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The Effects of Guanfacine on Context Processing Abnormalities in Schizotypal Personality Disorder

Published:September 04, 2006DOI:https://doi.org/10.1016/j.biopsych.2006.06.034

      Background

      The signature of impaired cognition in people with schizotypal personality disorder (SPD) may be centrally related to working memory impairments. Guanfacine, an α2A agonist that acts post-synaptically in the prefrontal cortex (PFC), has shown potential for reducing working memory limitations in other populations. This study examined the potential of guanfacine for improving context processing, a feature of working memory, in SPD.

      Methods

      29 individuals with SPD entered into a 4-week, randomized parallel-design, double-blind, placebo-controlled trial of guanfacine treatment, followed by a 4-week open-label extension. A modified version of the AX-Continuous Performance Test (AX-CPT) was administered. On this task, evidence of intact context processing includes few BX errors (false cue, correct probe) and higher levels of AY errors (correct cue, false probe).

      Results

      At the end of double-blind treatment, participants treated with guanfacine demonstrated a significant reduction in BX errors and a small but significant increase in AY errors, a pattern that was not seen in the participants treated with placebo.

      Conclusions

      SPD participants improved in their context processing toward a normal response bias, making fewer BX and more AY errors, after being treated with guanfacine.

      Key Words

      Impaired cognition, one of the most defining symptoms of schizophrenia (
      • Heinrichs R.W.
      The primacy of cognition in schizophrenia.
      ), is also found in individuals with schizophrenia spectrum disorders such as schizotypal personality disorder (SPD;
      • Siever L.J.
      • Kalus O.
      • Keefe R.S.
      The boundaries of schizophrenia.
      ). SPD patients have impairments in several areas, such as episodic (
      • Cadenhead K.S.
      • Perry W.
      • Shafer K.
      • Braff D.L.
      Cognitive functions in schizotypal personality disorder.
      ) and working memory (
      • Roitman S.E.
      • Mitropoulou V.
      • Keefe R.S.
      • Silverman J.M.
      • Serby M.
      • Harvey P.D.
      • et al.
      Visuospatial working memory in schizotypal personality disorder patients.
      ), cognitive inhibition (
      • Moritz S.
      • Mass R.
      Reduced cognitive inhibition in schizotypy.
      ), abstraction (
      • Voglmaier M.
      • Seidman L.J.
      • Salisbury D.
      • McCarley R.W.
      Neuropsychological dysfunction in schizotypal personality disorder: A profile analysis.
      ), and sustained attention (
      • Roitman S.E.L.
      • Cornblatt B.A.
      • Bergman A.
      • Obuchowski M.
      • Mitropoulou V.
      • Keefe R.S.
      • et al.
      Attentional functioning in schizotypal personality disorder.
      ). In a recent paper (
      • Mitropoulou V.
      • Harvey P.D.
      • Zegarelli G.
      • New A.S.
      • Silverman J.M.
      • Siever L.J.
      Neuropsychological performance in schizoypal personality disorder: importance of working memory.
      ), we argued that the entire signature of cognitive impairments in SPD patients could be explained by deficits in working memory. Thus, the search for pharmacological interventions for these cognitive impairments should logically focus on compounds with promise to reduce working memory abnormalities.
      The role of the noradrenergic system in normal cognitive functions has been systematically evaluated in numerous animal studies, and it appears that the prefrontal cortex (PFC) is particularly important for tasks that require working memory and sustained attention (
      • Friedman J.L.
      • Adler D.N.
      • Davis K.L.
