Comparing efficacy of serotonergic, opioidergic, and glutamatergic drugs in gambling disorder: A pooled analysis of response trajectories versus placebo

Various pharmacological treatments have been explored to alleviate the symptoms and clinical manifestations of gambling disorder (GD) by targeting different neurotransmitter systems. This study retrospectively analyzed subjects with GD treated with serotonergic drugs, opioid antagonist drugs, and glutamatergic drugs compared to placebo, through a pooled analysis of clinical trials conducted at the University of Chicago. The Gambling Symptom Assessment Scale (G-SAS) was employed as the outcome measure. Temporal uniformity was ensured by managing timepoints as follows: baseline, early (4–5 weeks), intermediate (6–8 weeks), and final (10–16 weeks) from the start of treatment. A total of 253 treatment-seeking subjects were included, receiving either glutamatergic drugs (N-acetylcysteine, memantine), opioidergic drugs (naltrexone), serotonergic drugs (paroxetine, escitalopram), or placebo. Within-group analysis demonstrated significant improvement in GD symptoms across all treatment groups. When comparing interventions over time, glutamatergic drugs proved more effective than placebo from the early observation timepoint and onwards. Opioidergic drugs were more effective than placebo at the final observation timepoint, while serotonergic drugs showed no significant effect compared to placebo. Our findings reveal distinct efficacy patterns among the pharmacological classes, likely due to their different mechanisms of action and the various aspects of GD phenomenology they address. The significant placebo effect observed aligns with previous studies, underscoring the complexity of treating GD. In conclusion, given the heterogeneous nature of GD, these results emphasize the necessity of identifying and precisely characterizing GD subtypes to facilitate more tailored treatment approaches.