6 Original article
Adjunctive lisdexamfetamine in bipolar depression: a preliminary randomized, placebo-controlled trial Susan L. McElroya,b, Brian E. Martensa,b, Nicole Moria,b, Thomas J. Bloma,b, Leah S. Casutoa, John M. Hawkinsa and Paul E. Keck Jra,b This study evaluated the efficacy and tolerability of lisdexamfetamine (LDX) in the treatment of bipolar depression. Twenty-five outpatients with bipolar I or II disorder and syndromal depression despite at least 4 weeks of stable mood stabilizer and/or antipsychotic therapy were randomized to receive LDX (N = 11) or placebo (N = 14) in an 8-week, prospective, parallel-group, double-blind study. In the primary longitudinal analysis, LDX and placebo produced similar rates of improvement in depressive symptoms as assessed by the Montgomery–Asberg Depression Scale. However, LDX was associated with a statistically significantly greater rate of improvement in self-reported depressive symptoms and daytime sleepiness, and with greater reductions in fasting levels of low-density lipoprotein and total cholesterol. In the secondary baseline-to-endpoint analysis, LDX was associated with statistically significant improvements in self-reported measures of depression, daytime sleepiness, fatigue, and binge eating, as well as with improvements in fasting levels of triglycerides and low-density lipoprotein
and total cholesterol. LDX was well tolerated and was not associated with any serious adverse events, but there was one case of suspected misuse. The small sample size (because of premature study termination by the funding sponsor) may have limited the detection of important drug–placebo differences. Larger studies on the use of psychostimulants for treatment of bipolar depression seem warranted. Int Clin Psychopharmacol 30:6–13 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Introduction
Lisdexamfetamine dimesylate (LDX; marketed as Vyvanse) is a prodrug of D-amphetamine that has been approved for the treatment of attention deficit hyperactivity disorder in children at least 6 years of age and in adults (Steer et al., 2012). Following contact with red blood cells, LDX is enzymatically cleaved to form Damphetamine, which reduces the rate of appearance and concentration of D-amphetamine in the blood and brain when compared with immediate-release D-amphetamine (Hutson et al., 2014). Thus, the subsequent increase in striatal DA efflux is less prominent and slower to attain a maximal effect as compared with that following an equimolar dose of D-amphetamine. It has been hypothesized that these pharmacokinetic and pharmacodynamic properties of LDX may impact its clinical properties. In human abuse liability studies, for example, LDX had lower drug-liking scores compared with immediate-release D-amphetamine (Steer et al., 2012). Moreover, a recent open-label study found that LDX improved anthropometric and metabolic parameters and depressive symptoms in patients with stable bipolar disorder (McIntyre et al., 2013).
Augmentation of treatment-resistant bipolar depression with classic psychostimulants (i.e. amphetamine and methylphenidate) is a commonly used strategy (Dell’Osso et al., 2013) and has been described as effective in case reports (Meyers, 1978; Bannet et al., 1980; Drimmer et al., 1983; Schaller and Behar, 1998; Adida and Azorin, 2014), case series (Davidoff and Reifenstein, 1939; Fawcett et al., 1991; Carlson et al., 2004; Lydon and El-Mallakh, 2006), and in one open trial (El-Mallakh, 2000). This strategy is further supported by the rationale that bipolar depression may be associated with deficient dopamine (DA) function (Willner, 1995; Anand et al., 2011; Mah et al., 2011), as well as by data showing that patients with treatment-resistant bipolar depression may respond to other agents that enhance DA function, including the weak DA transporter antagonists modafinil and armodafinil (Frye et al., 2007; Calabrese et al., 2010; sometimes called stimulant alternatives) and the full DA D2/D3 receptor agonist pramipexole (Goldberg et al., 2004; Zarate et al., 2004). However, use of stimulant augmentation for bipolar depression has been limited by the lack of controlled data for this indication, and by the concern for abuse, cardiovascular adverse effects, and stimulant-induced hypomanic and manic states (Wingo and Ghaemi, 2008; Salvadore et al., 2010). 0268-1315 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
International Clinical Psychopharmacology 2015, 30:6–13 Keywords: bipolar disorder, lisdexamfetamine, psychostimulants a
Lindner Center of HOPE, Mason and bDepartment of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA Correspondence to Susan L. McElroy, MD, Lindner Center of HOPE, Research Institute, 4075 Old Western Row Road, Mason, OH 45040, USA Tel: + 1 513 536 0700; fax: + 1 513 536 0709; e-mail: [email protected] Received 26 June 2014 Accepted 4 September 2014
We therefore hypothesized that LDX would be an efficacious, safe, and well-tolerated adjunctive treatment for bipolar depression and conducted a preliminary one-site, DOI: 10.1097/YIC.0000000000000051
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Lisdexamfetamine in bipolar depression McElroy et al. 7
8-week, randomized, parallel-group, double-blind, placebo-controlled, flexible-dose study of LDX in 25 outpatients with bipolar I or II disorder and syndromal depression who were inadequately responsive to optimized mood stabilizer and/or antipsychotic therapy. The primary objective was to show that LDX is superior to placebo in reducing depressive symptoms in patients with bipolar depression. The secondary objectives were to show that LDX is superior to placebo in improving associated symptoms of bipolar depression [e.g. fatigue, daytime sleepiness, food craving, binge eating, and metabolic abnormalities (McElroy and Keck, 2014)] and is safe and well tolerated in patients with bipolar depression receiving mood stabilizers and/or antipsychotics (e.g. not associated with an elevated switch rate to mania or with increased suicidality).
heart rhythm abnormality, coronary artery disease, stroke, or other serious cardiovascular problems; an ECG with significant arrhythmias or conduction abnormalities; uncontrolled hypertension (>160/100) or tachycardia (heart rate > 110); narrow angle glaucoma; Tourette’s syndrome; or current use of a monoamine oxidase inhibitor. Women who were pregnant, lactating, or of childbearing potential and not using adequate contraceptive measures were also excluded. The institutional review board at the University of Cincinnati Medical Center approved the study protocol, and the study was conducted in compliance with the Declaration of Helsinki. All patients signed approved written informed consent forms after the study procedures had been fully explained and before any study procedures were performed. Patients were enrolled from 27 January 2010 to 29 January 2014.
