Author’s Accepted Manuscript

Long-term safety and efficacy of armodafinil in

bipolar depression: A 6 -month open-label extension
study

Terence A. Ketter, Jess Amchin, Mark A. Frye,

Nicholas Gross
www.elsevier.com/locate/jad

PII: S0165-0327(15)30779-5
DOI: http://dx.doi.org/10.1016/j.jad.2016.02.050
Reference: JAD8068
To appear in: Journal of Affective Disorders
Received date: 14 August 2015
Revised date: 16 February 2016
Accepted date: 25 February 2016
Cite this article as: Terence A. Ketter, Jess Amchin, Mark A. Frye and Nicholas
Gross, Long-term safety and efficacy of armodafinil in bipolar depression: A
6-month open-label extension study, Journal of Affective Disorders,
http://dx.doi.org/10.1016/j.jad.2016.02.050
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Long-term safety and efficacy of armodafinil in bipolar depression: A
6-month open-label extension study

Terence A. Ketter, MD1*; Jess Amchin, MD, JD2; Mark A. Frye, MD3; Nicholas
Gross, MS2

1
Stanford University School of Medicine, Stanford, CA, USA; 2Teva
Pharmaceuticals, Frazer, PA, USA; 3Mayo Clinic, Rochester, MN, USA

*Correspondence: Terence A. Ketter, MD, Professor of Psychiatry and Behavioral

Sciences, Chief, Bipolar Disorders Clinic, Stanford University School of Medicine,

401 Quarry Road, Room 2124, Stanford, CA 94305-5723; Tel: 650-723-2515; Fax: 650-

723-2507; E-mail: tketter@stanford.edu

1
Abstract

Background: Safe/well-tolerated treatments for bipolar I depression remain

limited. We assessed safety/tolerability of adjunctive open-label armodafinil, a

wakefulness-promoting agent evaluated in three acute, controlled efficacy

studies with variable efficacy results.

Methods: Completers of three 8-week, double-blind, placebo-controlled

adjunctive armodafinil studies (150-200 mg/day added to ongoing stable

maintenance doses of 1 or 2 protocol-defined mood stabilizers) in bipolar I

depression could enter this 6-month, open-label extension study. Objectives

included evaluation of safety/tolerability (primary) and efficacy (secondary).

Results: 867 patients enrolled; 863 received ≥1 dose of armodafinil and 506

(58%) completed the 6-month study. Headache, insomnia, and anxiety were the

most common adverse events (AEs) reported, whereas akathisia, nausea,

sedation/somnolence, and weight increase were uncommon. Mean measures

assessing emergence of mania, anxiety, insomnia, or suicidality showed no

worsening. Discontinuations due to AEs occurred in 57 (7%) patients. Serious

AEs occurred in 27 (3%) patients and were considered treatment-related in 8

(1%) patients. Depressive symptoms improved over the 6 months, as did patient

functioning.

Limitations: Lack of placebo control.

Conclusions: Adjunctive armodafinil was generally safe and well tolerated over

6 months of open-label treatment at 150 to 200 mg/day when taken with protocol-

defined mood stabilizers for bipolar I depression. This 6-month open-label study

2
suggested that armodafinil augmentation of bipolar maintenance therapies may

have a favorable risk profile and may improve depressive symptoms in some

patients with bipolar I depression.

Keywords: bipolar depression, bipolar I disorder, armodafinil, long-term safety,

wakefulness

Highlights

• Safe, well-tolerated treatments for bipolar I depression are limited.

• Over 6 months, open-label adjunctive armodafinil was generally safe and

well tolerated.

• Mean measures for emergence of mania, suicidality, anxiety, or insomnia

did not worsen.

• Results suggest a positive risk profile of adjunctive armodafinil in bipolar I

depression.

• Adjunctive armodafinil efficacy remains to be established, and it does not

have an FDA indication for bipolar I depression.

