ARTICLE. Chika Sumiyoshi 1, Tomiki Sumiyoshi 2,3, Ajanta Roy 3, Karu Jayathilake 3 and Herbert Y. Meltzer 3

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1 International Journal of Neuropsychopharmacology (2006), 9, Copyright f 2005 CINP doi: /s Atypical antipsychotic drugs and organization of long-term semantic memory: multidimensional scaling and cluster analyses of category fluency performance in schizophrenia ARTICLE Chika Sumiyoshi 1, Tomiki Sumiyoshi 2,3, Ajanta Roy 3, Karu Jayathilake 3 and Herbert Y. Meltzer 3 1 Faculty of Human Development and Culture, Fukushima University, Fukushima, Japan 2 Department of Neuropsychiatry, University of Toyama School of Medicine, Toyama, Japan 3 Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA Abstract Organization of semantic memory, one of the domains of cognitive function, is impaired in patients with schizophrenia, and is predictive of functional outcomes. The Category Fluency Task (CFT) has been used to evaluate organization of long-term semantic memory by means of visualizing semantic associations in the form of cognitive map and cluster structures. While atypical antipsychotic drugs (AAPDs) have been shown to ameliorate overall cognitive deficits, little is known about the efficacy of AAPDs for improving higher cognitive functions, such as semantic memory organization. The purpose of the present study was to determine if treatment with olanzapine or ziprasidone has beneficial influence on organization of semantic memory, as revealed by analysis of data from the CFT, in patients with schizophrenia. A retrospective analysis of an open-label trial was conducted for 33 patients with schizophrenia who were treated with either olanzapine or ziprasidone. Nineteen subjects were unmedicated at baseline. The CFT and Letter Fluency Task, as well as the Brief Psychiatric Rating Scale (BPRS) and Quality of Life Scale (QLS), were administered at baseline and of the treatment. Semantic structures were obtained by multidimensional scaling analysis and hierarchical cluster analysis of verbal outputs from the CFT. At baseline, no meaningful dimension or cluster was observed in the semantic structure; however, knowledge-based dimensions (wild vs. domestic) appeared after treatment with olanzapine or ziprasidone. Cluster structures also became organized, especially after treatment with olanzapine. Scores of QLS, but not those of BPRS, improved during treatment with the AAPDs. These results suggest a facilitative influence of AAPDs on higher cognitive functions, such as organization of semantic memory, in patients with schizophrenia. Received 10 August 2005; Reviewed 4 September 2005; Revised 18 September 2005; Accepted 21 September 2005; First published online 29 November 2005 Key words: Memory organization, schizophrenia, second-generation antipsychotics, semantic memory, verbal fluency. Introduction Patients with schizophrenia exhibit a wide range of cognitive dysfunction in the domains of language, memory, and executive functions (Green et al., 2000). Address for correspondence : T. Sumiyoshi, M.D., Ph.D., Department of Neuropsychiatry, University of Toyama School of Medicine, Toyama 2680 Sugitani, Toyama , Japan. Tel. : Fax : sumiyo@ms.toyama-mpu.ac.jp Thus, cognitive impairment in patients with schizophrenia should be regarded as generalized deficits (Dickinson et al., 2004). Executive function and longterm semantic memory are most severely impaired among various domains of cognition (Saykin et al., 1991). Semantic memory is a component of long-term memory, defined as stored representation of meaning of words and knowledge about the world (Mckay et al., 1995). Executive function and long-term semantic memory can be assessed by the verbal fluency tasks (VFTs),

2 678 C. Sumiyoshi et al. typically included in the cognitive assessment in patients with schizophrenia. In the VFTs, subjects are required to retrieve words in a designated time (usually 1 min). Typically, two types of task, i.e. the Letter Fluency Task (LFT) and Category Fluency Task (CFT), are administered. In the LFT, an initial letter is given as a cue (e.g. F, A, S ), while certain category (e.g. ANIMAL) is given as a cue in the CFT. Previous studies report that the amount of word production in patients with schizophrenia is decreased by 1 S.D. compared to the average of normal subjects (Harvey and Keefe, 1997; Saykin et al., 1991). Specifically, a meta-analysis study (Bokat and Goldberg, 2003) revealed that performance on the CFT is more disturbed than the LFT in alphabetical-language speakers with schizophrenia (in the case of patients using a non-alphabetical language, see Sumiyoshi et al. 2004a). The selective impairment in performance on the CFT is considered to reflect disorganized semantic memory function in schizophrenia. While