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The Impact of Antipsychotics on Cognitive Functioning in Schizophrenia

The Impact of Antipsychotics on Cognitive Functioning in Schizophrenia

There is broad consensus that cognitive deficits play a crucial role for both the pathogenesis and prognosis of schizophrenic psychoses. Cognitive disturbances often precede the first psychotic episode (Cannon et al., 2000) and persist over the different stages of the illness (Goldberg et al., 1993). It is important to note, however, that not all patients display neurocognitive disturbances and that contrary to early descriptions of the disorder (Kraepelin, 1893), recent cross-sectional and longitudinal studies suggest that schizophrenia is a neurodevelopmental disorder rather than a neurodegenerative one (Moritz et al., 2002a; Rund, 1998).

A more recent tradition of research has shed light on the impact of neurocognitive disturbances on outcome and treatment-related variables. Meta-analysis research conducted indicated that cognitive deficits, especially impairments in the domains of memory and vigilance, are significant predictors of functional outcome (e.g., community outcome, social problem solving and skill acquisition) (Green, 1996; Green et al., 2000). In addition, neurocognitive functioning is related to insight (Rossell et al., 2003) and coping skills (Wilder-Willis et al., 2002). Further, there is increasing evidence that neurocognitive dysfunction may severely compromise medication compliance (Donohoe et al., 2001).

At least two factors may underlie this relationship. First, it is well-known that several psychotropic agents--especially anticholinergic medication (Nishiyama et al., 1998) and benzodiazepines (Rammsayer et al., 2000; Tonne et al., 1995)--decrease neurocognitive functioning in some patients. Should such side effects remain undetected by clinicians and not be adequately dealt with, patients are likely to discontinue drug intake, deciding the side effects outweigh the benefit of drug treatment. Secondly, noncompliance can result from forgetting (Fenton et al., 1997) due to primary or induced (prospective) memory problems, which are frequently observed in psychiatric disorders (Moritz et al., in press).

Neurocognitive Functioning

Because of its impact on psychopathology, functional outcome and treatment-related variables, the amelioration of neurocognitive deficits is increasingly considered a target domain of antipsychotic treatment. The majority of studies conducted to date have shown that typical antipsychotics have a negligible impact on most neurocognitive functions. However, verbal fluency (e.g., verbal production of animals, nouns that begin with a certain letter) and spatial processing (e.g., block design test) are sometimes decreased under conventional medication (Moritz, 2002).

Some of the results indicating stable cognitive functioning with conventional medications may in fact obscure real cognitive decline since patients' overall health state generally normalizes over the course of clinical trials and improved psychopathology in turn is often accompanied by modest neurocognitive improvement. (See Moritz et al. [2003] for a method to verify real memory change in patients taking antipsychotics--Ed.) Moreover, familiarity with the assessment procedures and practice effects also predicts some increase in achievement even without real change.

In addition, the induction of extrapyramidal side effects due to the administration of conventional D2 antagonists often necessitates prescription of anticholinergic medication, which, as outlined, has negative effects on learning and memory. Taken together, the conventional "treatment package" (D2 antagonists and anti-Parkinson agents) potentially harms the already decreased cognitive capacity of patients with schizophrenia.

With the possible exception of clozapine (Clozaril), for which divergent findings have been collected with respect to memory, studies investigating the efficacy of atypical antipsychotic agents have mostly found enhancing effects on neurocognition (Keefe et al., 1999; Potvin et al., 2003). Although there is evidence that atypical antipsychotics directly exert beneficial effects on neurocognitive functioning, some of the positive effects of atypical antipsychotics on neurocognition stem from a more pronounced remission of negative symptoms relative to conventional agents.

The positive impact of atypical antipsychotics on neurocognitive functioning embraces the domains of memory (short- and long-term), selective attention, executive functioning and verbal fluency (Bilder et al., 2002; Stip et al., 2003b). As spatial processing rarely has been assessed, no solid conclusions can yet be drawn regarding this domain (Moritz, 2002).

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