Adjunctive lisdexamfetamine dimesylate therapy in adult outpatients with predominant negative symptoms of schizophrenia: open-label and randomized-withdrawal phases

Abstract

Negative symptoms of schizophrenia (NSS), related to hypodopaminergic activity in the mesocortical pathway and prefrontal cortex, are predictive of poor outcomes and have no effective treatment. Use of dopamine-enhancing drugs (eg, psychostimulants) has been limited by potential adverse effects. This multicenter study examined lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, as adjunctive therapy to antipsychotics in adults with clinically stable schizophrenia and predominant NSS. Outpatients with stable schizophrenia, predominant NSS, limited positive symptoms, and maintained on stable atypical antipsychotic therapy underwent a 3-week screening, 10-week open-label adjunctive LDX (20-70 mg/day), and 4-week, double-blind, randomized, placebo-controlled withdrawal. Efficacy measures included a modified Scale for the Assessment of Negative Symptoms (SANS-18) and Positive and Negative Syndrome Scale (PANSS) total and subscale scores. Ninety-two participants received open-label LDX; 69 received double-blind therapy with placebo (n=35) or LDX (n=34). At week 10 (last observation carried forward; last open-label visit), mean (95% confidence interval) change in SANS-18 scores was -12.9 (-15.0, -10.8; P<0.0001). At week 10, 52.9% of participants demonstrated a minimum of 20% reduction from baseline in SANS-18 score. Open-label LDX was also associated with significant improvement in PANSS total and subscale scores. During the double-blind/randomized-withdrawal phase, no significant differences (change from randomization baseline) were found between placebo and LDX in SANS-18 or PANSS subscale scores. In adults with clinically stable schizophrenia, open-label LDX appeared to be associated with significant improvements in negative symptoms without positive symptom worsening. Abrupt LDX discontinuation was not associated with positive or negative symptom worsening. Confirmation with larger controlled trials is warranted.

Figures

Figure 1

Participant disposition. aSafety analysis and full analysis sets included all enrolled participants who took ⩾1 dose of LDX and had one postbaseline safety/efficacy assessment in the open-label phase. AEs, adverse events; LDX, lisdexamfetamine dimesylate.

Figure 2

(a) Mean (95% CI) change from baseline in Scale for the Assessment of Negative Symptoms (SANS-18) total score: open-label phase (last observation carried forward; N=92). Data labels represent mean (SD). *P<0.0001 vs baseline. (b) LS mean (95% CI) change from randomization baseline (week 10) in SANS-18 total score: double-blind/randomized-withdrawal phase (randomized FAS; terminal observation carried forward; n=69). Data labels represent mean. P⩾0.2086 placebo vs LDX for all. ET, end of treatment.

Figure 3

(a) Positive and Negative Syndrome Scale (PANSS) total and subscale scores at baseline and open-label endpoint (week 10 using a last observation carried forward approach; N=92). Data labels represent mean. *P<0.0001 vs baseline. (b) PANSS total and subscale scores at week 10 randomization baseline and week 14/ET of the double-blind/randomized-withdrawal phase (randomized FAS; using a terminal observation carried forward approach; placebo, n=35; LDX, n=34). Data labels represent mean or LS mean values as appropriate for each bar. P⩾0.0680 placebo vs LDX for all. ET, end of treatment.