Methods Patient population
Study participants were outpatients at the Lindner Center of HOPE, Mason, Ohio, who were recruited by clinician referral and advertisement. Participants were included if they met the following inclusion criteria: (i) were male or female between 18 and 55 years of age, inclusive; (ii) had bipolar I or II disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. – text revision (DSM-IV-TR; American Psychiatric Association, 2000) criteria, as determined by the Structured Clinical Interview for DSM-IV-TR (First et al., 2002); and (iii) were currently experiencing a major depressive episode that was inadequately responsive to adequate mood stabilizer and/or antipsychotic therapy, with or without concomitant antidepressant therapy, received for at least 4 weeks. To be randomized, patients also had to have a score of at least 26 on the self-report version of the Inventory for Depressive Symptomatology (IDS-SR; Rush et al., 1996) and a score of at least 4 on the Clinical Global Impression for Bipolar Illness (CGI-BP) Depression Severity Scale (Spearing et al., 1997). All concomitant mood stabilizers, antipsychotics, and antidepressants had to be at stable doses for at least 4 weeks before randomization. Participants were excluded if they showed clinically significant signs of suicidality [operationalized as a score ≥ 4 on item 10 of the Montgomery–Asberg Depression Scale (MADRS; Montgomery and Asberg, 1979), a score ≥ 3 on item 18 of the IDS-SR, or a suicide attempt within the past year, as defined by the Columbia-Suicide Severity Scale (Posner et al., 2007)], had a DSM-IV-TR diagnosis of substance abuse or dependence (except nicotine dependence) within 6 months before randomization, had a baseline Young Mania Rating Scale (YMRS; Young et al., 1978) score of at least 8, or had a lifetime history of stimulant-induced mania. Other exclusion criteria were as follows: clinically unstable medical disease; a history of a structural cardiac abnormality, cardiomyopathy, serious
Study design
This was an 8-week, prospective, randomized, parallelgroup, double-blind, placebo-controlled, flexible-dose study conducted at one site. The study consisted of three phases: a 1–4-week prerandomization screening period, an 8-week double-blind treatment period; and a 4-week follow-up period. Patients were evaluated at least twice during the screening period, weekly during the 8-week treatment period, and twice during the follow-up period. All psychotropic medications that the patients were taking at study entry were continued unchanged throughout the course of the study, except in instances in which a medication required dose reduction for side effect management. An increase in the dose of baseline mood stabilizer, antipsychotic medication, or antidepressant medication or the addition of a new psychotropic medication (except for hypnotics, see below) resulted in patient termination from the protocol. All study medications were in the form of identical tablets (20 or 30 mg LDX or matching placebo) supplied in numbered containers and dispensed to the patients according to a predetermined randomization schedule. LDX was begun at 20 mg/day and increased at weekly intervals by 10 mg/day until a dose of 70 mg/day was achieved, response occurred, or side effects intervened. Study medication dosage could be decreased because of side effects. The minimum dosage of study medication allowed was 20 mg/day, the maximum dosage allowed was 70 mg/day. Concomitant hypnotic medication (e.g. zolpidem or temazepam) was allowed on an as-needed basis for the management of insomnia. Participants were randomized to receive LDX or placebo in a 1 : 1 ratio according to computer-generated coding. Randomization was balanced by the use of permuted blocks. Allocation concealment was achieved by having the research pharmacy perform the randomization,
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8 International Clinical Psychopharmacology 2015, Vol 30 No 1
package the study medication, and maintain the integrity of the blinded information throughout the trial. Outcome measures
The primary efficacy variable was the MADRS score. Secondary efficacy variables included scores on the selfreport IDS-SR (Rush et al., 1996), the Depression and Overall Severity Scales of the CGI-BP (Spearing et al., 1997), the YMRS (Young et al., 1978), the Epworth Sleepiness Scale (ESS; Johns, 1991), the Fatigue Severity Scale (FSS; Krupp et al., 1989), the Food Craving Inventory (FCI; White et al., 2002), and the Binge Eating Scale (BES; Gormally et al., 1982). Other criteria for efficacy assessment were the proportions of patients who achieved a response (≥50% reduction from the baseline MADRS score at endpoint), remission (endpoint MADRS score ≤ 12), and moderate or greater improvement on the Depression Improvement Scale of the CGIBP. Changes in metabolic variables were also evaluated, including body weight, BMI, fasting glucose level, insulin level, hemoglobin A1C level (A1C), and lipid profile, as well as changes in high-sensitivity C-reactive protein (hs-CRP) level. Safety was assessed by regular monitoring of vital signs, laboratory tests, ECGs, and assessment for adverse events. Testing for hematologic parameters, liver function tests, blood chemistry analysis, urinalysis, and drug screening tests were conducted at screening and at treatment weeks 4 and 8 (or at premature discontinuation). A physical examination was carried out at screening and at week 8 (or at premature discontinuation). Adherence with study medication was assessed with returned pill counts. Statistical methods
As no data from placebo-controlled randomized trials on use of a psychostimulant for bipolar depression were available, baseline and endpoint data from two positive studies on use of pramipexole for bipolar depression (Goldberg et al., 2004; Zarate et al., 2004) were used in the power analysis. The effect size estimates in these trials were 1.1 and 1.4, respectively. A more conservative estimate of 0.85 was used in the power analysis for the effect of treatment on MADRS score change. Using a two-sample t-test, a significance level of 0.05, and a power of 0.80, the required number in each group was found to be 23, giving a total required sample size of 46. We initially planned to enroll 50 patients with bipolar depression, but the funding sponsor terminated the study prematurely after failure of the phase 3 program on LDX in major depressive disorder (Shire, 2014). The baseline characteristics of each group were compared by using Fisher’s exact test for categorical variables and Wilcoxon’s rank sum tests for continuous variables. SAS software (version 9.2; SAS Institute Inc., Cary, North Carolina, USA) was used to carry out all analyses.
All statistical tests and confidence intervals were twosided, with a significance level of 0.05. Given the premature termination of the study and, thus, the possibility of an underpowered study, P-values at a trend level (i.e. 0.05–0.10) were also acknowledged in the efficacy analyses. The primary efficacy analysis was a longitudinal analysis comparing the rate of change of the MADRS total score during the treatment period between groups. The same analysis was applied to the secondary outcome measures. The difference in the rate of change was estimated by random regression methods, as described by Fitzmaurice et al. (2004) and Gibbons et al. (1993). We used a model for the mean of the outcome variable that included terms for treatment, time, and the treatment-by-time interaction. Time was modeled as a continuous variable, expressed as the square root of days since randomization (baseline). For the analyses of triglyceride, glucose, insulin, hemoglobin A1C, and hs-CRP levels, we used logarithmic transformations to correct for non-normality of the data. To simultaneously account for individual differences in the initial level of the outcome, the rate of change over time, and serial autocorrelation, we used the SAS procedure MIXED. These mixed models allowed for random coefficients for the intercept and/or time variables, and/or correlated error terms (chosen from compound symmetric, first-order antedependence and first-order autoregressive). The best fitting model was determined by the lowest Akaike Information Criterion corrected value. The longitudinal analyses included all available observations from all participants. Several secondary analyses were carried out. Using the last observation carried forward, baseline-to-endpoint change scores were computed for each measure and two-sample t-tests or Wilcoxon’s rank sum tests were used to compare these changes between the treatment groups. Fisher’s exact test was used to analyze the categorical response to treatment and adverse events. For other laboratory measures, the mean difference between endpoint and baseline measures was computed for each treatment group and then compared using Wilcoxon’s rank sum tests.
Results Of 90 individuals assessed for eligibility, 65 were not randomized (Fig. 1). Of the 25 patients who met the entry criteria, 11 were randomly assigned to receive LDX and 14 to receive placebo. All 25 patients had at least one postrandomization efficacy measure and safety evaluation. The two treatment groups were similar across demographic and clinical variables at baseline except the LDX group had a higher mean IDS-SR score (Table 1). There was no difference between the LDX and placebo groups in number of patients receiving lithium, valproate,
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Lisdexamfetamine in bipolar depression McElroy et al. 9
Fig. 1
90 patients assessed for
65 patients not randomized (a) Did not meet inclusion/exclusion criteria (56) (b) Lost to follow-up (8) (c) Administrative (1)∗
25 patients randomized
11 assigned to lisdexamfetamine
11 intention to treat population (a) 10 completed (b) 1 discontinued (i) Administrative (1)†
11 safety population‡
14 assigned to placebo group
14 intention to treat population (a) 11 completed (b) 3 discontinued (i) Adverse event (1) (ii) Lost to follow-up (2)
14 safety population‡
Population disposition. *Patient in screening when study was terminated. †Patient was excluded by investigator for tampering with the study medication. ‡Safety population: all randomized patients for whom at least one postbaseline safety measure was available.
