فیزوستیگمین و شناخت در اختلال شخصیت

Abstract There is evidence that reduced cholinergic activity may play a role in the pathophysiology of cognitive impairment in the schizophrenia spectrum. We tested the effects of physostigmine, an anticholinesterase inhibitor, on visuospatial working memory as evaluated by the Dot test, and on verbal learning and recall as measured by a serial learning task in patients with schizotypal personality disorder. Physostigmine tended to improve the Dot test, but not serial verbal learning performance in these patients.

. Introduction Reduced cholinergic activity may play a role in the pathophysiology of schizophrenia. Decreased choline acetyltransferase has been noted in post-mortem brains of schizophrenic patients (Karson et al., 1993), as have decreased numbers of nicotine receptors in the hippocampi of schizophrenic patients post-mortem. Specifically, in seven of eight schizophrenic brains there was less alpha-bungarotoxin labelling than in the comparison non-schizophrenic brains (alpha-bungarotoxin binds to a subset of nicotine receptors). Thus a possible mechanism for cholinergic dysfunction in schizophrenia is a deficit in nicotinic post-synaptic receptors for acetylcholine (Freedman et al., 1995). Reduced cholinergic activity may also play a role in the cognitive impairment of schizophrenia. An overwhelming amount of evidence favoring the importance of central cholinergic systems in learning and memory exists. In animals, a variety of cholinergic drugs have been shown to enhance retention of learned responses (Haroutunian et al., 1985). Specifically, physostigmine in rats enhanced both memory consolidation and memory retrieval processes (Santucci et al., 1989). In a study of the effects of four cholinomimetics on cognition in rats following disruption by scopolamine or by lists of objects, physostigmine was clearly the most efficacious and best tolerated agent examined (Rupniak et al., 1989). Physostigmine has also improved memory processes in normal humans (Davis et al., 1978). While there is a well-documented association between cognitive impairment and decreased cholinergic activity in Alzheimer's disease (Perry et al., 1978), there is also evidence to support the role of reduced cholinergic activity in the cognitive impairment of schizophrenia, including a significant correlation between the reduced choline acetyltransferase concentration (Karson et al., 1993) and two domains of cognitive performance in schizophrenia (Karson et al., 1996). Further evidence comes from studies of the alpha-7 nicotine receptor, showing that dysfunction of this receptor may be responsible for the abnormal sensory gating found in schizophrenia, and may also predispose patients to difficulty with learning efficiency and accuracy (Adler et al., 1998). Nicotine administration, via a patch, has improved attentiveness during a continuous performance task and has reversed some of the haloperidol dose-related impairments in a variety of cognitive tests that assess memory performance in patients with schizophrenia (Levin, 1996). Schizotypal personality disorder (SPD) is a disorder of the schizophrenia spectrum, similar to schizophrenia in its biology, genetics, and treatment (Siever et al., 1993). Cognitive impairment exists in both disorders (Siever et al., 1993 and Weinberger et al., 1986) and includes abnormalities in verbal learning, attention, and working memory (Bergman et al., 1998, Lees Roitman et al., 2000 and Trestman et al., 1995). The cognitive impairment in SPD is hypothesized to be associated with frontal cortical hypodopaminergia; administration of the dopamine releasing agent amphetamine improves cognitive performance in SPD patients (Kirrane et al., 2000 and Siegel et al., 1996). There is also evidence that nicotine modulates dopaminergic neurotransmission, and there are significant differences in nicotinic regulation of cortical and subcortical dopaminergic activity; for example, chronic nicotine treatment changes dopamine metabolism in the prefrontal cortex but not in the dorsal striatum (Dalack et al., 1998). Preclinical studies suggest that chronic nicotine treatment affects cortical sensitivity to nicotine challenges to a greater extent than it does subcortical nicotinic receptor sensitivity, consistent with the hypothesis of cortical/subcortical dissociation in schizophrenia (Dalack et al., 1998 and Davis et al., 1991). A complex interaction between the cholinergic and dopaminergic systems may thus play a role in the pathophysiology of cognitive impairment in the schizophrenia spectrum. SPD patients may be a suitable population in which to study the basis of this cognitive impairment, as they are less affected by confounding factors such as chronic psychosis and long-term antipsychotic administration. We hypothesized that physostigmine, an indirectly-acting cholinomimetic which works by inhibiting anticholinesterase, would ameliorate the cognitive impairment found in SPD. We studied its effects on visuospatial working memory and verbal learning in SPD patients.

3. Results 10 SPD patients participated (8 M/2 F; age 39.7±12.1; years of education 13.5±1.9; six had never been treated with psychiatric medication, mean length of time off medication in months for the other four was 19.7±34.8, range 1–72 months). Physostigmine infused over 20 min tended to improve working memory at the 20 and 30 s delay conditions of the Dot test compared with placebo (drug vs. placebo paired t-test at 20 s delay: t=2.0, d.f. 5, p=0.09; paired t-test for 30 s delay: t=2.2, d.f. 5, p=0.07). While physostigmine infused over 60 min had a non-significant effect over placebo (drug vs. placebo paired t-test: t<1, d.f. 7, p=n.s. both delays). Restricting the sample in the four patients receiving both infusions, the short infusion appeared to improve working memory at the 20 s delay (sample size too small for meaningful analysis). Physostigmine (short or long infusion) did not have any effect on Serial Word List learning and recall task. There were no significant differences in side effect profiles between the two infusions (short: 0.89±1.18; long 0.50±0.8; t<1.4, d.f. 3, p=n.s.). Side effect profiles were uncorrelated with performance (all r<0.2, p=n.s.). Physostigmine in either infusion did not produce significant anxiogenic effects (measured as anxiety response) compared with placebo (see Table 1; all t<0.1, p=n.s.), and it was also uncorrelated with performance (all r<0.2, p=n.s.). Table 1. Physostigmine/placebo and cognitive performance SPD (n=10) Short infusion (n=6) Long infusion (n=8) Placebo (n=10) Words learned 5.50±2.8 6.50±3.9 6.50±3.6 Visuospatial working memory (Dot test) cm error (10 s) 1.16±1.9 0.81±0.7 0.49±0.4 cm error (20 s) 0.63±0.6a 1.40±0.7 1.71±1.5 cm error (30 s) 0.83±1.5b 1.50±1.2 1.34±1.1 Side effects (cm) nausea scale 0.8±1.1 0.50±0.8 0.8±0.6 anxiety response 2.1±3.2 1.3±3.3 0.4±2.3 a paired t: t=2.0, d.f. 5, p=0.09. b paired t: t=2.2, d.f. 5, p=0.07.