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Implications for Models of Cognitive Deficits in Schizophrenia

Daniel Umbricht, MD; Liselotte Schmid, licphil; Rene Koller, licphil; Franz X. Vollenweider, MD; Daniel Hell, MD; Daniel C. Javitt, MD, PhD

Arch Gen Psychiatry. 2000;57:1139-1147.

Background  In patients with schizophrenia, deficient generation of mismatch negativity (MMN)—an event-related potential (ERP) indexing auditory sensory ("echoic") memory—and a selective increase of "context dependent" ("BX") errors in the "A-X" version of the Continuous Performance Test (AX-CPT) indicate an impaired ability to form and use transient memory traces. Animal and human studies implicate deficient N-methyl-D-aspartate receptor (NMDAR) functioning in such abnormalities. In this study, effects of the NMDAR antagonists ketamine on MMN generation and AX-CPT performance were investigated in healthy volunteers to test the hypothesis that NMDARs are critically involved in human MMN generation, and to assess the nature of ketamine-induced deficits in AX-CPT performance.

Methods  In a single-blind placebo-controlled study, 20 healthy volunteers underwent an infusion with subanesthetic doses of ketamine. The MMN-to-pitch and MMN-to-duration deviants were obtained while subjects performed an AX-CPT.

Results  Ketamine significantly decreased the peak amplitudes of the MMN-to-pitch and MMN-to-duration deviants by 27% and 21%, respectively. It induced performance deficits in the AX-CPT characterized by decreased hit rates and specific increases of errors (BX errors), reflecting a failure to form and use transient memory traces of task relevant information.

Conclusions  The NMDARs are critically involved in human MMN generation. Deficient MMN in schizophrenia thus suggests deficits in NMDAR-related neurotransmission. N-methyl-D-aspartate receptor dysfunction may also contribute to the impairment of patients with schizophrenia in forming and using transient memory traces in more complex tasks, such as the AX-CPT. Thus, NMDAR-related dysfunction may underlie deficits in transient memory at different levels of information processing in schizophrenia.

From the Department of Research, Psychiatric University Hospital, Zurich, Switzerland (Drs Umbricht, Vollenweider, and Hell and Mss Schmid and Koller); and Program in Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY (Dr Javitt).

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