      The role of norepinephrine in the pathophysiology of cognitive disorders: potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer’s disease.
      ). A recent vein of research, focusing on the role of norepinephrine in the treatment of deficits in these domains, has demonstrated that the activation of α2A-adrenoceptors (for review, see
      • Arnsten A.F.T.
      Adrenergic targets for the treatment of cognitive deficits in schizophrenia.
      ) may ameliorate some of these cognitive limitations. Pharmacological agents such as guanfacine, an α2a agonist that acts post-synaptically in the PFC, would thus seem to be promising intervention possibilities. The one published study (
      • Friedman J.L.
      • Adler D.N.
      • Temporini H.D.
      • Kemether E.
      • Harvey P.D.
      • White L.
      • et al.
      Guanfacine treatment of cognitive impairment in schizophrenia.
      ) that attempted to use guanfacine to treat cognitive impairments in schizophrenia had encouraging results, in that working memory and vigilance were specifically improved, but findings of an interaction with type of antipsychotic medication patients were taking made the establishment of clear efficacy for guanfacine in schizophrenia challenging. Thus, the examination of guanfacine for cognitive impairment in SPD seems a reasonable step, as SPD patients demonstrate cognitive deficits that are intrinsically related to working memory but are largely free from the potential confounds found in schizophrenia samples, such as psychosis and the effects of antipsychotic medications (
      • Siever L.J.
      • Kalus O.
      • Keefe R.S.
      The boundaries of schizophrenia.
      ).
      We have also shown that individuals with SPD, like individuals with schizophrenia, experience a substantial deficit in the ability to appropriately represent and maintain contextual information (
      • Barch D.M.
      • Mitropoulou V.
      • Harvey P.D.
      • New A.S.
      • Silverman J.M.
      • Siever L.J.
      Context-processing deficits in schizotypal personality disorder.
      ). Context is defined as prior task-relevant information that is represented in such a form that it influences selection of the appropriate behavioral response. Such context representations can include task instructions, a specific prior stimulus, or the result of processing a sequence of prior stimuli. Thus, three cognitive functions that are often treated as independent—attention, active memory, and inhibition—are all influenced by a single mechanism responsible for the processing of context (
      • Cohen J.D.
      • Barch D.M.
      • Carter C.
      • Servan-Schreiber D.
      Context-processing deficits in schizophrenia: Converging evidence from three theoretically motivated cognitive tasks.
      ). Therefore, Cohen and colleagues have argued that disturbances in attention, working memory, and inhibition in schizophrenia can all be understood in terms of a deficit in context-processing (
      • Barch D.M.
      • Carter C.S.
      • Braver T.S.
      • Sabb F.W.
      • MacDonald 3rd, A.
      • Noll D.C.
      • et al.
      Selective deficits in prefrontal cortex regions in medication naive schizophrenia patients.
      ,
      • Braver T.S.
      • Barch D.M.
      • Cohen J.D.
      Cognition and control in schizophrenia: A computational model of dopamine and prefrontal function.
      ,
      • Braver T.S.
      • Cohen J.D.
      Dopamine, cognitive control, and schizophrenia: The gating model.
      ,
      • Cohen J.D.
      • Barch D.M.
      • Carter C.
      • Servan-Schreiber D.
      Context-processing deficits in schizophrenia: Converging evidence from three theoretically motivated cognitive tasks.
      ,
      • Cohen J.D.
      • Servan-Schreiber D.
      Context, cortex and dopamine: A connectionist approach to behavior and biology in schizophrenia.