lamotrigine, an antipsychotic, an antidepressant, a benzodiazepine, or a hypnotic (data not shown). Twenty-one patients completed the 8-week treatment trial. Four patients (one receiving LDX and three placebo) did not complete all 8 weeks of treatment (Fisher’s exact test, P = 0.60). The patient receiving LDX who did not complete the trial was excluded by the investigators because he tampered with the study medication. The primary efficacy analysis showed that both groups improved similarly on the MADRS (Table 2). By contrast, patients receiving LDX showed a significantly greater rate of reduction than did patients receiving placebo on the IDS-SR and ESS. These LDX-treated patients also had trend-level greater reductions on the FSS and BES. There were no differences in the rates of change in scores on the CGI-BP-Depression or Overall Severity Scales, YMRS, or FCI. Findings from the secondary analysis of baseline-toendpoint changes were similar. There were no differences between LDX and placebo groups in changes in scores on the MADRS, YMRS, or FCI. Patients receiving LDX, however, showed a statistically significant improvement on the IDS-SR, ESS, FSS, and BES, as well as improvement that trended toward significance on
the CGI-BP-Depression and Overall Severity scales. The associated standard effect sizes were moderate to large (d = 0.75–1.18). Patients in the LDX group were more likely to respond, attain remission, and show at least moderate improvement (Table 3). Although observed at a trend level, the odds ratio estimate for the effect of LDX on categorical improvement on the CGI-BPDepression Improvement Scale was large [4.8 (95% confidence interval: 0.9, 26.8)]. With regard to metabolic outcomes, LDX produced significant reductions in fasting LDL and total cholesterol levels in the primary and secondary analyses (Table 2). Moreover, in the secondary analysis, LDX produced significant decreases in fasting triglyceride levels. Although not statistically significant, trends were observed for greater reductions in insulin levels, weight, and BMI in the LDX group as compared with the placebo group. The mean average daily dose of LDX was 38.8 mg; the mean final daily dose was 52.7 mg. Only one participant (receiving placebo) administered a hypnotic during the trial for insomnia. The most common adverse events associated with LDX were headache, insomnia, dry mouth, jittery feeling, and
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10 International Clinical Psychopharmacology 2015, Vol 30 No 1
Table 1
Baseline demographic information and clinical characteristics by treatment groupa
Sex (number of women) [n (%)] Age (years) Race (number of Whites) [n (%)] White African-American Bipolar disorder type (number with type I) [n (%)] Rapid cycling [n (%)] Age at onset of depression (n = 24) Age at onset of mania/hypomania (n = 24) Prior hospitalization for depression (n = 24) [n (%)] Prior suicide attempt (n = 24) [n (%)] Anxiety disorder lifetime (n = 24) [n (%)] Substance use disorder lifetime (n = 24) [n (%)] Hypertension [n (%)] Diabetes [n (%)] Obesity [n (%)] MADRS IDS-SR CGI-severity-depression CGI-severity-overall CGI-severity-mania YMRS ESS FSS BES FCI Weight (kg) BMI (kg/m2) Triglycerides Total cholesterol LDL cholesterol HDL cholesterol Glucose Systolic BP (mmHg) Diastolic BP (mmHg) Pulse (bpm)
Total (n = 25)
LDX (n = 11)
Placebo (n = 14)
P-valueb
17 (68) 43.0 (9.7)
8 (73) 42.9 (9.1)
9 (64) 43.1 (10.5)
1.00 0.98 1.00
23 2 9 14 18.8 24.0 12 11 18 10 8 2 19 24.7 38.0 4.7 4.7 1.3 4.3 9.5 49.0 31.7 2.4 97.4 34.5 167.1 197.4 111.0 51.4 92.6 120.6 79.8 76.8
(92) (8) (36) (56) (7.9) (9.9) (50) (46) (75) (42) (32) (8) (76) (4.9) (7.7) (0.5) (0.5) (0.5) (2.3) (4.3) (8.7) (10.0) (0.6) (24.1) (7.1) (93.9) (38.8) (30.2) (13.3) (26.4) (12.4) (7.9) (11.6)
10 1 4 7 16.1 20.1 4 6 7 4 2 0 8 24.4 41.0 4.8 4.8 1.4 4.2 9.6 50.2 31.2 2.2 98.7 34.6 149.5 198.3 115.9 52.6 85.5 121.4 78.5 73.1
(91) (9) (36) (64) (4.6) (7.6) (36) (55) (64) (36) (18) (0) (73) (5.5) (6.1) (0.4) (0.4) (0.5) (2.3) (3.7) (7.5) (11.4) (0.7) (25.0) (8.5) (67.5) (31.0) (30.1) (15.6) (6.1) (9.0) (7.0) (12.4)
13 1 5 7 20.8 26.9 8 5 11 6 6 2 11 24.9 35.7 4.6 4.6 1.3 4.4 9.4 48.0 32.1 2.6 96.4 34.5 180.9 196.8 106.8 50.4 98.2 120.0 80.7 79.8
(93) (7) (36) (50) (9.2) (10.7) (62) (38) (85) (46) (43) (14) (79) (4.5) (8.3) (0.5) (0.5) (0.5) (2.3) (4.8) (9.9) (9.3) (0.6) (24.2) (6.2) (111.0) (45.1) (31.0) (11.7) (34.4) (14.9) (8.6) (10.4)
1.00 0.69 0.18 0.08 0.41 0.68 0.36 0.70 0.23 0.49 1.00 0.85 0.04 0.36 0.36 0.71 0.87 0.83 0.60 0.91 0.29 1.00 0.81 0.68 0.83 0.50 1.00 0.27 0.85 0.49 0.30
BES, Binge Eating Scale; BP, blood pressure; CGI, Clinical Global Impression; ESS, Epworth Sleepiness Scale; FCI, Food Craving Inventory; FSS, Fatigue Severity Scale; HDL, high-density lipoprotein; IDS-SR, self-report version of the Inventory for Depressive Symptomatology; LDL, low-density lipoprotein; LDX, lisdexamfetamine; MADRS, Montgomery–Asberg Depression Scale; YMRS, Young Mania Rating Scale. a Mean (SD) or n (%) shown. b Fisher’s exact tests or Wilcoxon’s rank sum tests were used to determine statistical differences between the LDX and placebo groups.
tremor (Table 4). Dry mouth and feeling jittery were statistically significantly more common among patients receiving LDX than among those receiving placebo. Only one patient discontinued the study drug (placebo) due to an adverse event (exacerbation of migraine headaches). No patient receiving LDX experienced a serious adverse event. The participant who was excluded by the investigators for medication tampering denied misuse of the study drug. There were no instances of suicidality, hypomania, or mania. All patients had a CGIBP-Mania Severity score of 2 or lower at endpoint. There were no significant changes in vital signs, other physical examination findings, ECG findings, or laboratory test findings.
Discussion In this small study of 25 patients with bipolar depression, adjunctive LDX was not superior to placebo in reducing depressive symptoms as assessed by MADRS. However, compared with placebo, LDX produced significantly greater reductions in self-reported measures of depressive symptoms and excessive daytime sleepiness,
significantly larger decreases in fasting levels of LDL and total cholesterol, and trend-level improvements in fatigue and binge eating. In the secondary analysis, LDX was found to be superior to placebo in reducing self-reported depressive symptoms, excessive daytime sleepiness, fatigue, binge eating behavior, triglyceride levels, LDL cholesterol levels, and total cholesterol levels, as well as in decreasing overall severity of depressive and bipolar symptoms at a trend level. The odds ratio estimate for the effect of LDX on categorical global improvement in depressive symptoms was large. Finally, LDX was well tolerated. The most common side effects were dry mouth, feeling jittery, and nausea. There were no instances of suicidality or hypomania/mania, but one patient receiving LDX was suspected of misusing the drug. Although extremely preliminary, these findings are consistent with open-label reports of successful treatment of bipolar depression with methylphenidate and Damphetamine, as well as with findings that LDX may improve metabolic parameters in patients with bipolar disorder (McIntyre et al., 2013). The lack of manic or hypomanic switch is consistent with findings from
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Lisdexamfetamine in bipolar depression McElroy et al. 11
Table 2
Primary (longitudinal) and secondary (endpoint) analyses of each outcome measure (N = 25) Longitudinal analysis
Outcome measure
a
Mean group difference (95% CI)
MADRS IDS-SR CGI-severity-depression CGI-severity-overall CGI-severity-mania YMRS ESS FSS BES FCI Weight (kg) BMI (kg/m2) Triglycerides Total cholesterol LDL cholesterol HDL cholesterol Glucose Insulin Hemoglobin A1C Hs-CRP Systolic BP (mmHg) Diastolic BP (mmHg) Pulse (bpm)
− 2.7 − 10.3 − 0.9 − 0.9 − 0.2 − 0.4 − 4.4 − 11.7 −6 − 0.1 − 2.1 − 0.7 0.7 − 30.6 − 15.9 − 0.1 1.0 0.5 1.0 1.2
(− 10.2, 4.7) (− 20.1, − 0.4) (− 2, 0.2) (− 2, 0.2) (− 0.5, 0.1) (− 2.7, 1.9) (− 7.5, − 1.3) (− 25.8, 2.3) (− 12.3, 0.4) (− 0.4, 0.3) (− 4.2, 0.1) (− 1.5, 0) (0.5, 1.1)d (− 49.7, − 11.4) (− 30.7, − 1.1) (− 4.6, 4.4) (0.9, 1.2)d (0.2, 1)d (1, 1)d (0.6, 2.4)d
Endpoint analysis P-value 0.47 0.04 0.12 0.11 0.29 0.72 < 0.01 0.10 0.07 0.77 0.06 0.06 0.08 < 0.01 0.04 0.98 0.64 0.06 0.99 0.66
Mean group difference (95% CI)b − 3.1 − 11.3 − 0.9 − 0.9 0.0 0.2 − 4.0 − 12.4 − 6.0 0.0 − 2.3 − 0.8 − 64.5 − 31.5 − 16.8 − 1.4 7.6 − 16.6 0.0 2.4 0.5 1.0 7.1
(− 11.0, 4.7) (− 20.3, − 2.4) (− 1.9, 0.1) (− 1.9, 0.1) (− 0.4, 0.4) (− 2.7, 3.0) (− 6.8, − 1.2) (− 23.8, − 1.0) (− 12.4, 0.3) (− 0.4, 0.3) (− 4.4, − 0.3) (− 1.5, − 0.1) (− 141.9, 12.9) (− 51.8, − 11.2) (− 32.3, − 1.3) (− 8.0, 5.2) (− 9.3, 24.4) (− 35.4, 2.2) (− 0.1,0.2) (− 2.5, 7.2) (− 7.8, 8.8) (− 4.6, 6.5) (− 2.8, 17.1)
P-value
Effect sizec
0.42 0.02 0.09 0.09 0.91 0.91 < 0.01 0.01 0.03 0.82 0.07 0.07 0.03 < 0.01 0.04 0.97 0.53 0.09 0.46 0.46 0.90 0.72 0.15
0.33 1.05 0.75 0.75 0.00 − 0.06 1.18 0.92 0.79 0.00 0.96 0.97 0.74 1.39 0.99 0.19 − 0.40 0.81 0.00 − 0.45 − 0.05 − 0.15 − 0.60
BES, Binge Eating Scale; BP, blood pressure; CGI, Clinical Global Impression; CI, confidence interval; ESS, Epworth Sleepiness Scale; FCI, Food Craving Inventory; FSS, Fatigue Severity Scale; HDL, high-density lipoprotein; Hs-CRP, high-sensitivity C-reactive protein; IDS-SR, self-report version of the Inventory for Depressive Symptomatology; LDL, low-density lipoprotein; LDX, lisdexamfetamine; MADRS, Montgomery–Asberg Depression Scale; YMRS, Young Mania Rating Scale. a Group difference = (LDXweek 8 − LDXbaseline) − (Placeboweek 8 − Placebobaseline). b Group difference = (LDXendpoint − LDXbaseline) − (Placeboendpoint − Placebobaseline); last observation used for endpoint. c Cohen’s d; positive value indicates greater reduction in the LDX group. d Log transformation used; table shows original scale and equals ratio of (LDXweek 8/LDXbaseline) to (Placeboweek8/Placebobaseline).
