.7 (25.1)
Family Assessment Device–General
Functioning Subscale Score
⬍2.00
2.0 (0.5)
2.2 (0.5)
2.0 (0.7)
2.0 (0.6)
LIFE-RIFT (QOL measure)
⬍9
13.9 (3.8)
13.8 (3.3)
11.8 (3.6)
11.8 (4.8)
Self-controlling
and seeking
social support
Self-controlling
and positive
reappraisal
Self-controlling
Self-controlling
and positive
reappraisal
Ways of Copingd
Abbreviations: LIFE-RIFT ⫽ Longitudinal Interval Follow-up Evaluation–Range of Impaired Functioning Tool; QOL ⫽ quality
of life.
a
Analysis of covariance, comparing change from baseline to exit across conditions, covarying for baseline; return to baseline imputed for missing values at exit; no between-condition p values were significant at ␣ ⫽ 0.05.
b
For all assessments, except those marked with an asterisk, a higher score indicates a worse condition.
c
Cutoff/anchor scores in controls and healthy subjects from the literature.
d
Coping method most used.
ity.21,22 Future studies may benefit from stratifying
groups on the presence of personality disorders.
None of the prior PNES treatment studies approached Class I evidence.3,4,23-25 This pilot study
misses only 1 Class I criterion (68% enrollment, vs
criterion d, at least 80% completion).26 Although results did not attain significance at the customary 5%
Table 4
Mean and median psychogenic nonepileptic seizure frequency as a
function of visita
Placebo (n ⴝ 19)
Sertraline (n ⴝ 19)
2-wk count at:
Mean (SD)
Median
Mean (SD)
Median
Baseline (retrospective
2 wk prior)
11.3 (12.1)
6.0
19.9 (43.5)
5.0
8.9 (8.5)
6.0
17.8 (37.7)
3.0
Week 4
10.3 (10.6)
5.0
16.1 (31.5)
2.0
Week 6
10.9 (16.4)
3.0
13.1 (31.5)
1.0
Week 8
12.1 (17.4)
3.0
12.1 (24.4)
1.0
Week 10
11.7 (12.4)
7.0
18.7 (30.7)
2.5
Week 12
11.6 (14.0)
6.0
11.7 (20.3)
0.0
Week 2 (prospectively collected
from days 1–14)
a
Raw means and medians provided with standard deviation of biweekly seizure count.
Overdispersed Poisson regression with return to baseline imputed for missing values at
follow-up visit; no between-condition p values were significant at ␣ ⫽ 0.05.
level, the present study provides Class II evidence
that flexible-dose sertraline up to a maximum dose of
200 mg is associated with a nonsignificant reduction
in PNES rate compared with a placebo control arm
(RR 0.51, 95% CI 0.25–1.05, p ⫽ 0.29), adjusting
for differences at baseline. The study also provides
preliminary evidence of a serotonergic-mediated intervention directly on PNES, because seizure reduction in the sertraline group was not accompanied by
a mean reduction in symptoms in common comorbidities of depression or PTSD. Based on this study,
we modified our initial hypothesis that treating comorbidities may reduce PNES. SSRIs may have a
direct effect on PNES. In fact, other studies have
recently reported a direct effect of SSRIs on somatoform disorders, independent of mood and anxiety
symptoms.8,27 That the treatment group began showing seizure improvement at lower doses of the SSRI
may indicate that somatoform disorders may have a
lower serotonergic response threshold than mood
and anxiety disorders. This response was not observed in the placebo group, arguing against an early
placebo response in the treatment group.
Half of the patients had received an antidepressant before enrollment. Despite using antidepresNeurology 75
September 28, 2010
1171
sants at some point in the past, they did not have
symptomatic improvement in seizures during their
pre-enrollment regimen, suggesting that optimizing
the dose of antidepressant may be an important treatment component. Also, patients who do not respond
to one SSRI may respond to another. The patients
taking AEDs at baseline were prescribed the drug not
only for seizures, once thought epilepsy, but also for
other AED-responsive conditions, including migraine prophylaxis (n ⫽ 4), mood disorder (n ⫽ 3),
pain (n ⫽ 4), and comorbid epilepsy (n ⫽ 2). One
could argue that ongoing AED use can in some cases
reflect lack of confidence in the diagnosis of PNES,
and that may influence outcomes. However, the explanation given to the participants was clear that 1)
AEDs do not treat PNES, and 2) if they continued
on their AED for other indications, it was not being
used for seizure reduction in their treatment. The
patients understood the indication for their AEDs,
and with this clarification, we hoped to mitigate any
reduction in confidence in the PNES diagnosis.