      ).
      This deficit is revealed during performance of the modified AX-Continuous Performance Task (AX-CPT). Participants are presented with cue-probe pairs and are told to respond affirmatively to an “X” (probe), but only when it is preceded by an “A” (cue). The task also includes three types of non-target trials that allow one to selectively assess context processing deficits: AY trials (“A” cue followed by any letter other than “X”); BX trials (non-“A” cue followed by an “X” probe); and BY trials (non-“A” cue followed by a non-“X” probe). The target, or AX, trials occur with high frequency (70%), creating two important response biases. First, this high AX frequency creates a bias to make a target response to any stimulus following an A cue (as a probe “X” occurrence is highly likely following an “A” cue). In healthy individuals, maintenance of context is demonstrated by the tendency to make a false alarm after occurrence of the A cue (leading to increased AY errors), or a slowing of reaction times on correct AY responses (as the prepotent bias to make a target response needs to be overcome). The second bias created by the high AX frequency is the tendency to make a target response to the “X” probe, as this is the correct response the majority of the time. On BX trials, maintenance of the context provided by the cue (non-A) is needed to prevent BX false alarms. Therefore, on the AX-CPT, deficits in context processing are not indicated by an overall increase in any type of false alarm, but rather a specific pattern (decreased AY errors and increased BX errors). Thus, successful performance on the AX-CPT depends upon an individual’s ability to attend to the stimuli, maintain stimuli in working memory, and effectively use the prior information of the cue when deciding whether or not to respond to the probe. In our previous study, patients with SPD made fewer AY than BX errors (
      • Barch D.M.
      • Mitropoulou V.
      • Harvey P.D.
      • New A.S.
      • Silverman J.M.
      • Siever L.J.
      Context-processing deficits in schizotypal personality disorder.
      ), in contrast to healthy individuals where these error tendencies were reversed. Such a pattern in SPD individuals is consistent with a specific deficit in context processing and in working memory, similar to that found in individuals with schizophrenia (
      • Barch D.M.
      • Carter C.S.
      • Braver T.S.
      • Sabb F.W.
      • MacDonald 3rd, A.
      • Noll D.C.
      • et al.
      Selective deficits in prefrontal cortex regions in medication naive schizophrenia patients.
      ,
      • Braver T.S.
      • Barch D.M.
      • Cohen J.D.
      Cognition and control in schizophrenia: A computational model of dopamine and prefrontal function.
      ,
      • Braver T.S.
      • Cohen J.D.
      Dopamine, cognitive control, and schizophrenia: The gating model.
      ,
      • Cohen J.D.
      • Barch D.M.
      • Carter C.
      • Servan-Schreiber D.
      Context-processing deficits in schizophrenia: Converging evidence from three theoretically motivated cognitive tasks.
      ,
      • Cohen J.D.
      • Servan-Schreiber D.
      Context, cortex and dopamine: A connectionist approach to behavior and biology in schizophrenia.
      ), as maintenance of the cue in working memory would result in a higher rate of AY errors and a lower rate of BX errors.
      The goal of the present study was to evaluate the ability of guanfacine to improve context processing in individuals with SPD, indexed by more “normal” performance on the AX-CPT, in a double-blind, placebo controlled study. We hypothesized that guanfacine would lead to a reduction in the BX errors and an increase in the AY errors made by individuals in the SPD group, so that their post-treatment performance would be more similar to the way that healthy controls have performed in prior studies.

