A Promising Approach to Improve Cognition

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RESEARCH UPDATE

Schizophrenia is associated with impaired cognition, which persists despite current treatments, and is an important determinant of quality of life and overall function. Presently, there are no approved pharmacological treatments for this indication. Thus, this represents a huge area of unmet need.

Alpha-7 nicotinic cholinergic receptors are found on pre- and post-synaptic receptors in the hippocampus and cerebral cortex, and they play a key role in cognitive function.¹ ABT-126 is a potent and highly selective partial agonist of the alpha-7 neuronal nicotinic cholinergic receptor. ABT-126 has shown pro-cognitive effects in non-clinical models and has been generally well-tolerated in patients with schizophrenia and Alzheimer disease and in healthy volunteers.

Haig and colleagues² performed a phase 2 randomized, double-blind, placebo-controlled, parallel-group trial to assess the efficacy and safety of ABT-126 in the management of cognitive impairment in patients with schizophrenia treated with atypical antipsychotics and in the residual phase of illness.

Patients with schizophrenia were randomized to 25 mg of ABT-126, 10 mg of ABT, or placebo in a 1:1:1 fashion. Inclusion criteria were age 20 to 55; clinically stable in the 4 months prior to screening; treatment with stable doses of 1 or 2 antipsychotics; diagnosis and/or treatment of schizophrenia for at least 2 years; Positive and Negative Syndrome Scale item scores of 4 or lower for delusions, conceptual disorganization, hallucinatory behavior, and excitement; and a Calgary Depression Scale for Schizophrenia total score of 10 or lower at screening.

Exclusion criteria were clinically significant extrapyramidal symptoms; significant neurological disease; uncontrolled mental illness; a history of substance abuse, hepatitis B or C, or HIV infection; and prior treatment with clozapine, tricyclic antidepressants, or monoamine oxidase inhibitors for more than 8 weeks.

The primary efficacy measure was the change from baseline to week 12 compared with placebo on the MATRICS Consensus Cognitive Battery (MCCB) composite score. Secondary efficacy measures were the total score on the UCSD Performance-Based Skills Assessment-2 (UPSA), the total score on the Negative Symptom Assessment, and the 7 individual domain scores of the MCCB.

The researchers screened 358 subjects, and 207 were randomized (67 to placebo, 69 to 10 mg of ABT-126, and 71 to 25 mg of ABT-126). A total of 203 subjects were treated at 22 sites in the US, of whom 165 (81%) completed the study. Mean subject age was 42, and mean duration of illness was 17 years.

The primary efficacy analysis showed improvement in cognition versus placebo but failed to reach statistical significant for both the ABT-126 10 mg (P = .088) and 25 mg (P = .067) groups, although effects were stronger and statistically significant in non-smokers. Statistically significant improvements versus placebo were found for attention-vigilance for both the 10 mg and 25 mg ABT-126 groups. There was no significant treatment effect of ABT-126 on cognitive functional capacity as measured by the UPSA.

The most frequent adverse events in the ABT-126 groups were diarrhea, dizziness, headache, nausea, fatigue, and nasopharyngitis. There was no difference in the prevalence of premature discontinuation due to adverse events across study groups; worsening of schizophrenia symptoms was the only adverse event that occurred in more than one subject.

The authors concluded that ABT-126 demonstrated a dose-dependent improvement in cognition that-although non-significant in the total sample-was associated with a significant, large effect (effect size > 0.8) in non-smoking subjects (an a priorisubgroup analysis).

Findings were broadly consistent with previous studies that found pro-cognitive effects of acute nicotine treatment as well as chronic treatment with alpha-7 receptor agonists in patients with schizophrenia who are either non-smokers or smokers with considerable abstinence. Nicotine exposure results in desensitization of nicotinic receptors, which may explain the lack of efficacy of nicotinic receptor agonists in chronic smokers.

The bottom line
ABT-126 demonstrated pro-cognitive effects in stable, non-smoking subjects with schizophrenia and was generally safe and well-tolerated, which supports its further investigation in this disorder.

Disclosures:

Dr Miller is Associate Professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, GA, and Schizophrenia Section Editor for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.

References:

1. Mazurov A, Hauser T, Miller CH. Selective alpha7 nicotinic acetylcholine receptor ligands. Curr Med Chem. 2006;13:1567-1584.

2. Haig GM, Bain EE, Robieson WZ, et al. A randomized trial to assess the efficacy and safety of ABT-126, a selective alpha-7 nicotinic acetylcholine receptor agonist, in the treatment of cognitive impairment in schizophrenia. Am J Psychiatry. 2016. Doi: 1.1176/appi.ajp.2015.15010093.