An open-label, flexible dose adaptive study evaluating the efficacy of vortioxetine in subjects with panic disorder

We designed an open-label 10 week-long study with fixed doses (5, 10, or 20 mg) to evaluate the safety, tolerability, and efficacy of vortioxetine for the treatment of PD, see Fig. 1 for the transparent reporting of evaluations with nonrandomized design (TREND) flowchart. 27 male and female subjects aged between 18 and 60 years, who met DSM-IV criteria for PD with or without agoraphobia, or who had a Panic Disorder Severity Scale (PDSS) score > 8 at baseline were screened. Institutional Review Board (IRB) approval for this study was obtained from the Schulman Associates IRB (Approval #: 201500056) and this study was conducted according to the World Medical Association Declaration of Helsinki. Only patients with active ongoing panic disorder were selected (as diagnosed by the Investigator as per the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition [DSM-IV] criteria using the MINI International Neuropsychiatric Interview 6.0); the previous treatment had not succeeded in eliminating their symptoms. Five patients were excluded for not meeting inclusion criteria, or not wishing to participate. After providing written informed consent, 22 subjects underwent a 7–14 day washout period of their current SSRI or SNRI medications. In the case of a subject taking a medication with a long half-life such as fluoxetine, a 5-week washout period prior to Baseline was allowed. There was no washout requirement for subjects using benzodiazepines or hypnotics prior to study enrollment. Subjects were allowed to continue concomitant treatment with these medications during the study; however, treatment was not initiated with benzodiazepines or hypnotics for any of the enrolled subjects, which allowed for a better overall assessment in the efficacy of vortioxetine for panic disorder. All subjects who participated in the study met the designated inclusion criteria and none of the exclusion criteria. Four patients discontinued the study, suffering from diarrhea, nausea, akathisia, dry skin, and itchiness. All patients with adverse events were monitored, serious, or otherwise. One patient suffered a serious adverse event (SAE) of a pulmonary embolus after completing the study; this event was not deemed as related to the study treatment.

Subjects received 5 mg of vortioxetine and were instructed to take one capsule orally, once daily in the morning, starting at the baseline visit (visit 1). Subjects were then seen bi-weekly following the baseline visit for a period of 10 weeks. The study medication was given on a flexible titration schedule until an optimal dose or response (in the opinion of the investigator) had been achieved for each subject. This design allowed the investigator to focus on the most effective dose for each subject with the total daily dose of vortioxetine not exceeding 20 mg.

Two efficacy and two safety assessments were used. The efficacy assessments consisted of the Panic Disorder Severity Scale (PDSS) and the Quality-of-Life Scale (QOLS). The PDSS is a questionnaire developed for measuring the severity of PD and is considered a reliable tool for monitoring treatment outcome [24, 25]. The safety assessments included the Monitoring of Side Effects Scale (MOSES) and the Columbia-Suicide Severity Rating Scale (C-SSRS) [26, 27].

From March to May 2016, 27 subjects were screened in the study, of which 20 were female. The median [IQR] age of the subjects was 39 (age range 23.5–49 years) (Fig. 2a). The median BMI of the patient population was 26.25 (range 23.58–29.2), and 59% were overweight (Fig. 2b). Major depressive disorder was the most frequent co-morbidity in this patient population, followed by agoraphobia (Fig. 2c).

PDSS score was used as a reliable method for measuring the severity of PD on each clinic visit. PDSS scores assess seven important criteria: panic frequency, distress during the panic attack, panic-focused anticipatory anxiety, phobic avoidance of situations, phobic avoidance of physical sensations, impairment in work functioning, and impairment in social functioning, and provide an overall score for PD severity. A total of 18 subjects, 12 females and six males, completed the study. A statistically significant decrease was observed between the baseline PDSS scores and final scores upon completing the study (p < 0.05), with a mean decrease of 8.89 (Fig. 3).

The MOSES scale was used to document the safety and tolerability of vortioxetine. The MOSES has 73 items presented in layperson’s language organized into nine body areas representing a typical physical examination. A statistically significant decrease (an improvement) was observed between the baseline MOSES score and the score upon completing the study (p = 0.014), with a mean decrease of 1.06 on the MOSES scale (Fig. 4).

The Quality-of-Life (QOL) scale is a valid instrument for measuring the quality of life across the patient groups [9]. The QOLS has 16 items rated on 7-point response scales. Higher scores indicate a higher quality of life. A trend towards an increase was observed in QOL score upon the completion of the study (p = 0.061), with a mean gain of 4.944 (Fig. 5).