      Methods and Materials

      Participants

      Participants were 29 individuals with DSM-IV SPD. Recruitment, diagnosis, and exclusion criteria have been presented in previous publications (for a full description, please see
      • Mitropoulou V.
      • Harvey P.D.
      • Zegarelli G.
      • New A.S.
      • Silverman J.M.
      • Siever L.J.
      Neuropsychological performance in schizoypal personality disorder: importance of working memory.
      ). Consensus diagnoses were reached in a meeting of all raters with an expert diagnostician (k = .73 for SPD). Demographic characteristics are shown in Table 1. All participants signed informed consent forms in accordance with the IRB approvals of this study at both the James J. Peters VAMC and Mt. Sinai School of Medicine.
      Table 1Sample Characteristics
      Guanfacine Group N = 20Placebo Group N = 9
      M (SD)M (SD)
      Age (in years)38.6 (11.2)40.3 (8.2)
      Sex (% male)65.0 88.9 
      Education (in years)14.9 (2.2)14.2 (4.1)
      Vocabulary Score10.3 (2.8)10.2 (2.9)
      Block Design Score9.9 (2.7)10.2 (3.7)

      AX-CPT Task

      Participants performed three conditions of the AX-CPT: standard, degraded and interference; due to space limitations, only the standard version will be considered. Sequences of letters were visually presented one at a time in a continuous fashion on a computer display. Participants were instructed to make an affirmative response on target trials and a negative response otherwise (for a full description, please see
      • Barch D.M.
      • Mitropoulou V.
      • Harvey P.D.
      • New A.S.
      • Silverman J.M.
      • Siever L.J.
      Context-processing deficits in schizotypal personality disorder.
      ). The delay between cue and probe was manipulated so that half of the trials had a short delay and half had a long delay. On short delay trials, the cue-probe interval was 1 sec, and the inter-trial interval was 4900 msec. On long delay trials, the cue-probe interval was 5 sec and the inter-trial interval was 1 sec. Thus, the total trial duration was equivalent across conditions, providing a means of controlling for general factors that might affect performance (e.g., pace of the task, response frequency, total time on task). The task was presented in 4 blocks of 50 trials, all of which were either short (2 blocks) or long (2 blocks) delay trials, with the order of short and long delay blocks counterbalanced across subjects. Participants were asked to respond as quickly as possible to each stimulus while maintaining accuracy.

      Procedure

      Following a baseline assessment, participants entered into a 4-week, double-blind, parallel design treatment phase during which they were randomly assigned to receive either guanfacine or placebo, followed by an open-label extension. Participants were assigned at a 2:1 ratio for guanfacine as compared to placebo. Participants on active drug were titrated to 2.0 mg daily over the first two weeks and remained on 2.0 mg for the duration of the study. The AX-CPT was administered at baseline and repeated biweekly.

      Data Analysis

      Data were analyzed using error rates (misses on AX trials and false alarms on all other trials) and reaction times (medians for correct trials) following double-blind treatment, with a last observation carried forward (LOCF) plan. We focused on the two error types that have been shown to be most sensitive to the integrity of context processing performance (BX and AY) at the two delay conditions (short and long), across the two treatment conditions (active and placebo) within each subject group. We used an ANCOVA with trial type (AY, BX), delay (short, long), and session (baseline, post-treatment) as within-subject factors and treatment (placebo, active) as the between-subjects factor. WAIS-R Vocabulary and Block Design Scores were included as covariates, to adjust for individual differences in IQ.

      Results

      The ANCOVA revealed a main effect of trial type, F(1,24) = 4.58, p<.05, with overall more BX than AY errors. There was also a session by trial type by treatment interaction, F(1,24) = 7.6, p<.05. To understand the source of the session by trial type by treatment interaction, we computed separate trial type by treatment ANCOVAs for the baseline and post-treatment sessions. There was a significant trial type by treatment interaction for the post-treatment scores, F(1,24) = 5.07, p<.05, but not for baseline scores, F(1,24) = .03, p>.8.
      As illustrated in Figure 1, planned contrasts indicated that BX errors showed the predicted decrease from baseline to post-treatment with guanfacine (p<.05), consistent with an improvement in context processing. In contrast, BX errors actually showed a significant increase from baseline to post-treatment with placebo (p<.05). Also as predicted, there was a small but significant increase in AY errors from baseline to post-treatment with guanfacine (p<.05), a pattern consistent with an improvement in context processing. Again, in contrast, AY errors actually displayed a slight decrease from baseline to post-treatment in the placebo condition.
      Figure thumbnail gr1
      Figure 1Percent AY and BX errors at baseline and post treatment, adjusted for differences in IQ, for individuals with SPD treated with guanfacine compared to those treated with placebo.
      We did not find significant session by trial type by treatment interactions or session by trial type by delay by treatment interactions for reaction times (all ps>.10) (Table 2).
      Table 2Maintenance of Context with the AX-CPT: Performance Errors in Both Treatment Conditions
      Guanfacine GroupPlacebo Group
      PrePostPrePost
      M (SD)M (SD)M (SD)M (SD)
      Short Delay
       AX3.1 (4.8)3.0 (5.5)1.6 (1.7)2.3 (3.5)
       AY4.5 (7.6)6.5 (10.4)10.0 (20)2.2 (4.4)
       BX14.1 (28.6)6.7 (12.8)13.3 (33.2)21.1 (32.1)
       BY2.0 (4.1)2.0 (5.2)1.1 (3.3)1.1 (3.3)
      Long Delay
       AX19.1 (23.2)22.7 (30.1)14.8 (31.3)14.7 (18.6)
       AY5.1 (7.9)5.1 (6.9)4.3 (9.7)3.3 (5.0)
       BX16.7 (28.7)12.2 (18.6)20.1 (33.4)32.6 (41.2)
       BY1.0 (4.5)1.5 (3.7).0 (.0).0 (.0)
      Data are percentage of errors.

