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 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 generalizability.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% 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 antidepressants 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 vEEG-documented 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.