3
INTRODUCTION

Bipolar I disorder has an estimated lifetime prevalence of 1% in the United States

(Merikangas et al., 2007). Recurrent mood symptoms that characterize the

disorder can lead to severe disability (Calabrese et al., 2004; Post et al., 2003;

World Health Organization, 2008), and it is estimated that there are 22.2 million

patients with bipolar disorder worldwide who endure moderate to severe

functional impairment (World Health Organization, 2008). Although the manic

phase of the illness has received more attention in terms of pharmaceutical

development, patients experience depressive symptoms 3 times more frequently

than manic symptoms (Judd et al., 2002; Kupka et al., 2007; Post et al., 2003). In

addition, compared with manic episodes, the depressed phase of bipolar I

disorder is associated with more frequent and severe disability, including

functional and occupational deficits, and higher risk of suicide (Baldessarini et al.,

2012; Bauer et al., 2001; Calabrese et al., 2004; Merikangas et al., 2007;

Merikangas et al., 2011).

Management of bipolar I depression is challenging, and currently there are only 3

treatments that have been approved by the US Food and Drug Administration

(FDA) for acute depressive episodes occurring in the context of bipolar I disorder

(Frye et al., 2014; Ketter et al., 2014). Unfortunately, a recent meta-analysis

found that standard antidepressants that are effective in the relief of unipolar

depression did not provide any significant advantage over placebo for acute

4
bipolar I depression (Sidor et al., 2011). Thus, there remains a large unmet need

for new treatment options in acute bipolar I depression (Frye et al., 2014).

Armodafinil (R-modafinil) is an indirect dopamine agonist that binds in vitro to the

dopamine transporter, inhibiting dopamine reuptake. Armodafinil promotes

wakefulness, similar to amphetamine and methylphenidate, but has a different

pharmacologic profile. Because of its efficacy in wakefulness promotion,

armodafinil is currently approved by the FDA for the treatment of excessive

sleepiness associated with the conditions of shift work disorder (Czeisler et al.,

2009), narcolepsy (Harsh et al., 2006), or obstructive sleep apnea (Hirshkowitz et

al., 2007; Roth et al., 2006). A placebo-controlled phase 2 investigation of

armodafinil (150 mg/day for 8 weeks) administered adjunctively to lithium,

valproic acid, and/or olanzapine in bipolar I depression showed significant

improvement in depressive symptoms, relative to placebo, as assessed by the

30-Item Inventory of Depressive Symptomatology-Clinician Rated (IDS-C30)

(Calabrese et al., 2010). Based on these results, a phase 3 clinical development

program was initiated to further assess the potential efficacy and safety of

armodafinil in bipolar I depression. This included 3 similarly designed acute-

phase studies of adjunctive armodafinil vs placebo and a long-term open-label

extension study.

In the first of these phase 3 studies, adjunctive armodafinil significantly improved

depressive symptomatology over adjunctive placebo, supporting the prior phase

2 results (Calabrese et al., 2014). Two subsequent phase 3 studies found a

5
generally favorable tolerability profile of adjunctive armodafinil in bipolar I

depression, but positive efficacy findings from earlier studies were not replicated

(Frye et al., 2015; Ketter et al., 2015). Thus, insufficient efficacy results prompted

a decision by the sponsor to terminate the clinical development of armodafinil for

this indication.

Here we report results from an open-label, long-term extension trial. The primary

hypothesis was that open-label adjunctive armodafinil 150 to 200 mg/day for 6

months in recently depressed bipolar I disorder patients was safe and well

tolerated; the secondary hypothesis was that open-label adjunctive armodafinil

150 to 200 mg/day for 6 months in recently depressed bipolar I disorder patients

was efficacious for depressive symptoms and global functioning.

METHODS

Study Design

This phase 3, multicenter, 6-month, open-label extension study (NCT01121536)

evaluated armodafinil at dosages of 150 and 200 mg/day, given adjunctively to

ongoing bipolar maintenance therapies. For those who participated, the final visit

of the previous double-blind acute study served as the enrollment visit for the

open-label extension study. At enrollment, armodafinil was initiated at a dose of

50 mg/day and was increased to 100 mg/day on day 2 and to 150 mg/day on day

4. Thereafter, armodafinil could be increased to 200 mg/day on day 6 or later at

the discretion of the investigator based on efficacy and/or safety and tolerability.

6
The study protocol was approved by independent ethics committees or

institutional review boards associated with each study center, and the study was

conducted according to Good Clinical Practice guidelines as approved by the

International Council for Harmonisation. All patients provided written informed

consent prior to any study procedures or assessments. An external data and

safety monitoring board reviewed safety on a regular basis.