both types of the VFTs effectively measure executive function, the CFT is also used to estimate semantic memory function by means of constructing semantic structures from the verbal outputs in the task (Aloia et al., 1996; Moelter et al., 2001; Paulsen et al., 1996; Rossell et al., 1999; Sumiyoshi et al., 2001c, 2005). In this analysis, the sequential verbal outputs from the CFT are transformed to dissimilarity values to which multidimensional scaling (MDS) analysis or cluster analysis is applied. A specific algorithm (Chan et al., 1993) is used to convert the order of verbal outputs into subjective similarity matrices. In MDS analysis, associations of items are expressed in a form of map in which subjectively similar items are closely located. On the other hand, cluster analysis provides supplementary information on the coherence of subjective similarity. The semantic structure analysis, using verbal outputs from the CFT, has been used to evaluate semantic memory function of clinical samples, as the task, free recall of words, is not demanding even for patients with relatively severe general cognitive deficits. Thus, the analysis has also been used in clinical studies of patients with Alzheimer s disease and Huntington s disease (Chan et al., 1993), as well as in developmental studies of normal children (Crowe and Storm, 2003; Storm, 1980). Previous studies using MDS analysis revealed that perceptual or knowledge-based dimensions (i.e. size, domesticity, ferocity), which are characteristic of the semantic structure in normal people, are absent in patients with schizophrenia (Aloia et al., 1996; Sumiyoshi et al., 2001c, 2005). Similarly, data from cluster analysis indicate the presence of inconsistent grouping of words in these patients (Aloia et al., 1996; Moelter et al., 2001). Also, both positive and negative psychotic symptoms are associated with semantic memory disorganization (Rossell et al., 1999; Sumiyoshi et al., 2005). For example, we and other investigators reported that the semantic structure of patients with severe alogia symptoms (i.e. difficulties in fluent thinking), is more disorganized than that in patients without these symptoms (Rossell et al., 1999; Sumiyoshi et al., 2005). Atypical antipsychotic drugs (AAPDs), such as clozapine, melperone, olanzapine, risperidone, quetiapine, and ziprasidone, have been shown to improve various domains of cognitive function in subjects with schizophrenia (Meltzer and Sumiyoshi, 2003; Sumiyoshi et al., 2003; Woodward et al., 2005). Specifically, a number of studies report the ability of olanzapine and ziprasidone to enhance word production in the CFT (Daniel et al., 1999; Harvey et al., 2004a, b; McGurk et al., 2004; Simpson et al., 2004; Stip et al., 2003). The cognitive benefit of these AAPDs may be related to potent 5-HT 2A receptor antagonist activity with a relatively weak D 2 -blocking effect (Meltzer et al., 1989; Stockmeier et al., 1993; Sumiyoshi et al., 1995). Besides antagonist activity at 5-HT 2A receptors, olanzapine has high affinity for other 5-HT receptor subtypes, e.g. 5-HT 6 receptors. On the other hand, ziprasidone has high affinity for 5-HT 2C, 5-HT 1B, and, especially, 5-HT 1A receptors (Schmidt et al., 2001). Moreover, they activate 5-HT 1A receptors either directly (ziprasidone) or indirectly (olanzapine), as indicated by microdialysis studies of dopamine (DA) release in the prefrontal cortex and hippocampus (Ichikawa et al., 2001). It is thus hypothesized that partial 5-HT 1A agonist activity of AAPDs may contribute to the ability of these agents to improve cognitive functions, such as verbal memory (Sumiyoshi et al., 2001a, b; Sumiyoshi and Meltzer, 2004). Our previous study (Sumiyoshi et al., 2001b) revealed that organization of episodic memory, as measured by the Logical Memory subtest of the Wechsler Memory Scale Revised (WMS-R), was significantly improved by augmentation therapy with tandospirone, a partial 5-HT 1A agonist. However, little is known about the effect of AAPDs on organization of semantic memory in patients with schizophrenia, although this cognitive domain plays a key role in the improvement of the quality of life and social function. Araki et al. (In Press) reported that treatment with perospirone, an AAPD with potent partial 5-HT 1A agonist property, was associated with improvement in verbal memory organization, as assessed by the Auditory Verbal Learning Test (AVLT) (Gold et al., 1992; Nohara et al., 2000). Their result indicates the

