Typical and atypical antipsychotic medications differentially affect two nondeclarative memory tasks in schizophrenic patients: a double dissociation
Introduction
Memories can be declarative (DM), consciously recollected facts and events, or nondeclarative (NDM), expressed through performance without conscious recall. DM is impaired following damage to medial temporal or diencephalic structures; NDM includes several subtypes that rely on a number of brain structures (Squire and Knowlton, 2000).
Parkinsonians performing a probabilistic classification learning (PCL) task had intact DM but impaired NDM. The task required them to view a pattern and to predict the weather, rain or shine. Patterns were associated probabilistically with outcomes. Controls gradually predicted accurately over trials and performed well on a DM questionnaire. Amnesics also learned the PCL task but performed poorly on the questionnaire. Parkinson's patients failed to learn the PCL task but had intact DM (Knowlton et al., 1996). As Parkinson's patients suffer from a loss of striatal dopamine (DA), results implicated striatal DA in NDM. This conclusion is consistent with the results of a number of studies using a variety of NDM tasks in Parkinson's patients Allain et al., 1995, Charbonneau et al., 1996, Heindel et al., 1989, Koeing et al., 1999, Saint-Cyr et al., 1988, Swainson et al., 2000.
Learning of a gambling task, that required choosing a card from four decks, was impaired by bilateral damage to the ventromedial prefrontal cortex (vmPFC; Tranel et al., 1999). Each choice resulted in a payoff of play money and sometimes a penalty. Two decks produced low payoffs and occasionally low penalties and were advantageous over trials; the others produced large payoffs but occasionally large penalties and were disadvantageous over trials. Controls began by choosing from the disadvantageous decks but gradually shifted to the advantageous decks. Shifting began before participants could declare awareness of the contingencies, suggesting that the task assess NDM. Participants with vmPFC damage failed to shift to the less risky decks even after repeated testing implicating this structure in NDM Bechara et al., 1997, Bechara et al., 1999, Bechara et al., 2000. Note that Knowlton et al. (1996) reported that PCL of frontal patients was not related to frontal damage, suggesting that PCL and the gambling task may assess different types of NDM.
Schizophrenics are treated with antipsychotics, classified as typical or atypical based on several indices including their side-effects profile. Typicals, e.g., chlorpromazine and haloperidol, often produce extrapyramidal side effects (EPS) including parkinsonism, implicating striatal DA receptor blocking action of these agents in EPS liability. In contrast, atypicals, e.g., clozapine and risperidone, are defined by low EPS liability Arnt and Skarsfeldt, 1998, Remington and Kapur, 2000, Waddington and O'Callaghan, 1997. This suggests that these two classes of antipsychotics influence different brain regions. Animal research supports this view; for example, typical and atypical antipsychotics differentially affect neurotransmitter receptors (Taylor and Creese, 2000). Studies of induction of the immediate early gene c-fos in normal animals show that typicals induce c-fos in the dorsal striatum and nucleus accumbens but not in the frontal cortex whereas atypicals induce c-fos in the frontal cortex and nucleus accumbens but not the striatum Wan et al., 1995, Weinberger and Lipska, 1995.
These considerations led us to test the following hypotheses. Schizophrenic patients treated with typical antipsychotics but not those treated with atypicals will be impaired on the PCL but not on the gambling task. Schizophrenic patients treated with atypical antipsychotics but not those treated with typicals will be impaired on the gambling task but not on the PCL task. Although the classification of antipsychotic medications as typical or atypical is not perfectly delineated and may depend on dose (Remington and Kapur, 2000), for the purposes of the present study, as typicals we included phenothiazines, flupenthixol, haloperidol and loxapine and as atypicals we included clozapine, risperidone, olanzapine and quetiapine.
Section snippets
Participants
The probabilistic classification and gambling studies included 72 and 54 participants, respectively, with three groups in each experiment: 20 and 18 schizophrenic patients treated with typicals, 20 and 18 schizophrenic patients treated with atypicals and 32 and 18 controls. All patients had a DSM-IV (American Psychiatric Association, 1994) diagnosis of schizophrenia and were over 18 years old. They were recruited at Providence Continuing Care Centre Mental Health Services (formerly Kingston
Results
For the PCL task, the dependent variable was mean number of correct responses on the first 100 trials, analyzed in blocks of 20 trials (Fig. 1A). Performance of the control group improved to near asymptote from the first to the second block and that of the schizophrenic group treated with atypical antipsychotic medications similarly showed the greatest improvement from the first to the second block. The schizophrenic group treated with typical antipsychotic medications showed little evidence of
Discussion
Controls performing the PCL task learned over the first two trial blocks in agreement with the control data of Knowlton et al. (1996). Similarly, schizophrenics treated with atypical antipsychotics learned. Schizophrenic participants treated with typicals, alternatively, failed to learn. This failure is comparable to that of the Parkinson patients of Knowlton et al. (1996). Controls performing the gambling task learned over the first two trial blocks, shifting their choices to the advantageous
Acknowledgments
Funded by the Research Dept. of the Providence Continuing Care Centre Mental Health Services and an Investigator Initiated Grant from Eli Lilly Canada to R.J.B.
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