Participants

Patients who had completed 8 weeks of treatment in 1 of the previous acute

phase 3 double-blind studies evaluating adjunctive armodafinil vs adjunctive

placebo in bipolar I depression (Studies 3071 [NCT01072929], 3072

[NCT01072630], or 3073 [NCT01305408]) (Calabrese et al., 2014; Frye et al.,

2015; Ketter et al., 2015) were eligible for this open-label study. Enrollment in the

double-blind studies required patients to be between the ages of 18 and 65 years

and in good physical health. The diagnosis of bipolar I disorder with a current

major depressive episode was made on the basis of the Diagnostic and

Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-

TR) criteria. Patients with other Axis I or II disorders, psychotic symptoms, or

suicidal ideation were ineligible. For patients to be included in the extension

study, the clinical investigator must have determined that they were in need of

continued treatment for depression. Patients also were required to have a Young

Mania Rating Scale (YMRS) total score ≤14. In addition, patients were required

to be willing to continue 1 or 2 of the following protocol-allowed mood stabilizers:

7
lithium, valproic acid, olanzapine, quetiapine, aripiprazole, lamotrigine,

risperidone, or ziprasidone (ziprasidone only if taken in combination with lithium,

valproic acid, or lamotrigine). If 2 protocol-allowed mood stabilizers were taken at

baseline, 1 had to be lithium, valproate, or lamotrigine. The use of any

antipsychotics or anticonvulsants other than those listed above was prohibited;

no antidepressant agents were allowed. Adjunctive benzodiazepines (up to 2 mg

of lorazepam-equivalents per day) or hypnotics (zolpidem 5-10 mg at bedtime or

zaleplon 5-10 mg at bedtime) were allowed provided their use did not occur

within 12 hours of any study assessment and did not exceed 3 times per week.

Assessments

The final visit of the previous double-blind acute study served as the baseline

visit for this open-label extension study. Study center visits during open-label

treatment were conducted at week 1 and months 1, 2, 4, and 6 (or early

termination if prior to month 6). In addition, telephone contacts were made at

weeks 2 and 3 and at months 3 and 5 to evaluate study drug tolerability through

assessment of adverse events (AEs) and to collect data on concomitant

medication use. Protocol-defined treatment-emergent AEs of clinical interest,

including skin rash, hypersensitivity reaction, suicidal ideation or suicide attempt,

and psychosis were monitored for expedited reporting. Safety assessments

collected during the 5 study center visits included vital sign measurements, the

YMRS, the Columbia-Suicide Severity Rating Scale-Since Last Visit (C-SSRS-

SLV), and the Insomnia Severity Index (ISI). At month 6 or the last post-baseline

8
visit, clinical laboratory test results, electrocardiography (ECG), physical

examination, and Hamilton Anxiety Rating Scale (HAM-A) score were monitored.

The efficacy of adjunctive armodafinil was assessed at week 1, and months 1, 2,

4, and 6 (or last post-baseline visit) using the total score from the IDS-C30 and

the Clinician Global Impression of Severity (CGI-S) for depression. The 16-Item

Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16)

derived from the IDS-C30 was obtained at week 1 and months 1, 2, 4, and 6 (or

last post-baseline visit). The Global Assessment of Functioning (GAF) scale

score was assessed at month 6 (or last post-baseline visit).

Statistical Analysis

Sample size was not based upon a statistical power analysis; approximately 800

to 900 patients were planned for enrollment to obtain at least 200 patients who

received adjunctive armodafinil for 6 months. The safety analysis set included all

patients who took ≥1 dose of study drug. The full analysis set included all

patients in the safety analysis set who had ≥1 post-baseline efficacy assessment.

Descriptive statistics were used to describe patient disposition, demographic and

baseline characteristics, study drug exposure, incidence of AEs, and all other

safety assessments. Efficacy analyses used the full analysis set and included

descriptive statistics summarizing change from baseline in the double-blind

studies to endpoint in the current open-label study for the IDS-C30, QIDS-C16,

9
CGI-S, and GAF scale. All data were processed and summarized using SAS®

Version 9.3 (SAS Institute, Inc., Cary, NC).