3 Semantic organization and second-generation antipsychotics 679 Table 1. Demographic and cognitive variables ability of intrinsic 5-HT 1A agonist activity of AAPDs to encode new information in a consistent manner. However, it is not clear whether acquired semantic memory or knowledge, which is impaired in schizophrenia, would be restored by AAPDs. The principal aim of the present study was to determine if olanzapine or ziprasidone improves semantic memory organization. For this purpose, MDS and cluster analyses were conducted using verbal outputs from the CFT to construct semantic structures. We also assessed the change in psychotic symptoms and quality of life during treatment with these AAPDs. Method Subjects Patients treated with olanzapine (n=14) Patients treated with ziprasidone (n=19) Male/Female 11/3 17/2 Age (yr) (10.18) (11.73) Education (yr) 12.29(1.73) (1.99) Antipsychotic dose (mg/d)* 8.86 (12.22) 5.33 (7.29) 6.41 (1.98) 3.13 (1.80) Onset of illness (yr) (10.96) (7.62) Duration of (9.32) (12.56) illness (yr) CFT (ANIMAL) (2.72) ( 4.34) (3.02) (5.25) LFT (FAS mean) 8.61 (2.39) (3.69) 8.64 (2.22) (3.65) CFT, Category Fluency Task; LFT, Letter Fluency Task. Values represent mean (standard deviation). * Haloperidol equivalent. Thirty-three patients meeting DSM-IV criteria for schizophrenia entered the study. They were recruited from the Psychiatric Hospital at Vanderbilt. Nineteen had paranoid schizophrenia while 14 had undifferentiated schizophrenia. Two subjects were in-patients. The protocol was approved by Institutional Review Board of University Hospitals of Vanderbilt. Patients known to be abusing alcohol or other illicit drugs, or those with epilepsy, brain damage, or neurological disorders, were excluded from the study. Nineteen patients were unmedicated at baseline. Fourteen patients (male/female=11/3) received treatment with olanzapine while 19 patients (male/female=17/2) were treated with ziprasidone. Written informed consent was obtained after explanation of the study. Demographic variables (age, education, and sex) were matched between the two groups. The clinical profiles are summarized in Table 1. Design and procedure Olanzapine or ziprasidone was given to patients with an open-label manner. The dose of these drugs was adjusted depending on the need for controlling psychotic symptoms or agitation. Fourteen patients had been treated with the following antipsychotic drugs at baseline: haloperidol (n=4), fluphenazine (n=2) for the olanzapine group; and haloperidol (n=1), flupherazine (n=2), risperidone (n=2), and olanzapine (n=3) for the ziprasidone group; they were switched stepwise to monotherapy with olanzapine or ziprasidone within the first 2 wk. Patients were assessed with the following measures at baseline and after of treatment: the CFT and LFT, Brief Psychiatric Rating Scale (BPRS), and Quality of Life Scale (QLS; Heinrichs et al., 1984). The instruction of the VFTs followed the usual norm in which subjects were asked to produce as many words as possible in 1 min (Spreen and Strauss, 1998). ANIMAL was used for the cues in the CFT, while F, A, and S were used for the LFT. Statistical analysis Three-way analysis of variance (ANOVA) was conducted with drug (olanzapine vs. ziprasidone) as between-subject factor and task type (CFT vs. LFT scores) and time (baseline vs. ) as within-subject factor. The number of verbal outputs for ANIMAL was used for the CFT score while the average of outputs for F, A, and S were used for the LFT score. In order to evaluate the change in BPRS and QLS scores across the patients, the two treatment groups were merged, and the paired t test was conducted to compare these variables between baseline and. Demographic data of the two treatment groups were compared by t test. MDS analysis was conducted to construct semantic structures in each treatment group. Hierarchical cluster analysis was performed to examine the coherence of the category items in the semantic structures. The words most frequently produced across baseline and were used for both analyses. A few items differed between the two time-points, since frequency of items were not uniform. A specific algorithm was used to

4 680 C. Sumiyoshi et al. (a) Olanzapine-treated group obtain the dissimilarity matrices from verbal outputs in the CFT. The details of the algorithm have been described previously (Chan et al., 1993; Paulsen et al., 1996; Sumiyoshi et al., 2001c). MDS and cluster analyses were performed using SPSS version 13.0 (SPSS Inc., Chicago, IL, USA). The interval scale was applied for MDS analysis, and the average linkage method was used for cluster analysis. It was considered statistically significant when the p value was <0.05. Results MONKEY Stress=0.29, RSQ=0.62 Demographic profile Age (t=0.66, n.s.), education (t=0.51, n.s.), age of onset (t=1.43, n.s.), and duration of illness (t=0.54, n.s.) did not differ between the olanzapine and ziprasidone groups (Table 1). Verbal fluency scores WOLF (b) Ziprasidone-treated group RABBIT Stress=0.35, RSQ=0.46 Domestic Wild Stress=0.25, RSQ=0.60 ANOVA revealed that drug (ziprasidone > olanzapine; F=10.89, d.f.