Table 3
Categorical response by treatment group
Response definition MADRS response (≥50% reduction) MADRS remission (MADRS ≤ 12) CGI-improvement-overall response (1 or 2) CGI-improvement-depression response (1 or 2)
LDX (n = 11) [n (%)]
Placebo (n = 14) [n (%)]
Odds ratio (95% CI)
P-value
6 (55) 6 (55) 8 (73)
4 (29) 4 (29) 5 (36)
3.0 (0.6, 15.8) 3.0 (0.6, 15.8) 4.8 (0.9, 26.8)
0.24 0.24 0.07
8 (73)
5 (36)
4.8 (0.9, 26.8)
0.07
CGI, Clinical Global Impression; CI, confidence interval; LDX, lisdexamfetamine; MADRS, Montgomery–Asberg Depression Scale.
randomized controlled trials in patients with bipolar disorder and comorbid attention deficit hyperactivity disorder, in whom stimulants did not cause worsening of mood symptoms (Scheffer et al., 2005; Findling et al., 2007). Several limitations of this study should be considered. The most important is that because of the small sample size (because of premature termination by the funding sponsor), the study may have been underpowered to detect important therapeutic or adverse effects. Conversely, positive findings, especially those at trend levels, could reflect type 1 errors and should not be over interpreted. In addition, although the two treatment groups were balanced on most variables, the LDX group had a higher baseline mean IDS-SR score. Thus, the group receiving LDX may have shown more improvement on this outcome variable because there was more room for change. Another limitation is that because the
duration was only 8 weeks, findings cannot be generalized to longer periods of treatment. Furthermore, as bipolar patients with certain medical comorbidities or stimulant abuse were excluded, the findings cannot be generalized to these populations. In summary, in an 8-week trial in 25 outpatients with inadequately responsive bipolar I or II depression, adjunctive LDX was not superior to placebo in improving clinician-rated depressive symptoms. However, LDX was superior to placebo in reducing self-reported measures of depressive symptomatology, excessive daytime sleepiness, fatigue, and binge eating, and in improving some metabolic variables. Moreover, except for one instance of probable misuse, LDX was well tolerated. Further trials of LDX and other psychostimulants for the treatment of bipolar depression seem warranted.
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12 International Clinical Psychopharmacology 2015, Vol 30 No 1
Adverse events reported by two or more patients by treatment group
an effective amount of tramadol to an individual, filed 25 March 1999 and approved 14 March 2002. For the remaining authors, there are no conflicts of interest.
Table 4
Adverse event
Total (n = 25) [n (%)]
Headache Insomnia Decreased appetite Dry mouth Feeling jittery Fatigue Nausea Pyrexia (fever, increased body temperature) Tremor Anxiety Diarrhea Irritability Palpitations Gastroenteritis Sinus congestion Strep throat Upper respiratory infection symptoms
LDX (n = 11) [n (%)]
Placebo (n = 14) [n (%)]
P-value
7 5 4 4 4 3 3 3
(28) (20) (16) (16) (16) (12) (12) (12)
5 4 2 4 4 1 2 2
(45) (36) (18) (36) (36) (9) (18) (18)
2 1 2 0 0 2 1 1
(14) (7) (14) (0) (0) (14) (7) (7)
0.18 0.13 1.00 0.03 0.03 1.00 0.56 0.56
3 2 2 2 2 2 2 2 2
(12) (8) (8) (8) (8) (8) (8) (8) (8)
3 2 1 2 1 0 2 1 1
(27) (18) (9) (18) (9) (0) (18) (9) (9)
0 0 1 0 1 2 0 1 1
(0) (0) (7) (0) (7) (14) (0) (7) (7)
0.07 0.18 1.00 0.18 1.00 0.49 0.18 1.00 1.00
LDX, lisdexamfetamine.