RESULTS

Participants

In total, 867 patients were enrolled in the open-label extension study, which was

conducted between April 22, 2010, and October 9, 2013. Enrollees had

completed one of the three previous acute, double-blind, placebo-controlled

studies (3071, 3072, 3073), expressed a desire to transition to the open-label

study, met entry criteria, and were believed by the investigator to be in need of

continued treatment. Of these patients, 863 received ≥1 dose of open-label

armodafinil (safety analysis set), while 859 completed ≥1 post-baseline efficacy

assessment (full analysis set for efficacy; Figure 1). A total of 506 (58%) patients

completed the 6-month study. In total, 361 (42%) patients withdrew from study;

the most commonly cited reason was “other,” in 118 (14%) patients. This

included withdrawals that resulted from a business decision by the sponsor to

terminate the open-label study early when it became apparent that efficacy of

armodafinil for the adjunctive treatment of acute bipolar I depression had only

been demonstrated in 1 of 3 acute, double-blind trials (n=79) and other

withdrawals because of the sponsor’s decision (n=21). The study was not

terminated for any safety reasons. Other frequently reported reasons for

withdrawal were consent withdrawn in 65 (7%) patients, AEs in 63 (7%) patients,

lost to follow-up in 39 (4%) patients, and lack of efficacy in 35 (4%) patients. The

10
majority of patients (576 [67%]) received adjunctive armodafinil treatment for >4

months, and the mean ± standard deviation (SD) duration of exposure was 137.7

± 59.5 days.

Patient demographics and baseline characteristics are shown in Table 1. Mean

age was 44.2 years; the majority of patients were women (61%) and white (82%).

Concomitant psycholeptics were used by 579 (67%) patients, most commonly

lithium (147 [17%]), risperidone (133 [15%]), olanzapine (121 [14%]), aripiprazole

(119 [14%]), quetiapine (47 [5%]), and zolpidem (32 [4%]). Antiepileptics were

used concomitantly by 437 (51%) patients, most commonly valproate in 267

(31%) patients and lamotrigine in 146 (17%) patients.

Safety

At least 1 AE was reported by 423 (49%) patients (Table 2). A total of 219 (25%)

patients had AEs that were considered treatment related by clinical investigators.

The most commonly reported AEs were headache (11%), insomnia (6%), and

anxiety (5%). Weight increase was reported in 8 patients (<1%);

sedation/somnolence in only 4 patients (<1%), and akathisia in 1 patient (<1%).

Most AEs were mild to moderate in severity. Only 26 (3%) patients had an AE

that was rated as severe; of these, only headache (n=3), insomnia (n=3), and

nausea (n=2) occurred in >1 patient. During the study, 57 (7%) patients withdrew

because of AEs. The most frequent of these were mania (n=11); anxiety (n=7);

depression, nausea, and insomnia (n=5 each); and hypomania (n=3). Two

11
patients withdrew because of suicidal ideation. No patient discontinued due to

akathisia or sedation/somnolence.

A total of 27 (3%) patients had ≥1 serious adverse event (SAE) during the open-

label study, and an additional 2 patients had SAEs that began before the start of

open-label treatment. SAEs experienced by >2 patients included mania (n=5),

bipolar I disorder (n=3), and suicidal ideation (n=3). SAEs were considered

treatment related in 8 (1%) patients as follows: mania with psychosis and acute

cholecystitis, acute hepatitis, moderate mania which progressed to severe mania,

bipolar mixed state with suicidal ideation, mania, bipolar I disorder with

worsening of depression, myocardial infarction, and suicidal ideation. There were

no deaths in this study.

Nineteen (2%) patients reported ≥1 protocol-defined treatment-emergent AE for

expedited reporting (i.e., skin rash, hypersensitivity reaction, suicidal ideation or

suicide attempt, and psychosis) with adjunctive armodafinil treatment. Of 8

patients with skin reactions, 4 were considered related to study drug: recurrent

mild maculopapular rash, mild leukocytoclastic vasculitis, and mild perioral

dermatitis, all of which resolved without residual effect; the fourth skin reaction,

lichen planus, was ongoing at last contact. Two patients reported hypersensitivity

reactions: 1 allergy to plants and 1 allergy to cat dander, but neither was

considered treatment related. Eight patients had AEs of suicidal ideation (n=7) or

12
suicide attempt (n=1); all cases resolved with no residual effect. Acute psychosis

occurred as an AE in 1 patient who discontinued because of this AE.