The major limitation of this pilot study’s conclusions is sample size. A full-scale RCT is needed to
establish efficacy for a pharmacologic intervention
for PNES. The future full-scale trial will need to adjust for potential dropouts, which largely occurred in
this trial because of the patients’ concern that they
would receive the placebo, despite the equipoise that
exists for PNES treatments. Although the evenly dispersed baseline slight differences among the 2 groups
could have contributed to the apparent treatment
difference, our analyses confirmed that there were no
significant differences among any of the factors related to illness severity. One of the major strengths
of this study was that all patients had vEEGdocumented PNES. However, excluding patients
who did not have vEEG may present a potential sampling bias.
The trial provides feasibility and patient tolerability for a pharmacologic intervention for PNES. The
potential influence of patient characteristics was also
highlighted in this pilot study. Future studies on response durability, documenting treatment effect duration, need to be conducted. A multicenter RCT is
being designed to address the efficacy of treatments
for PNES.
AUTHOR CONTRIBUTIONS
Statistical analyses were conducted by Drs. George D. Papandonatos and
Jason T. Machan.
ACKNOWLEDGMENT
The authors thank Drs. Orrin Devinsky and Michael Trimble for initial
conceptual guidance; Dr. Lawrence Hirsch, who acted as data safety monitor for this trial; and Joan Kelley for database management.
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DISCLOSURE
Dr. LaFrance serves on the editorial boards of Epilepsia and Epilepsy &
Behavior; receives royalties from the publication of Gates and Rowan’s
Nonepileptic Seizures, 3rd ed. (Cambridge University Press, 2010); receives research support from the NIH (NINDS 5K23NS45902 [PI]),
Rhode Island Hospital, the American Epilepsy Society, the Epilepsy
Foundation, and the Siravo Foundation; and has acted a legal expert
for Healthcare Litigation Support. Dr. Keitner reports no disclosures.
Dr. Papandonatos serves on the editorial boards of the Journal of Consulting and Clinical Psychology and Health Psychology; has served as a
statistical consultant for Weinstock & Barylick Associates; receives
research from the NIH (R01AG016335 [Biostatistician],
P50CA84719 [Biostatistician], R01DA019558 [Biostatistician],
R01DA018079 [Biostatistician], R01HL064342 [Biostatistician], R01HL064342 [Biostatistician], R01MH079153 [Biostatistician],
R01NR010559 [Biostatistician], R01AA016799 [Biostatistician],
R21CA137211 [Biostatistician], R01CA132854 [Biostatistician], and
U01CA150387-0 [Biostatistician]); and receives research support from the
American Legacy Foundation and Miriam and Rhode Island Hospitals. Dr.
Blum serves as Editor of BMC Neurology; receives royalties from the publication of The Clinical Neurophysiology Primer (Humana-Springer, 2007); serves
as Medical Supervisor for DigiTrace/SleepMed Inc.; and receives/has received
research support from UCB, Eisai Inc., and Abbott. Dr. Machan receives
research support from the NIH (5P20 RR024484 [Biostatistician],
5R01CA123544 [Biostatistician], 5U19AI070202 [Biostatistician], NIAMS
1R01-AR056834 [Biostatistician], 1R01 AR056834 – 01S1 [Biostatistician],
and 1R01AA017895-01A2 [Biostatistician]). Dr. Ryan receives royalties
from the publication of Evaluating and Treating Families: The McMaster Approach (Routledge, 2005); and has received research support from the Firan
Foundation. Dr. Miller receives research support from the NIH (NIMH R34
MH070743-01 [Coinvestigator], NIMH R34 MH078855 [PI], NIMH
R01 MH071766 [Coinvestigator], NIAAA R01 AA015950 [PI], NIMH
R34 MH073625 [PI], NIMH R34MH079108 [Coinvestigator],
R01DA023072 [PI], NIDA R01DA023190 [Coinvestigator], NIMH
R34MH083065-01 [Coinvestigator], NIMH U01MH088278 [Co-PI], and
NIMH R34MH08221 [Coinvestigator]).
Received November 20, 2009. Accepted in final form May 27, 2010.
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