=1, 31, p<0.01) and task (CFT>LFT; F=88.53, d.f.=1, 31, p<0.01) effects were Domestic Wild Stress=0.28, RSQ=0.70 Figure 1. Two-dimensional semantic structure, as revealed by multidimensional scaling analysis, in patients treated with (a) olanzapine (n=14) or (b) ziprasidone (n=19). DIM, Dimension. significant. No significant interaction effect was obtained between the two factors. Time effect approached significance (F=0.35, d.f.=1, 31, p=0.07). The number of produced words in the CFT did not correlate with antipsychotic dose either at baseline (Pearson s correlation, r=0.11, n.s.) or (r=x0.39, n.s.). Organization of semantic memory The semantic structures for the olanzapine and ziprasidone groups are shown in Figure 1. In both groups, they were disorganized at baseline; no meaningful dimensions were noted (Figure 1, left-hand panels). In contrast, a wild-domestic dimension appeared after 6-wk treatment with either drug. In the semantic configuration of patients treated with olanzapine, wild animals (e.g.,,, ) gathered on the right upper quadrant, while domestic ones (e.g.,, ) were placed on the left lower quadrant (Figure 1a, right). Similar division was also found after treatment with ziprasidone for, in a manner that wild animals were placed in the right lower quadrant while domestic ones were on the left upper quadrant (Figure 1b, right). The cluster structures are shown in Figure 2. As for the olanzapine group, the clusters became organized at compared to baseline (Figure 2a); items were gathered in clusters roughly according to size (i.e.,,,, subsequently include,,,,, subsequently include ) at. Further, in the ziprasidone group, some coherent clusters (i.e.,,,, and,,, and so on) emerged at (Figure 2b, right), which was not evident at baseline (Figure 2b, left). Psychopathology and quality of life Mean (S.D.) scores of clinical variables at baseline and were 17.6 (8.4) and 16.5 (8.5) for BPRS, and 63.4 (16.3) and 69.6 (18.6) for QLS. Paired t test revealed a significant change in QLS [t=2.28, p<0.05, effect size (ES)=0.33] but not BPRS (t=0.76, n.s., ES=x0.12) during treatment. Discussion The present study provides the first evidence for the facilitative effect of AAPDs on organization of longterm semantic memory in subjects with schizophrenia. MDS analysis revealed that treatment with olanzapine or ziprasidone was associated with the emergence of a wild-domestic dimension in the semantic structure. Similarly, cluster structures became consistent during

5 Semantic organization and second-generation antipsychotics 681 (a) Olanzapine-treated group WOLF MONKEY (b) Ziprasidone-treated group RABBIT Figure 2. Cluster structures in patients treated with (a) olanzapine (n=14) or (b) ziprasidone (n=19). treatment with either drug. The change in organization of semantic memory concurred with improvement of the QLS score, which showed a moderate effect size. Perceptual (i.e. size) and knowledge (i.e. domesticity, ferocity) based dimensions have been shown to be characteristic of the semantic structure of normal adults (Aloia et al., 1996; Paulsen et al., 1996; Sumiyoshi et al., 2001c, 2005). Thus, results from the present study indicate that organization of semantic memory in patients approached the pattern of normal control subjects during treatment with AAPDs. Organized semantic structure enables patients to access the contents of thought efficiently, leading to better management of daily life. Goldberg et al. (2000) reported that the recovery of semantic memory, as assessed by priming effect, improves the QLS score. Moreover, Yamashita et al. (2005) found a significant correlation between the score of the idea fluency task and problem-solving skills, suggesting a link between fluent thought and better social functioning. The findings from these previous studies are consistent with the present data showing that improvement of the QLS score concurred with the recovery of semantic memory organization. Although psychotic symptoms, as measured by BPRS, did not change significantly, they may have been improved with a longer period of treatment. Although the number of words produced in the CFT did not increase, this executive aspect of performance on the CFT would have been enhanced by more prolonged treatment with AAPDs, i.e. after semantic memory organization was fully improved. This speculation may be supported by Goldberg et al. (2000) who found that patients treated with AAPDs exhibited improved semantic associations while the amount of word production in the CFT remained unchanged. It may be that semantic memory organization and the retrieval process of words are partially independent functions. The neurochemical mechanisms by which olanzapine and ziprasidone improved organization of semantic memory