No clinically meaningful trends in mean changes in clinical laboratory tests, vital

signs, physical examination findings (including body weight), and ECG were

observed over 6 months. Mean ± SD QTc interval increased by 2.2 ± 19.5 msec

(422.0 ± 22.3 msec at baseline to 424.1 ± 21.4 msec at endpoint) using the

Bazett correction and by 1.9 ± 15.4 msec (408.4 ± 19.1 msec at baseline to

410.3 ± 18.3 msec at endpoint) using the Fridericia correction. Mean ± SD weight

change at study endpoint with adjunctive armodafinil treatment was -0.8 ± 5.67

kg; clinically significant weight gain (i.e., ≥7%) occurred in 61/788 (8%) patients.

Reported changes from week 1 to endpoint in suicidal behavior as assessed by

the C-SSRS-SLV included 1 suicide attempt reported at month 6 (endpoint), 1

patient with nonsuicidal self-injurious behavior, and 1 patient with preparatory

acts or behavior. In patients in whom any emergent suicidal ideation was

detected, the majority of patient responses reflected positive responses on the

passive suicidal ideation scale item “wish to be dead.”

Over the 6-month course of open-label treatment, mean changes from baseline

in YMRS, HAM-A, and ISI total scores suggested clinical improvement. The

mean ± SD YMRS total score decreased by 0.7 ± 4.3 from 3.6 ± 2.1 at baseline

to 2.9 ± 4.2 at endpoint. Mean ± SD HAM-A total score decreased by 6.2 ± 5.7

13
from 12.5 ± 2.9 at baseline to 6.3 ± 5.2 at endpoint. Likewise, mean ± SD ISI total

score decreased by 9.1 ± 7.7 from 15.8 ± 5.5 at baseline to 6.8 ± 6.6 at endpoint.

Efficacy

Improvement in depressive symptoms, as measured by mean change from

baseline in the IDS-C30 and the QIDS-C16, occurred at each successive visit over

6 months of adjunctive armodafinil treatment (Figure 2). Mean ± SD baseline

IDS-C30 was 43.1 ± 7.67 and decreased to 15.6 ± 11.57 at endpoint, representing

a 64% decrease. Similarly, the mean ± SD QIDS-C16 score at baseline (16.8 ±

2.71) decreased to 6.2 ± 4.51 at endpoint, representing a 63% decrease.

Correspondingly, improvements in mean ± SD CGI-S scores were also observed

at each study visit, with reductions equaling -1.7 ± 1.17 at week 1; -1.9 ± 1.17 at

month 1; -2.0 ± 1.18 at month 2; -2.2 ± 1.16 at month 4; -2.3 ± 1.18 at month 6;

and -2.0 ± 1.31 at endpoint. The mean ± SD GAF scale score improved by 17.7 ±

13.61 at endpoint from 53.3 ± 7.36 at baseline to 71.0 ± 12.79.

DISCUSSION

The morbidity associated with bipolar I depression, limited number of approved

treatment options, and related challenges in maintaining treatment adherence to

agents used clinically (whether or not FDA approved for this indication) due to

inadequate efficacy (Sidor et al., 2011) or safety and tolerability issues (Kemp,

2014) have contributed to searches for new treatment options. In this open-label

extension study, adjunctive armodafinil over 6 months in patients with bipolar I

14
depression was generally well tolerated. The most common AEs experienced by

patients (headache, insomnia, and anxiety) were consistent with the reported

AEs noted in research supporting armodafinil’s approved indications (Nuvigil PI,

2015). The severity of AEs was mostly mild to moderate; overall, 7% of patients

withdrew due to AEs. Very few SAEs (i.e., mania, bipolar I disorder, and suicidal

ideation) were experienced by >2 patients each.

The initiation of standard antidepressant therapy for the treatment of bipolar

depression may be less effective than when used in unipolar depression.

Additionally, the potential risk of affective switching is cause for concern with the

use of these agents. Leverich and coworkers examined the risks of affective

switching in patients with bipolar depression despite ongoing mood stabilizer

treatment who were subsequently randomized to adjunctive bupropion,

sertraline, or venlafaxine administration in acute (10-week) and continuation (1-

year) studies. The overall combined switch rate into syndromal hypomania or

mania occurred in 19.3% of patients during acute trials and reached 36.8% in

continuation trials (Leverich et al., 2006). Of the three antidepressants examined,

the putative noradrenergic and dopaminergic reuptake inhibitor bupropion was

associated with the lowest ratio of threshold switches to subthreshold brief

hypomania in both acute and continuation studies (Leverich et al., 2006).