Acknowledgements The authors would like to acknowledge Genie Groff for manuscript preparation. Clinical Trials.gov Identifier: NCT01093963. This study was supported by a grant from Shire Inc. Conflicts of interest
Dr McElroy is a consultant to, or member of, the scientific advisory boards, and/or a principal or co-investigator on research studies sponsored by the Agency for Healthcare Research & Quality (AHRQ), Alkermes, Bracket, Cephalon, F. Hoffman-La Roche Ltd., Forrest Laboratories, Marriott Foundation, MedAvante, National Institutes of Mental Health, Naurex, Novo Nordisk, Orexigen Therapeutics, Shire, Sunovion, and Takeda Pharmaceutical Company. She is also inventor on the US Patent No. 6,323,236 B2, Use of sulfamate derivatives for treating impulse control disorders, and, along with the patient’s assignee, University of Cincinnati, Cincinnati, Ohio, USA, has received payment from Johnson & Johnson Pharmaceutical Research & Development L.L.C., which has exclusive rights under the patent, filed 18 February 2000 and approved 27 November 27 2001. Dr Keck is a consultant to, or member of, the scientific advisory boards, and/or a principal or co-investigator on research studies sponsored by Alkermes, Forest, Cephalon, Marriott Foundation, National Institute of Mental Health (NIMH), Shire, and Sunovion. He is also an inventor on the US Patent No. 6,387,956: Shapira NA, Goldsmith TD, Keck, PE Jr (University of Cincinnati), Methods of treating obsessive-compulsive spectrum disorder comprises the step of administering
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Lisdexamfetamine in bipolar depression McElroy et al. 13
McElroy SL, Keck PE Jr (2014). Metabolic syndrome in bipolar disorder: a review with a focus on bipolar depression. J Clin Psychiatry 75:46–61. McIntyre RS, Alsuwaidan M, Soczynska JK, Szpindel I, Bilkey TS, Almagor D, et al. (2013). The effect of lisdexamfetamine dimesylate on body weight, metabolic parameters, and attention deficit hyperactivity disorder symptomatology in adults with bipolar I/II disorder. Hum Psychopharmacol 28:421–427. Meyers B (1978). Treatment of imipramine-resistant depression and lithiumrefractory mania through drug interactions. Am J Psychiatry 135:1420–1421. Montgomery SA, Asberg M (1979). A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389. Posner K, Oquendo MA, Gould M, Stanley B, Davies M (2007). Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry 164:1035–1043. Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH (1996). The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med 26:477–486. Salvadore G, Quiroz JA, Machado-Vieira R, Henter ID, Manji HK, Zarate CA Jr (2010). The neurobiology of the switch process in bipolar disorder: a review. J Clin Psychiatry 71:1488–1501. Schaller JL, Behar D (1998). Treatment of a case of comorbid bipolar disorder and attention-deficit/hyperactivity disorder. J Neuropsychiatry Clin Neurosci 10:235–236. Scheffer RE, Kowatch RA, Carmody T, Rush AJ (2005). Randomized, placebocontrolled trial of mixed amphetamine salts for symptoms of comorbid ADHD
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Adjunctive lisdexamfetamine in bipolar depression: a preliminary randomized, placebo-controlled trial Susan L. McElroya,b, Brian E. Martensa,b, Nicole Moria,b, Thomas J. Bloma,b, Leah S. Casutoa, John M. Hawkinsa and Paul E. Keck Jra,b This study evaluated the efficacy and tolerability of lisdexamfetamine (LDX) in the treatment of bipolar depression. Twenty-five outpatients with bipolar I or II disorder and syndromal depression despite at least 4 weeks of stable mood stabilizer and/or antipsychotic therapy were randomized to receive LDX (N = 11) or placebo (N = 14) in an 8-week, prospective, parallel-group, double-blind study. In the primary longitudinal analysis, LDX and placebo produced similar rates of improvement in depressive symptoms as assessed by the Montgomery–Asberg Depression Scale. However, LDX was associated with a statistically significantly greater rate of improvement in self-reported depressive symptoms and daytime sleepiness, and with greater reductions in fasting levels of low-density lipoprotein and total cholesterol. In the secondary baseline-to-endpoint analysis, LDX was associated with statistically significant improvements in self-reported measures of depression, daytime sleepiness, fatigue, and binge eating, as well as with improvements in fasting levels of triglycerides and low-density lipoprotein
and total cholesterol. LDX was well tolerated and was not associated with any serious adverse events, but there was one case of suspected misuse. The small sample size (because of premature study termination by the funding sponsor) may have limited the detection of important drug–placebo differences. Larger studies on the use of psychostimulants for treatment of bipolar depression seem warranted. Int Clin Psychopharmacol 30:6–13 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Introduction
Lisdexamfetamine dimesylate (LDX; marketed as Vyvanse) is a prodrug of D-amphetamine that has been approved for the treatment of attention deficit hyperactivity disorder in children at least 6 years of age and in adults (Steer et al., 2012). Following contact with red blood cells, LDX is enzymatically cleaved to form Damphetamine, which reduces the rate of appearance and concentration of D-amphetamine in the blood and brain when compared with immediate-release D-amphetamine (Hutson et al., 2014). Thus, the subsequent increase in striatal DA efflux is less prominent and slower to attain a maximal effect as compared with that following an equimolar dose of D-amphetamine. It has been hypothesized that these pharmacokinetic and pharmacodynamic properties of LDX may impact its clinical properties. In human abuse liability studies, for example, LDX had lower drug-liking scores compared with immediate-release D-amphetamine (Steer et al., 2012). Moreover, a recent open-label study found that LDX improved anthropometric and metabolic parameters and depressive symptoms in patients with stable bipolar disorder (McIntyre et al., 2013).
Augmentation of treatment-resistant bipolar depression with classic psychostimulants (i.e. amphetamine and methylphenidate) is a commonly used strategy (Dell’Osso et al., 2013) and has been described as effective in case reports (Meyers, 1978; Bannet et al., 1980; Drimmer et al., 1983; Schaller and Behar, 1998; Adida and Azorin, 2014), case series (Davidoff and Reifenstein, 1939; Fawcett et al., 1991; Carlson et al., 2004; Lydon and El-Mallakh, 2006), and in one open trial (El-Mallakh, 2000). This strategy is further supported by the rationale that bipolar depression may be associated with deficient dopamine (DA) function (Willner, 1995; Anand et al., 2011; Mah et al., 2011), as well as by data showing that patients with treatment-resistant bipolar depression may respond to other agents that enhance DA function, including the weak DA transporter antagonists modafinil and armodafinil (Frye et al., 2007; Calabrese et al., 2010; sometimes called stimulant alternatives) and the full DA D2/D3 receptor agonist pramipexole (Goldberg et al., 2004; Zarate et al., 2004). However, use of stimulant augmentation for bipolar depression has been limited by the lack of controlled data for this indication, and by the concern for abuse, cardiovascular adverse effects, and stimulant-induced hypomanic and manic states (Wingo and Ghaemi, 2008; Salvadore et al., 2010). 0268-1315 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
International Clinical Psychopharmacology 2015, 30:6–13 Keywords: bipolar disorder, lisdexamfetamine, psychostimulants a
Lindner Center of HOPE, Mason and bDepartment of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA Correspondence to Susan L. McElroy, MD, Lindner Center of HOPE, Research Institute, 4075 Old Western Row Road, Mason, OH 45040, USA Tel: + 1 513 536 0700; fax: + 1 513 536 0709; e-mail: [email protected] Received 26 June 2014 Accepted 4 September 2014
We therefore hypothesized that LDX would be an efficacious, safe, and well-tolerated adjunctive treatment for bipolar depression and conducted a preliminary one-site, DOI: 10.1097/YIC.0000000000000051
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Lisdexamfetamine in bipolar depression McElroy et al. 7
8-week, randomized, parallel-group, double-blind, placebo-controlled, flexible-dose study of LDX in 25 outpatients with bipolar I or II disorder and syndromal depression who were inadequately responsive to optimized mood stabilizer and/or antipsychotic therapy. The primary objective was to show that LDX is superior to placebo in reducing depressive symptoms in patients with bipolar depression. The secondary objectives were to show that LDX is superior to placebo in improving associated symptoms of bipolar depression [e.g. fatigue, daytime sleepiness, food craving, binge eating, and metabolic abnormalities (McElroy and Keck, 2014)] and is safe and well tolerated in patients with bipolar depression receiving mood stabilizers and/or antipsychotics (e.g. not associated with an elevated switch rate to mania or with increased suicidality).
heart rhythm abnormality, coronary artery disease, stroke, or other serious cardiovascular problems; an ECG with significant arrhythmias or conduction abnormalities; uncontrolled hypertension (>160/100) or tachycardia (heart rate > 110); narrow angle glaucoma; Tourette’s syndrome; or current use of a monoamine oxidase inhibitor. Women who were pregnant, lactating, or of childbearing potential and not using adequate contraceptive measures were also excluded. The institutional review board at the University of Cincinnati Medical Center approved the study protocol, and the study was conducted in compliance with the Declaration of Helsinki. All patients signed approved written informed consent forms after the study procedures had been fully explained and before any study procedures were performed. Patients were enrolled from 27 January 2010 to 29 January 2014.
