Towards medication-enhancement of cognitive interventions in schizophrenia

Abstract

Current antipsychotic medications do little to improve real-life function in most schizophrenia patients. A dispassionate view of the dispersed and variable neuropathology of schizophrenia strongly suggests that it is not currently, and may never be, correctable with drugs. In contrast, several forms of cognitive therapy have been demonstrated to have modest but lasting positive effects on cognition, symptoms, and functional outcomes in schizophrenia patients. To date, attempts to improve clinical outcomes in schizophrenia by adding pro-cognitive drugs to antipsychotic regimens have had limited success, but we propose that a more promising strategy would be to pair drugs that enhance specific neurocognitive functions with cognitive therapies that challenge and reinforce those functions. By using medications that engage spared neural resources in the service of cognitive interventions, it might be possible to significantly enhance the efficacy of cognitive therapies. We review and suggest several laboratory measures that might detect potential pro-neurocognitive effects of drugs in individual patients, using a "test dose" design, aided by specific biomarkers predicting an individual's drug sensitivity. Lastly, we argue that drug classes viewed as "counter-intuitive" based on existing models for the pathophysiology of schizophrenia-including pro-catecholaminergic and NMDA-antagonistic drugs-might be important candidate "pro-cognitive therapy" drugs.

Fig. 1

Schematic of theoretical and empirical rationale for predictive value of laboratory measures in identifying potential “pro-CT” drugs

Fig. 2

Biomarker predicting drug-enhanced PPI in normal subjects (figure modified from Roussos et al. 2009). %PPI is shown on Y-Axis; trial type (intensity in dB and prepulse interval in ms) is shown on X-axis. As in SZ patients, clinically healthy subjects carrying the Val allele of the Val158Met COMT polymorphism exhibit lower basal levels of PPI; in this important report, the authors demonstrated that the COMT inhibitor, tolcapone, increases PPI selectively among Val/Val individuals

Fig. 3

Relationship between levels of sensorimotor gating, as measured by %PPI, and global functioning, as measured by GAF in male schizophrenia outpatients (from Swerdlow et al. 2006a). “N” indicated by numbers inside bars; *P<.004 vs “41–50” and vs “>50.” †P<.01 vs “41–50” and vs “>50” by Fisher protected least-significant difference. Clearly, the causal pathway from higher PPI to higher GAF is indirect, but these findings suggest that the ability of a drug to enhance PPI in schizophrenia patients might be one rational “signal” for selecting compounds with the potential for enhancing the functional impact of cognitive interventions

Fig. 4

“Rate-dependent” effects of AMPH (20 mg po) on measures of %PPI (left; Talledo et al. 2009) and working memory (MCCB domain T-scores; Swerdlow et al. 2011) in clinically normal adults. AMPH-enhanced PPI was detected in specific subgroups of healthy women with PPI- or personality-based phenotypes associated with the COMT Val/Val allele. Working memory-enhancing effects of AMPH were detected among a subgroup of 50 healthy men and women characterized by low-basal working memory performance. Schizophrenia patients as a group have reduced PPI and impaired working memory; thus, based solely on the rate-dependent effects detected in normal adults, schizophrenia patients would be predicted to show PPI- and working memory-enhancing effects of acute AMPH treatment. The latter finding was already reported by Barch and Carter (2005)

Fig. 5

In healthy men, PPI was significantly increased by 20 mg memantine at 120 ms prepulse intervals (left). When subjects were divided into those in the upper or lower 50% of baseline PPI values (right, “high” and “low”, respectively), ANOVA revealed PPI-enhancing effects of memantine only among the “low gaters” (Swerdlow et al. 2009b)