Bupropion has been studied in a small (n=12) open-label study as adjunctive

treatment to mood stabilizers and atypical antipsychotics in patients with bipolar I

depression and comorbid cocaine dependence, where it was found to improve

15
depressive symptoms without significant increases in YMRS scores and without

any manic/hypomanic switches (Sepede et al., 2014). Additionally, in a case

report detailing treatment of a 35-year-old woman with medication-resistant

bipolar depression, the addition of low-dose bupropion to a regimen of lithium

carbonate, lamotrigine, buspirone, and melatonin brought about sustained

remission of a depressive episode that had lasted for more than 2 years

(Nierenberg, 2009).

The unique MT1 and MT2 melatonergic agonist and serotonin 5-HT2C receptor

antagonist agomelatine has been studied in two open-label studies and one

randomized, placebo-controlled study in bipolar depression. The first study

(Calabrese et al., 2007) evaluated 25 mg/day of agomelatine over 6 weeks (with

an optional 46-week extension) added to lithium (n=14) or valproate (n=7) in

patients with bipolar I depression and a mean 17-item Hamilton Rating Scale for

Depression (HAM-D-17) score of 25.2. At endpoint, 81% of patients responded

(≥50% reduction from baseline in HAM-D-17 score). Eleven of 19 patients

entering the optional extension phase completed the study. Hypomanic or manic

episodes occurred in 3 patients treated with lithium during the extension phase, 2

of which were considered to be related to treatment. An additional open-label

study (Fornaro et al., 2013) assessed the efficacy and safety of agomelatine (25

mg/day) added to valproate (n=17) or lithium (n=11) in patients with bipolar II

depression with a mean baseline HAM-D-17 score of 25.9. Agomelatine yielded

response (>50% decrease in HAM-D-17 score) at 6 weeks in 70.6% of patients

16
receiving valproate and 54.5% receiving lithium. Respective response rates for

the two groups at 36 weeks were 82.4% and 90.9%. Four patients dropped out in

the acute phase including 1 patient with hypomania (valproate treated) and 1

patient with mania (lithium treated). Two additional cases of hypomania (1 each

for valproate and lithium groups) led to treatment discontinuation at week 36.

Most recently, a randomized, controlled study evaluated agomelatine (25-50

mg/day) vs placebo (8 weeks acute and 44 weeks of continuation therapy) as

adjunctive treatment to lithium or valproate in patients with bipolar I depression

(Yatham et al., 2016). Depressive symptom improvement did not differ between

agomelatine and placebo at either 8 or 52 weeks. Total scores on the YMRS

remained stable over both the acute and extension periods. The percentage of

patients who had emergent hypomanic or manic symptoms during acute

treatment was 4.1% in the agomelatine group and 3.5% in the placebo group.

During the extension phase, 7.6% of patients taking agomelatine and 4.1%

taking placebo had emergent hypomania/mania (Yatham et al., 2016).

A 6-week randomized, placebo-controlled study evaluated the efficacy and safety

of modafinil given adjunctively to a mood stabilizer with or without a concomitant

antidepressant and found rates of treatment-emergent affective switches that

were no different from those observed with placebo (14.6% vs 11.4%,

respectively) (Frye et al., 2007). In the three similarly designed acute,

randomized, placebo-controlled trials of adjunctive armodafinil vs adjunctive

placebo for patients with acute bipolar I depression from which patients entering

17
this extension study were derived, mean YMRS scores did not differ significantly

at endpoint; treatment-emergent hypomania or mania incidences were low and

similar to those observed with placebo (Calabrese et al., 2010; Frye et al., 2015;

Ketter et al., 2015). In the present 6-month open-label extension study,

armodafinil was associated with improvement in depressive symptoms. Changes

in mean YMRS scores (-0.7 point reduction) between baseline and endpoint

were not indicative of emergent hypomania or mania; AEs of mania or

hypomania occurred in <2% of treated patients and included 11 AEs of mania

and 5 AEs of hypomania, over the 6-month study period.