Methods Patient population
Study participants were outpatients at the Lindner Center of HOPE, Mason, Ohio, who were recruited by clinician referral and advertisement. Participants were included if they met the following inclusion criteria: (i) were male or female between 18 and 55 years of age, inclusive; (ii) had bipolar I or II disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. – text revision (DSM-IV-TR; American Psychiatric Association, 2000) criteria, as determined by the Structured Clinical Interview for DSM-IV-TR (First et al., 2002); and (iii) were currently experiencing a major depressive episode that was inadequately responsive to adequate mood stabilizer and/or antipsychotic therapy, with or without concomitant antidepressant therapy, received for at least 4 weeks. To be randomized, patients also had to have a score of at least 26 on the self-report version of the Inventory for Depressive Symptomatology (IDS-SR; Rush et al., 1996) and a score of at least 4 on the Clinical Global Impression for Bipolar Illness (CGI-BP) Depression Severity Scale (Spearing et al., 1997). All concomitant mood stabilizers, antipsychotics, and antidepressants had to be at stable doses for at least 4 weeks before randomization. Participants were excluded if they showed clinically significant signs of suicidality [operationalized as a score ≥ 4 on item 10 of the Montgomery–Asberg Depression Scale (MADRS; Montgomery and Asberg, 1979), a score ≥ 3 on item 18 of the IDS-SR, or a suicide attempt within the past year, as defined by the Columbia-Suicide Severity Scale (Posner et al., 2007)], had a DSM-IV-TR diagnosis of substance abuse or dependence (except nicotine dependence) within 6 months before randomization, had a baseline Young Mania Rating Scale (YMRS; Young et al., 1978) score of at least 8, or had a lifetime history of stimulant-induced mania. Other exclusion criteria were as follows: clinically unstable medical disease; a history of a structural cardiac abnormality, cardiomyopathy, serious
Study design
This was an 8-week, prospective, randomized, parallelgroup, double-blind, placebo-controlled, flexible-dose study conducted at one site. The study consisted of three phases: a 1–4-week prerandomization screening period, an 8-week double-blind treatment period; and a 4-week follow-up period. Patients were evaluated at least twice during the screening period, weekly during the 8-week treatment period, and twice during the follow-up period. All psychotropic medications that the patients were taking at study entry were continued unchanged throughout the course of the study, except in instances in which a medication required dose reduction for side effect management. An increase in the dose of baseline mood stabilizer, antipsychotic medication, or antidepressant medication or the addition of a new psychotropic medication (except for hypnotics, see below) resulted in patient termination from the protocol. All study medications were in the form of identical tablets (20 or 30 mg LDX or matching placebo) supplied in numbered containers and dispensed to the patients according to a predetermined randomization schedule. LDX was begun at 20 mg/day and increased at weekly intervals by 10 mg/day until a dose of 70 mg/day was achieved, response occurred, or side effects intervened. Study medication dosage could be decreased because of side effects. The minimum dosage of study medication allowed was 20 mg/day, the maximum dosage allowed was 70 mg/day. Concomitant hypnotic medication (e.g. zolpidem or temazepam) was allowed on an as-needed basis for the management of insomnia. Participants were randomized to receive LDX or placebo in a 1 : 1 ratio according to computer-generated coding. Randomization was balanced by the use of permuted blocks. Allocation concealment was achieved by having the research pharmacy perform the randomization,
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8 International Clinical Psychopharmacology 2015, Vol 30 No 1
package the study medication, and maintain the integrity of the blinded information throughout the trial. Outcome measures
The primary efficacy variable was the MADRS score. Secondary efficacy variables included scores on the selfreport IDS-SR (Rush et al., 1996), the Depression and Overall Severity Scales of the CGI-BP (Spearing et al., 1997), the YMRS (Young et al., 1978), the Epworth Sleepiness Scale (ESS; Johns, 1991), the Fatigue Severity Scale (FSS; Krupp et al., 1989), the Food Craving Inventory (FCI; White et al., 2002), and the Binge Eating Scale (BES; Gormally et al., 1982). Other criteria for efficacy assessment were the proportions of patients who achieved a response (≥50% reduction from the baseline MADRS score at endpoint), remission (endpoint MADRS score ≤ 12), and moderate or greater improvement on the Depression Improvement Scale of the CGIBP. Changes in metabolic variables were also evaluated, including body weight, BMI, fasting glucose level, insulin level, hemoglobin A1C level (A1C), and lipid profile, as well as changes in high-sensitivity C-reactive protein (hs-CRP) level. Safety was assessed by regular monitoring of vital signs, laboratory tests, ECGs, and assessment for adverse events. Testing for hematologic parameters, liver function tests, blood chemistry analysis, urinalysis, and drug screening tests were conducted at screening and at treatment weeks 4 and 8 (or at premature discontinuation). A physical examination was carried out at screening and at week 8 (or at premature discontinuation). Adherence with study medication was assessed with returned pill counts. Statistical methods
As no data from placebo-controlled randomized trials on use of a psychostimulant for bipolar depression were available, baseline and endpoint data from two positive studies on use of pramipexole for bipolar depression (Goldberg et al., 2004; Zarate et al., 2004) were used in the power analysis. The effect size estimates in these trials were 1.1 and 1.4, respectively. A more conservative estimate of 0.85 was used in the power analysis for the effect of treatment on MADRS score change. Using a two-sample t-test, a significance level of 0.05, and a power of 0.80, the required number in each group was found to be 23, giving a total required sample size of 46. We initially planned to enroll 50 patients with bipolar depression, but the funding sponsor terminated the study prematurely after failure of the phase 3 program on LDX in major depressive disorder (Shire, 2014). The baseline characteristics of each group were compared by using Fisher’s exact test for categorical variables and Wilcoxon’s rank sum tests for continuous variables. SAS software (version 9.2; SAS Institute Inc., Cary, North Carolina, USA) was used to carry out all analyses.
All statistical tests and confidence intervals were twosided, with a significance level of 0.05. Given the premature termination of the study and, thus, the possibility of an underpowered study, P-values at a trend level (i.e. 0.05–0.10) were also acknowledged in the efficacy analyses. The primary efficacy analysis was a longitudinal analysis comparing the rate of change of the MADRS total score during the treatment period between groups. The same analysis was applied to the secondary outcome measures. The difference in the rate of change was estimated by random regression methods, as described by Fitzmaurice et al. (2004) and Gibbons et al. (1993). We used a model for the mean of the outcome variable that included terms for treatment, time, and the treatment-by-time interaction. Time was modeled as a continuous variable, expressed as the square root of days since randomization (baseline). For the analyses of triglyceride, glucose, insulin, hemoglobin A1C, and hs-CRP levels, we used logarithmic transformations to correct for non-normality of the data. To simultaneously account for individual differences in the initial level of the outcome, the rate of change over time, and serial autocorrelation, we used the SAS procedure MIXED. These mixed models allowed for random coefficients for the intercept and/or time variables, and/or correlated error terms (chosen from compound symmetric, first-order antedependence and first-order autoregressive). The best fitting model was determined by the lowest Akaike Information Criterion corrected value. The longitudinal analyses included all available observations from all participants. Several secondary analyses were carried out. Using the last observation carried forward, baseline-to-endpoint change scores were computed for each measure and two-sample t-tests or Wilcoxon’s rank sum tests were used to compare these changes between the treatment groups. Fisher’s exact test was used to analyze the categorical response to treatment and adverse events. For other laboratory measures, the mean difference between endpoint and baseline measures was computed for each treatment group and then compared using Wilcoxon’s rank sum tests.
Results Of 90 individuals assessed for eligibility, 65 were not randomized (Fig. 1). Of the 25 patients who met the entry criteria, 11 were randomly assigned to receive LDX and 14 to receive placebo. All 25 patients had at least one postrandomization efficacy measure and safety evaluation. The two treatment groups were similar across demographic and clinical variables at baseline except the LDX group had a higher mean IDS-SR score (Table 1). There was no difference between the LDX and placebo groups in number of patients receiving lithium, valproate,
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Lisdexamfetamine in bipolar depression McElroy et al. 9
Fig. 1
90 patients assessed for
65 patients not randomized (a) Did not meet inclusion/exclusion criteria (56) (b) Lost to follow-up (8) (c) Administrative (1)∗
25 patients randomized
11 assigned to lisdexamfetamine
11 intention to treat population (a) 10 completed (b) 1 discontinued (i) Administrative (1)†
11 safety population‡
14 assigned to placebo group
14 intention to treat population (a) 11 completed (b) 3 discontinued (i) Adverse event (1) (ii) Lost to follow-up (2)
14 safety population‡
Population disposition. *Patient in screening when study was terminated. †Patient was excluded by investigator for tampering with the study medication. ‡Safety population: all randomized patients for whom at least one postbaseline safety measure was available.