      Discussion

      We have previously shown that individuals with SPD, like individuals with schizophrenia, demonstrate impaired context processing on a modified version of the AX-CPT. Consistent with our hypotheses, participants with SPD in the current study displayed performance changes suggesting better context processing following treatment with guanfacine. Specifically, individuals in the guanfacine group demonstrated a significant reduction in BX errors following treatment, while individuals treated with placebo actually demonstrated an increase in BX errors. There was also a small but significant increase in AY errors for the guanfacine group, but not for the placebo group.
      The pattern of errors is important as it argues against the idea that guanfacine simply led to an overall reduction in errors over time. Normalization of context processing requires simultaneous increases in one error type (AY) and a decrease in errors of another type (BX). This pattern was not found for individuals in the SPD placebo group, who showed changes reflective of concurrent changes in both error types.
      As an individual must maintain a representation of the cue in working memory during the delay, the increase in AY errors is consistent with an improvement in working memory in that participants were able to retain information that influenced their decisions to respond or not respond to the probe. Additionally, the decrease in BX errors also suggests that individuals were able to use the non-cue information to inhibit their responses, even to the correct probe. Thus, this pattern of responding suggests an increased ability to actively maintain information in working memory and to use that information to influence behavior and is consistent with the hypothesis that guanfacine would improve the working memory abilities of individuals with SPD, allowing them to better process contextual information.
      One unexpected result of the study was the tendency for individuals treated with placebo to demonstrate an increase in BX errors and a decrease in AY errors at the end of the study. Although this pattern was unexpected and cannot be definitively explained, it may be understandable. This finding might be an interaction of repeated participation with the cognitive deficits of SPD, such as poor attention or loss of novelty. The test is challenging and may have induced some frustration effects in the SPD participants on placebo that were not present in the group whose performance improved. In addition, it is of substantial interest that when the AX-CPT was administered to individuals with schizophrenia at baseline and again four weeks later, this patient group also demonstrated a reduction in AY errors, reflecting deterioration of context processing over time (
      • Barch D.M.
      • Carter C.S.
      • MacDonald 3rd, A.W.
      • Braver T.S.
      • Cohen J.D.
      Context processing deficits in schizophrenia: Diagnostic specificity, 4-week course, and relationships to clinical symptoms.
      ). However, the significant increase in AY errors and the significant decrease in BX errors seen in the guanfacine group suggest that even though the triple interaction may have been supported by the deterioration of context processing seen in our control group, the interaction between treatment and error type at the conclusion of double-blind treatment would have remained significant even if the placebo group had not been considered.
      Although the results of the current study are limited by the modest sample size, they indicate that guanfacine may ameliorate some of the cognitive limitations seen in the schizophrenia spectrum. As these changes are consistent with the theoretical underpinnings of context processing and with the previously identified pharmacological properties of guanfacine, they suggest a role in the schizophrenia spectrum for this agent or others with similar clinical effects.
      This research was supported by NIMH Grant Number MH 56140 (to LJS), NIMH Grant Number MH 63116 (to PDH), and by the VA VISN-3 MIRECC. This research was also supported by Grant Number MO1-RR-00071 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH.

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