Suicidal behavior represents a major public health concern. This is especially

true in patients with bipolar disorder, where the annual risk of suicide attempts

appears as high as 400-1400/100,000, or 30 to 60 times higher than in the

general population (Ahrens et al., 1995; Baldessarini et al., 2006a; Baldessarini

et al., 2006b). Risk factors for suicide attempt in bipolar disorder include female

gender (although males predominate in completed suicides), prior history of

suicide attempt or family history of suicide, presence of suicidal ideation, and the

presence of comorbid illness (anxiety, drug and alcohol abuse disorders, and

personality disorders), to name a few (Gonda et al., 2012). In the current study,

the occurrence of suicidal ideation or a suicide attempt was specifically evaluated

as an AE of interest because of its association with the underlying bipolar

disorder and agents that may relieve depression in pediatric and young adult

patients. In total, these AEs occurred in 8 patients (7 with suicidal ideation; 1 with

18
suicide attempt), representing <1% of those enrolled. All of these resolved with

no residual effects. In addition, results of the C-SSRS-SLV generally showed no

evidence of increased suicidality.

Mean YMRS, HAM-A, and ISI scores all improved over the 6-month treatment

period, suggesting a low propensity for armodafinil to precipitate

hypomanic/manic switching, cause anxiety, or induce insomnia. Skin and

hypersensitivity reactions were few (n=8 and n=2, respectively). Three of 4

treatment-related skin reactions resolved without residual effect; a case of lichen

planus was ongoing at the time of study withdrawal. Of importance, there were

no clinically meaningful changes in laboratory parameters, vital signs, physical

examinations, or ECGs. This study reported a low rate of somnolence (<1%),

mean change in body weight (-0.8 ± 5.67 kg), rate of clinically significant weight

gain (8%), and the lack of clinically significant mean QTc interval increases

(Ketter et al., 2014). Although the lack of a control group limits our ability to make

efficacy conclusions, decreases in depressive symptoms were evident, as noted

by IDS-C30 and QIDS-C16 score reductions. These findings, together with

improved patient functioning, are consistent with the possibility of some long-term

efficacy benefit for adjunctive armodafinil in this population. However, it is

important to keep in mind that armodafinil is not approved by the FDA for the

acute treatment or prevention of bipolar I depression.

19
Limitations

This study is limited by the open-label design and lack of control group, which

could have masked the efficacy of armodafinil with the natural course of episodes

of bipolar I depression during exit from the acute phase. Moreover, enrolling

patients who completed the double-blind acute-phase studies, this extension

study included a population that likely tolerated the study medication and

experienced meaningful improvement prior to continuing longer term treatment.

In addition, the (potentially beneficial) effect of adjunctive armodafinil on cognition

was not assessed in this study. Results from this study may have been

confounded by concomitant mood stabilizer medications. In addition, it is

possible that rare or gradually developing safety issues would not have been

observed over the 6-month study duration.

In conclusion, armodafinil was generally safe and well tolerated as adjunctive

treatment for bipolar I depression in this open-label study, with low rates of

akathisia, nausea, sedation/somnolence, weight gain, mania, and suicidality and

a lack of deterioration in anxiety or insomnia measures. Although improvements

in depressive symptoms and functioning were observed, the efficacy of

armodafinil observed during this treatment must be tempered by the open-label,

uncontrolled study design and the knowledge that 2 of 3 acute-phase, placebo-

controlled studies failed to provide a statistically significant efficacy benefit

compared with placebo, which prompted a business decision by the

manufacturer to stop clinical development of armodafinil for this indication.

20
Although armodafinil is not indicated for the treatment of bipolar I depression, the

current 6-month open-label study suggested that addition of armodafinil to

ongoing bipolar maintenance therapies was generally safe and well tolerated

(with low rates of manic switches and emergent suicidal ideation), and may have

improved depressive symptoms in at least some patients with bipolar I

depression.

Clinical Trial Registration

ClinicalTrials.gov Identifier: NCT01121536

Financial Support

This study was sponsored by Teva Pharmaceutical Industries, Ltd. (Petah Tikva,

Israel).

Conflict of Interest

Dr. J. Amchin has served as a consultant to Alkermes, AstraZeneca, BTG

International, Cephalon, Clinical Data, ClinSmart, Forest Laboratories, Gerson

Lehrman Group, Mallinckrodt Pharmaceuticals, MannKind Corporation, Orbis

Clinical, Pfizer, PharmaNet, ProPhase, ReSearch Pharmaceutical Services,

Otsuka, Regeneron, Sermo, Sepracor, Shire, Sucampo Pharmaceuticals, Taisho

21
Pharmaceuticals, Takeda, Teva Pharmaceuticals, ViroPharma, Wyeth,

YourEncore, and Yoh.