lamotrigine, an antipsychotic, an antidepressant, a benzodiazepine, or a hypnotic (data not shown). Twenty-one patients completed the 8-week treatment trial. Four patients (one receiving LDX and three placebo) did not complete all 8 weeks of treatment (Fisher’s exact test, P = 0.60). The patient receiving LDX who did not complete the trial was excluded by the investigators because he tampered with the study medication. The primary efficacy analysis showed that both groups improved similarly on the MADRS (Table 2). By contrast, patients receiving LDX showed a significantly greater rate of reduction than did patients receiving placebo on the IDS-SR and ESS. These LDX-treated patients also had trend-level greater reductions on the FSS and BES. There were no differences in the rates of change in scores on the CGI-BP-Depression or Overall Severity Scales, YMRS, or FCI. Findings from the secondary analysis of baseline-toendpoint changes were similar. There were no differences between LDX and placebo groups in changes in scores on the MADRS, YMRS, or FCI. Patients receiving LDX, however, showed a statistically significant improvement on the IDS-SR, ESS, FSS, and BES, as well as improvement that trended toward significance on
the CGI-BP-Depression and Overall Severity scales. The associated standard effect sizes were moderate to large (d = 0.75–1.18). Patients in the LDX group were more likely to respond, attain remission, and show at least moderate improvement (Table 3). Although observed at a trend level, the odds ratio estimate for the effect of LDX on categorical improvement on the CGI-BPDepression Improvement Scale was large [4.8 (95% confidence interval: 0.9, 26.8)]. With regard to metabolic outcomes, LDX produced significant reductions in fasting LDL and total cholesterol levels in the primary and secondary analyses (Table 2). Moreover, in the secondary analysis, LDX produced significant decreases in fasting triglyceride levels. Although not statistically significant, trends were observed for greater reductions in insulin levels, weight, and BMI in the LDX group as compared with the placebo group. The mean average daily dose of LDX was 38.8 mg; the mean final daily dose was 52.7 mg. Only one participant (receiving placebo) administered a hypnotic during the trial for insomnia. The most common adverse events associated with LDX were headache, insomnia, dry mouth, jittery feeling, and
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10 International Clinical Psychopharmacology 2015, Vol 30 No 1
Table 1
Baseline demographic information and clinical characteristics by treatment groupa
Sex (number of women) [n (%)] Age (years) Race (number of Whites) [n (%)] White African-American Bipolar disorder type (number with type I) [n (%)] Rapid cycling [n (%)] Age at onset of depression (n = 24) Age at onset of mania/hypomania (n = 24) Prior hospitalization for depression (n = 24) [n (%)] Prior suicide attempt (n = 24) [n (%)] Anxiety disorder lifetime (n = 24) [n (%)] Substance use disorder lifetime (n = 24) [n (%)] Hypertension [n (%)] Diabetes [n (%)] Obesity [n (%)] MADRS IDS-SR CGI-severity-depression CGI-severity-overall CGI-severity-mania YMRS ESS FSS BES FCI Weight (kg) BMI (kg/m2) Triglycerides Total cholesterol LDL cholesterol HDL cholesterol Glucose Systolic BP (mmHg) Diastolic BP (mmHg) Pulse (bpm)
Total (n = 25)
LDX (n = 11)
Placebo (n = 14)
P-valueb
17 (68) 43.0 (9.7)
8 (73) 42.9 (9.1)
9 (64) 43.1 (10.5)
1.00 0.98 1.00
23 2 9 14 18.8 24.0 12 11 18 10 8 2 19 24.7 38.0 4.7 4.7 1.3 4.3 9.5 49.0 31.7 2.4 97.4 34.5 167.1 197.4 111.0 51.4 92.6 120.6 79.8 76.8
(92) (8) (36) (56) (7.9) (9.9) (50) (46) (75) (42) (32) (8) (76) (4.9) (7.7) (0.5) (0.5) (0.5) (2.3) (4.3) (8.7) (10.0) (0.6) (24.1) (7.1) (93.9) (38.8) (30.2) (13.3) (26.4) (12.4) (7.9) (11.6)
10 1 4 7 16.1 20.1 4 6 7 4 2 0 8 24.4 41.0 4.8 4.8 1.4 4.2 9.6 50.2 31.2 2.2 98.7 34.6 149.5 198.3 115.9 52.6 85.5 121.4 78.5 73.1
(91) (9) (36) (64) (4.6) (7.6) (36) (55) (64) (36) (18) (0) (73) (5.5) (6.1) (0.4) (0.4) (0.5) (2.3) (3.7) (7.5) (11.4) (0.7) (25.0) (8.5) (67.5) (31.0) (30.1) (15.6) (6.1) (9.0) (7.0) (12.4)
13 1 5 7 20.8 26.9 8 5 11 6 6 2 11 24.9 35.7 4.6 4.6 1.3 4.4 9.4 48.0 32.1 2.6 96.4 34.5 180.9 196.8 106.8 50.4 98.2 120.0 80.7 79.8
(93) (7) (36) (50) (9.2) (10.7) (62) (38) (85) (46) (43) (14) (79) (4.5) (8.3) (0.5) (0.5) (0.5) (2.3) (4.8) (9.9) (9.3) (0.6) (24.2) (6.2) (111.0) (45.1) (31.0) (11.7) (34.4) (14.9) (8.6) (10.4)
1.00 0.69 0.18 0.08 0.41 0.68 0.36 0.70 0.23 0.49 1.00 0.85 0.04 0.36 0.36 0.71 0.87 0.83 0.60 0.91 0.29 1.00 0.81 0.68 0.83 0.50 1.00 0.27 0.85 0.49 0.30
BES, Binge Eating Scale; BP, blood pressure; CGI, Clinical Global Impression; ESS, Epworth Sleepiness Scale; FCI, Food Craving Inventory; FSS, Fatigue Severity Scale; HDL, high-density lipoprotein; IDS-SR, self-report version of the Inventory for Depressive Symptomatology; LDL, low-density lipoprotein; LDX, lisdexamfetamine; MADRS, Montgomery–Asberg Depression Scale; YMRS, Young Mania Rating Scale. a Mean (SD) or n (%) shown. b Fisher’s exact tests or Wilcoxon’s rank sum tests were used to determine statistical differences between the LDX and placebo groups.
tremor (Table 4). Dry mouth and feeling jittery were statistically significantly more common among patients receiving LDX than among those receiving placebo. Only one patient discontinued the study drug (placebo) due to an adverse event (exacerbation of migraine headaches). No patient receiving LDX experienced a serious adverse event. The participant who was excluded by the investigators for medication tampering denied misuse of the study drug. There were no instances of suicidality, hypomania, or mania. All patients had a CGIBP-Mania Severity score of 2 or lower at endpoint. There were no significant changes in vital signs, other physical examination findings, ECG findings, or laboratory test findings.
