Adjunctive use of lisdexamfetamine

Cognitively I suffer greatly – particularly in relation to sustained attention. It’s nice to see research towards improvements in cognitive deficits and negative symptoms:

Lisdexamfetamine dimesylate as adjunctive treatment with antipsychotics for predominant negative symptoms of schizophrenia: Concurrent neurocognitive and negative symptom improvement.

Background: Both neurocognitive impairments and negative symptoms of schizophrenia (NSS) are believed related to mesocortical dopaminergic hypofunction. This analysis examined the hypothesis that the dopamine agonist, d-amphetamine prodrug, lisdexamfetamine dimesylate (LDX), would improve neurocognition along with NSS in adults with clinically stable schizophrenia maintained on atypical antipsychotics. Methods: Outpatients with schizophrenia (>2 years) and predominant NSS, on antipsychotics (>12 weeks), underwent 10-week open-label (OL) LDX augmentation (20-70mg/d). Eligible participants (any SANS-18 improvement at week 10) entered 4-week, double-blind, placebo-controlled randomized withdrawal (RW). Efficacy measures included SANS-18 (primary), Brief Assessment of Cognition in Schizophrenia-Symbol Coding Subtest (BACS-SC), Hopkins Verbal Learning Test-Revised, Immediate Recall (HVLT-R), and Letter Number Span Test (LNS). Safety evaluations included treatment-emergent adverse events (TEAEs). Results: In 92 participants receiving OL LDX, SANS-18 mean change (95% CI; weeks 0-10 OL, LOCF) was -12.9 (-15.0, -10.8) (P<.0001). Mean change (95% CI) in BACS-SC T-score was 2.0 (0.1, 3.9) (P=.0369); mean change in HVLT-R and LNS T-scores were 0.4 (-1.1, 2.0) and 1.3 (-0.4, 3.0), respectively (both P=NS). During RW, no significant differences were noted (LDX vs placebo) for these outcomes. In the OL phase, 56/92 (60.9%) reported TEAEs; 3/92 (3.3%) reported serious TEAEs. Conclusions: LDX improved NSS without worsening positive symptoms of schizophrenia. This was accompanied by small but significant improvements in BACS-SC. Confirmation with larger placebo-controlled trials, various doses, and additional cognitive measures is warranted given the significant unmet need for treating negative and cognitive symptoms in schizophrenia.

The effects in rats of lisdexamfetamine in combination with olanzapine on mesocorticolimbic dopamine efflux, striatal dopamine D2 receptor occupancy and stimulus generalization to a d-amphetamine cue.

The etiology of schizophrenia is poorly understood and two principle hypotheses have dominated the field. Firstly, that subcortical dopamine function is enhanced while cortical dopamine function is reduced and secondly, that cortical glutamate systems are dysfunctional. It is also widely accepted that currently used antipsychotics have essentially no impact on cognitive deficits and persistent negative symptoms in schizophrenia. Reduced dopamine transmission via dopamine D1 receptors in the prefrontal cortex has been hypothesized to be involved in the aetiology of these symptom domains and enhancing cortical dopamine transmission within an optimal window has been suggested to be potentially beneficial. In these pre-clinical studies we have determined that combined administration of the d-amphetamine pro-drug, lisdexamfetamine and the atypical antipsychotic olanzapine increased dopamine efflux in the rat prefrontal cortex and nucleus accumbens to an extent greater than either drug given separately without affecting olanzapine’s ability to block striatal dopamine D2 receptors which is important for its antipsychotic activity. Furthermore, in an established rodent model used to compare the subjective effects of novel compounds the ability of lisdexamfetamine to generalize to a d-amphetamine cue was dose-dependently attenuated when co-administered with olanzapine suggesting that lisdexamfetamine may produce less marked subjective effects when administered adjunctively with olanzapine


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