Dr. M. A. Frye has received grant support from Assurex, Janssen Research &

Development, Mayo Foundation, Myriad, National Institute of Alcohol Abuse and

Alcoholism (NIAAA), National Institute of Mental Health (NIMH), and Pfizer;

served as a Consultant for (Mayo)-Janssen Research & Development, LLC,

Mitsubishi Tanabe Pharma Corporation, Myriad, Sunovion, Supernus

Pharmaceuticals, and Teva Pharmaceuticals. Mayo Clinic has a financial interest

in Assurex Health; this technology is not referenced in this publication.

N. Gross is an employee of Teva Pharmaceuticals.

Dr. T. A. Ketter has received research funding from the Agency for Healthcare

Research and Quality, AstraZeneca, Eli Lilly, Pfizer, Sepracor, Sunovion, and

Teva Pharmaceuticals (formerly Cephalon); has served as an advisor/consultant

to Allergan, Avanir, Forest, Janssen, Merck, Sepracor, Sunovion, Quintiles, and

Teva Pharmaceuticals (formerly Cephalon); and has served as a speaker and

received honoraria from Abbott, AstraZeneca, GlaxoSmithKline, and Otsuka. Dr.

T. A. Ketter’s spouse, Nzeera Ketter, MD, is employed by Janssen, Johnson &

Johnson and has stock ownership/options with Janssen, Johnson & Johnson.

22
Acknowledgments

Medical writing assistance was provided by John H. Simmons, MD, an employee

of Peloton Advantage, LLC, and Michelle McDermott, PharmD (Newtown, PA),

and was funded by Teva Branded Pharmaceutical Products R & D, Inc. (Frazer,

PA). Teva provided a full review of the article.

This manuscript was prepared according to the International Society for Medical

Publication Professionals’ “Good Publication Practice for Communicating

Company-Sponsored Medical Research: The GPP3 Guidelines.”

Contributors

All authors contributed equally and each was involved in study design, data

acquisition, or data analysis/interpretation and in drafting or critically revising the

manuscript. All authors reviewed the final manuscript and gave approval for

submission.

23
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FIGURES CAPTIONS [black and white]

Figure 1. Patient Disposition

Figure 2. Mean Change From Baseline in IDS-C30 and QIDS-C16 Total Scores

Over 6 Months of Open-Label Armodafinil Treatment (FAS; n=859)

*Double-blind study baseline

FAS = full analysis set; IDS-C30 = 30-Item Inventory of Depressive

Symptomatology-Clinician Rated; QIDS-C16 = 16-Item Quick Inventory of

Depressive Symptomatology-Clinician Rated; SEM = standard error of the mean.

30
Table 1. Demographic and Baseline Characteristics

Characteristic All Patients (N=867)

Age, mean (SD), years 44.2 (10.96)

Female, n (%) 525 (61)

Race, n (%)

White 709 (82)

Black 118 (14)

Asian 10 (1)

American Indian or Alaskan Native 1 (<1)

Pacific Islander 1 (<1)

Other 28 (3)

Weight, mean (SD), kg 83.7 (19.75)

BMI, mean (SD), kg/m2 29.4 (6.43)

Safety Parameters, mean (SD) n=863

YMRS 3.6 (2.06)

HAM-A 12.5 (2.87)

ISI 15.8 (5.54)

Efficacy Parameters, mean (SD) n=859

IDS-C30 43.1 (7.67)

QIDS-C16 16.8 (2.71)

CGI-S 4.6 (0.59)

GAF 53.3 (7.36)

31
BMI = body mass index; CGI-S = Clinical Global Impression of Severity; GAF = Global
Assessment of Functioning Scale; HAM-A = Hamilton Anxiety Scale; IDS-C30 =30-Item Inventory
of Depressive Symptomatology-Clinician Rated; ISI = Insomnia Severity Index; QIDS-C16 = 16-
Item Quick Inventory of Depressive Symptomatology-Clinician Rated; SD = standard deviation;
YMRS = Young Mania Rating Scale.

Table 2. Most Common Adverse Events (≥2% of patients)

Patients, n (%) All Patients (N=863)

≥1 adverse event 423 (49)

Headache 96 (11)

Insomnia 49 (6)

Anxiety 39 (5)

Nausea 38 (4)

Diarrhea 32 (4)

Dizziness 20 (2)

Nasopharyngitis 18 (2)

Back pain 15 (2)

Constipation 14 (2)

32
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