Discussion In this small study of 25 patients with bipolar depression, adjunctive LDX was not superior to placebo in reducing depressive symptoms as assessed by MADRS. However, compared with placebo, LDX produced significantly greater reductions in self-reported measures of depressive symptoms and excessive daytime sleepiness,
significantly larger decreases in fasting levels of LDL and total cholesterol, and trend-level improvements in fatigue and binge eating. In the secondary analysis, LDX was found to be superior to placebo in reducing self-reported depressive symptoms, excessive daytime sleepiness, fatigue, binge eating behavior, triglyceride levels, LDL cholesterol levels, and total cholesterol levels, as well as in decreasing overall severity of depressive and bipolar symptoms at a trend level. The odds ratio estimate for the effect of LDX on categorical global improvement in depressive symptoms was large. Finally, LDX was well tolerated. The most common side effects were dry mouth, feeling jittery, and nausea. There were no instances of suicidality or hypomania/mania, but one patient receiving LDX was suspected of misusing the drug. Although extremely preliminary, these findings are consistent with open-label reports of successful treatment of bipolar depression with methylphenidate and Damphetamine, as well as with findings that LDX may improve metabolic parameters in patients with bipolar disorder (McIntyre et al., 2013). The lack of manic or hypomanic switch is consistent with findings from
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Lisdexamfetamine in bipolar depression McElroy et al. 11
Table 2
Primary (longitudinal) and secondary (endpoint) analyses of each outcome measure (N = 25) Longitudinal analysis
Outcome measure
a
Mean group difference (95% CI)
MADRS IDS-SR CGI-severity-depression CGI-severity-overall CGI-severity-mania YMRS ESS FSS BES FCI Weight (kg) BMI (kg/m2) Triglycerides Total cholesterol LDL cholesterol HDL cholesterol Glucose Insulin Hemoglobin A1C Hs-CRP Systolic BP (mmHg) Diastolic BP (mmHg) Pulse (bpm)
− 2.7 − 10.3 − 0.9 − 0.9 − 0.2 − 0.4 − 4.4 − 11.7 −6 − 0.1 − 2.1 − 0.7 0.7 − 30.6 − 15.9 − 0.1 1.0 0.5 1.0 1.2
(− 10.2, 4.7) (− 20.1, − 0.4) (− 2, 0.2) (− 2, 0.2) (− 0.5, 0.1) (− 2.7, 1.9) (− 7.5, − 1.3) (− 25.8, 2.3) (− 12.3, 0.4) (− 0.4, 0.3) (− 4.2, 0.1) (− 1.5, 0) (0.5, 1.1)d (− 49.7, − 11.4) (− 30.7, − 1.1) (− 4.6, 4.4) (0.9, 1.2)d (0.2, 1)d (1, 1)d (0.6, 2.4)d
Endpoint analysis P-value 0.47 0.04 0.12 0.11 0.29 0.72 < 0.01 0.10 0.07 0.77 0.06 0.06 0.08 < 0.01 0.04 0.98 0.64 0.06 0.99 0.66
Mean group difference (95% CI)b − 3.1 − 11.3 − 0.9 − 0.9 0.0 0.2 − 4.0 − 12.4 − 6.0 0.0 − 2.3 − 0.8 − 64.5 − 31.5 − 16.8 − 1.4 7.6 − 16.6 0.0 2.4 0.5 1.0 7.1
(− 11.0, 4.7) (− 20.3, − 2.4) (− 1.9, 0.1) (− 1.9, 0.1) (− 0.4, 0.4) (− 2.7, 3.0) (− 6.8, − 1.2) (− 23.8, − 1.0) (− 12.4, 0.3) (− 0.4, 0.3) (− 4.4, − 0.3) (− 1.5, − 0.1) (− 141.9, 12.9) (− 51.8, − 11.2) (− 32.3, − 1.3) (− 8.0, 5.2) (− 9.3, 24.4) (− 35.4, 2.2) (− 0.1,0.2) (− 2.5, 7.2) (− 7.8, 8.8) (− 4.6, 6.5) (− 2.8, 17.1)
P-value
Effect sizec
0.42 0.02 0.09 0.09 0.91 0.91 < 0.01 0.01 0.03 0.82 0.07 0.07 0.03 < 0.01 0.04 0.97 0.53 0.09 0.46 0.46 0.90 0.72 0.15
0.33 1.05 0.75 0.75 0.00 − 0.06 1.18 0.92 0.79 0.00 0.96 0.97 0.74 1.39 0.99 0.19 − 0.40 0.81 0.00 − 0.45 − 0.05 − 0.15 − 0.60
BES, Binge Eating Scale; BP, blood pressure; CGI, Clinical Global Impression; CI, confidence interval; ESS, Epworth Sleepiness Scale; FCI, Food Craving Inventory; FSS, Fatigue Severity Scale; HDL, high-density lipoprotein; Hs-CRP, high-sensitivity C-reactive protein; IDS-SR, self-report version of the Inventory for Depressive Symptomatology; LDL, low-density lipoprotein; LDX, lisdexamfetamine; MADRS, Montgomery–Asberg Depression Scale; YMRS, Young Mania Rating Scale. a Group difference = (LDXweek 8 − LDXbaseline) − (Placeboweek 8 − Placebobaseline). b Group difference = (LDXendpoint − LDXbaseline) − (Placeboendpoint − Placebobaseline); last observation used for endpoint. c Cohen’s d; positive value indicates greater reduction in the LDX group. d Log transformation used; table shows original scale and equals ratio of (LDXweek 8/LDXbaseline) to (Placeboweek8/Placebobaseline).
Table 3
Categorical response by treatment group
Response definition MADRS response (≥50% reduction) MADRS remission (MADRS ≤ 12) CGI-improvement-overall response (1 or 2) CGI-improvement-depression response (1 or 2)
LDX (n = 11) [n (%)]
Placebo (n = 14) [n (%)]
Odds ratio (95% CI)
P-value
6 (55) 6 (55) 8 (73)
4 (29) 4 (29) 5 (36)
3.0 (0.6, 15.8) 3.0 (0.6, 15.8) 4.8 (0.9, 26.8)
0.24 0.24 0.07
8 (73)
5 (36)
4.8 (0.9, 26.8)
0.07
CGI, Clinical Global Impression; CI, confidence interval; LDX, lisdexamfetamine; MADRS, Montgomery–Asberg Depression Scale.
randomized controlled trials in patients with bipolar disorder and comorbid attention deficit hyperactivity disorder, in whom stimulants did not cause worsening of mood symptoms (Scheffer et al., 2005; Findling et al., 2007). Several limitations of this study should be considered. The most important is that because of the small sample size (because of premature termination by the funding sponsor), the study may have been underpowered to detect important therapeutic or adverse effects. Conversely, positive findings, especially those at trend levels, could reflect type 1 errors and should not be over interpreted. In addition, although the two treatment groups were balanced on most variables, the LDX group had a higher baseline mean IDS-SR score. Thus, the group receiving LDX may have shown more improvement on this outcome variable because there was more room for change. Another limitation is that because the
duration was only 8 weeks, findings cannot be generalized to longer periods of treatment. Furthermore, as bipolar patients with certain medical comorbidities or stimulant abuse were excluded, the findings cannot be generalized to these populations. In summary, in an 8-week trial in 25 outpatients with inadequately responsive bipolar I or II depression, adjunctive LDX was not superior to placebo in improving clinician-rated depressive symptoms. However, LDX was superior to placebo in reducing self-reported measures of depressive symptomatology, excessive daytime sleepiness, fatigue, and binge eating, and in improving some metabolic variables. Moreover, except for one instance of probable misuse, LDX was well tolerated. Further trials of LDX and other psychostimulants for the treatment of bipolar depression seem warranted.
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12 International Clinical Psychopharmacology 2015, Vol 30 No 1
Adverse events reported by two or more patients by treatment group
an effective amount of tramadol to an individual, filed 25 March 1999 and approved 14 March 2002. For the remaining authors, there are no conflicts of interest.
Table 4
Adverse event
Total (n = 25) [n (%)]
Headache Insomnia Decreased appetite Dry mouth Feeling jittery Fatigue Nausea Pyrexia (fever, increased body temperature) Tremor Anxiety Diarrhea Irritability Palpitations Gastroenteritis Sinus congestion Strep throat Upper respiratory infection symptoms
LDX (n = 11) [n (%)]
Placebo (n = 14) [n (%)]
P-value
7 5 4 4 4 3 3 3
(28) (20) (16) (16) (16) (12) (12) (12)
5 4 2 4 4 1 2 2
(45) (36) (18) (36) (36) (9) (18) (18)
2 1 2 0 0 2 1 1
(14) (7) (14) (0) (0) (14) (7) (7)
0.18 0.13 1.00 0.03 0.03 1.00 0.56 0.56
3 2 2 2 2 2 2 2 2
(12) (8) (8) (8) (8) (8) (8) (8) (8)
3 2 1 2 1 0 2 1 1
(27) (18) (9) (18) (9) (0) (18) (9) (9)
0 0 1 0 1 2 0 1 1
(0) (0) (7) (0) (7) (14) (0) (7) (7)
0.07 0.18 1.00 0.18 1.00 0.49 0.18 1.00 1.00
LDX, lisdexamfetamine.
Acknowledgements The authors would like to acknowledge Genie Groff for manuscript preparation. Clinical Trials.gov Identifier: NCT01093963. This study was supported by a grant from Shire Inc. Conflicts of interest
Dr McElroy is a consultant to, or member of, the scientific advisory boards, and/or a principal or co-investigator on research studies sponsored by the Agency for Healthcare Research & Quality (AHRQ), Alkermes, Bracket, Cephalon, F. Hoffman-La Roche Ltd., Forrest Laboratories, Marriott Foundation, MedAvante, National Institutes of Mental Health, Naurex, Novo Nordisk, Orexigen Therapeutics, Shire, Sunovion, and Takeda Pharmaceutical Company. She is also inventor on the US Patent No. 6,323,236 B2, Use of sulfamate derivatives for treating impulse control disorders, and, along with the patient’s assignee, University of Cincinnati, Cincinnati, Ohio, USA, has received payment from Johnson & Johnson Pharmaceutical Research & Development L.L.C., which has exclusive rights under the patent, filed 18 February 2000 and approved 27 November 27 2001. Dr Keck is a consultant to, or member of, the scientific advisory boards, and/or a principal or co-investigator on research studies sponsored by Alkermes, Forest, Cephalon, Marriott Foundation, National Institute of Mental Health (NIMH), Shire, and Sunovion. He is also an inventor on the US Patent No. 6,387,956: Shapira NA, Goldsmith TD, Keck, PE Jr (University of Cincinnati), Methods of treating obsessive-compulsive spectrum disorder comprises the step of administering
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