PITTSBURGH – Effective treatment of cognitive impairments in people with schizophrenia probably will require a combination of pharmacologic and psychosocial interventions, said Dr. Robert W. Buchanan.
His conclusion was based on data from a large body of previous studies that looked at potential cognitive-enhancing drugs with a variety of mechanisms.
"Given the pattern of observed effects of drugs on various cognitive processes to date, it seems unlikely to me that we’re going to find a drug that has broad spectrum effects. ... I think the best that we can hope for is to find a drug with a pronounced effect on a particular component of cognition. We’d then want to use that drug in combination with a psychosocial intervention to enhance cognition and functionality," said Dr. Buchanan, professor of psychiatry at the University of Maryland, Baltimore.
Dr. Robert W. Buchanan
First- and second-generation antipsychotics, although very effective in reducing hallucinations and delusions, have not demonstrated similar benefit in improving cognition. In a meta-analysis accounting for 208 effect sizes from 34 studies of first-generation antipsychotics, the overall effect size for nine cognitive measures was just 0.22. ("Small" was defined as 0.2, "moderate" was 0.5, and "large" was 0.7). Effect sizes for individual domains ranged from 0.13 (executive function) to 0.29 (automatic processing), to a negative effect of –0.11 for motor function (Biol. Psychiatry 2004;55:1013-22).
Initially, it had been hoped that through their unique pharmacologic profile, second-generation antipsychotics would be more beneficial than first-generation agents in improving cognition. But that was shown not to be the case in a substudy of 817 of the total 1,460 participants in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) project. At 2 months, patients who were randomized to the newer agents (olanzapine, quetiapine, risperidone, and ziprasidone) had similar, small neurocognitive improvements, compared with those taking the first-generation agent perphenazine (Arch. Gen. Psychiatry 2007;64:633-47).
"Second-generation antipsychotics offer little advantage vs. first-generation agents. Despite antipsychotic treatment, people with schizophrenia continue to exhibit marked cognitive impairments," Dr. Buchanan commented.
Indeed, it appears that there is a "cognitive cost" associated with medications – including antipsychotics – that raise serum anticholinergic activity. A study of 55 schizophrenia patients demonstrated a clear association between serum anticholinergic activity and impaired performance in verbal working memory and verbal learning and memory, independent of age, IQ, or symptom severity (Am. J. Psychiatry 2009;166:1055-62).
Various adjunctive pharmacologic approaches have been tried, with varying success. In a 12-week, double-blind, placebo-controlled, randomized trial, the acetylcholinesterase inhibitor galantamine had an insignificant overall effect on a composite of neuropsychological outcomes among 44 patients who received it, compared with 42 who got placebo. However, those taking galantamine did show significant improvements in certain measures, particularly processing speed and verbal memory (Am. J. Psychiatry 2008;165:82-9).
And in several small studies, galantamine appeared superior to placebo in improving attention, delayed memory, visual recognition, and emotional acuity.
The clinical observation that people with schizophrenia often appear to be self-medicating by cigarette smoking – as well as experimental findings of deficient expression of alpha(7)-nicotinic receptors in people with schizophrenia – led to interest in nicotinic acetylcholine receptors as possible therapeutic targets. In a 4-week, double-blind, crossover study of 31 nonsmoking people with schizophrenia, significant improvements over placebo were seen with a higher dose (150 mg twice daily) of the agent DMXBA (3-[2,4-dimethoxybenzylidene]-anabaseine) on SANS (Scale for the Assessment of Negative Symptoms) and BPRS (Brief Psychiatric Rating Scale) scores (Am. J. Psychiatry 2008;165:1040-7).
However, trials looking at other nicotinic receptor agonists, particularly the alpha4beta2 agent varenicline, have been uniformly negative, noted Dr. Buchanan, who was one of the authors of the DMXBA study.
Glutamatergic agents also have been studied. CONSIST (Cognitive and Negative Symptoms in Schizophrenia Trial), led by Dr. Buchanan, was a 16-week, double-blind, double-dummy, parallel group study of 157 patients who were randomized to adjunctive glycine, d-cycloserine, or placebo. There were no significant differences in the SANS scores or on a composite neuropsychological measure, suggesting that neither glycine nor d-cycloserine is effective for treating negative symptoms or cognitive impairments (Am. J. Psychiatry 2007;164:1593-602).
GABA (gamma aminobutyric acid) also has been looked at as a potential drug target. In another study led by Dr. Buchanan, the GABAA alpha2/alpha3 partial agonist MK-0777 was studied in 60 people in a 4-week, multicenter, double-blind, placebo-controlled randomized clinical trial. Again, results were negative: No significant group differences were found on the primary outcome measure, which was the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) consensus cognitive battery composite score. Moreover, secondary analysis suggested that patients who received placebo actually performed better on visual memory and reasoning/problem-solving tests than did those assigned to either of two MK-0777 doses (Biol. Psychiatry 2011;69:442-9).