may include direct or indirect 5-HT 1A agonist activity. It is reported that AAPDs, such as olanzapine and ziprasidone, enhance DA release in the prefrontal cortex and/or hippocampus via 5-HT 1A agonist action, which may be related with facilitative effect on long-term memory organization (Araki et al., In Press; Sumiyoshi et al., 2001a). Although olanzapine does not have noticeable affinity for 5-HT 1A receptors, the drug has been shown to exhibit 5-HT 1A agonistic action via intermediate neural activities in vivo (Ichikawa et al., 2001). Ichikawa et al. found that enhanced DA release in the prefrontal cortex by olanzapine or risperidone, which by themselves are not 5-HT 1A agonists, are partially blocked by pretreatment with a 5-HT 1A antagonist. Support for the contribution of 5-HT 1A agonism to the enhancement of verbal memory organization also comes from clinical observations that (1) augmentation therapy with tandospirone, an anxiolytic and partial 5-HT 1A agonist, improved organization of episodic memory, as assessed by the WMS-R, in patients treated with typical antipsychotic drugs (Sumiyoshi et al., 2001a), and that (2) perospirone, a ziprasidone-like AAPD with high affinity for 5-HT 1A receptors, ameliorated disturbances of word memory organization, as assessed by the AVLT in subjects with schizophrenia (Araki et al., In Press). On the other hand, we previously reported that plasma homovanillic acid levels, a peripheral measure of central dopaminergic activity, predict the change in memory performance in schizophrenia patients treated with clozapine (Sumiyoshi et al., 2004b). This observation supports the concept that some types of DA receptors, such as the D 1 receptor in the prefrontal cortex, may play a role in enhancing cognitive performance in subjects treated with AAPDs.

6 682 C. Sumiyoshi et al. The limitations of the present study should be mentioned here. First, this study was conducted retrospectively with an open-label basis, although this does not necessarily introduce systematic bias, as previously discussed (Meltzer and McGurk, 1999). Second, the inclusion of a control group, such as patients receiving typical antipsychotic drugs, would have determined if AAPDs are more effective in ameliorating impaired memory organization in schizophrenia. Third, it is worthwhile to determine whether other types of AAPDs (e.g. risperidone) would improve semantic memory in order to identify specific pharmacological properties related to the ability of olanzapine and ziprasidone to enhance this domain of cognition. In summary, olanzapine and ziprasidone were shown to be effective in treating impaired semantic memory organization in schizophrenia. Whether this cognitionenhancing profile is related to the ability of AAPDs to improve the quality of life deserves further study. Acknowledgements This work was supported by a Grant-in-Aid from the Ministry of Education and Science of Japan (No ) to Dr Chika Sumiyoshi, as well as a Young Investigator Award from NARSAD, a Pharmacopsychiatry Research Grant from the Mitsubishi Pharma Research Foundation, a fellowship from the Ministry of Education and Science of Japan, and a Grant-in-Aid for Scientific Research (No ) from Japan Society for the Promotion of Science to Dr Tomiki Sumiyoshi. The authors are grateful to Ms. Kaori Watanabe, Chie Tana, and Ayumi Matsukawa for technical assistance. Statement of Interest None. References Aloia MS, Gourovitch ML, Weinberger DR, Goldberg TE (1996). An investigation of semantic space in patients with schizophrenia. Journal of International Neuropsychological Society 2, Araki T, Yamasue H, Sumiyoshi T, Kuwabata H, Suga M, Iwanami A, Kato N, Kasai K (In Press). Perospirone in the treatment of schizophrenia : effect on verbal memory organization. Progress in Neuro-psychopharmacology & Biological Psychiatry. Bokat CE, Goldberg TE (2003). Letter and category fluency in schizophrenic patients : a meta-analysis. Schizophrenia Research 64, Chan AS, Butters N, Salmon DP, McGuire KA (1993). Dimensionality and clustering in the semantic network of patients with Alzheimer s disease. Psychology of Aging 8, Crowe SJ, Storm C (2003). Continuity and change in the development of category structure: Insights from the semantic fluency task. International Journal of Behavioral Development 27, Daniel DG, Zimbroff DL, Potkin SG, Reeves KR, Harrigan EP, Lakshminarayanan M (1999). Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder : a 6-week placebo-controlled trial. Ziprasidone Study Group. Neuropsychopharmacology 20, Dickinson D, Iannone VN, Wilk CM, Gold JM (2004). General and specific cognitive deficits in schizophrenia. Biological Psychiatry 55, Gold JM, Randolph C, Carpenter CJ, Goldberg TE, Weinberger DR (1992). Forms of memory failure in schizophrenia. Journal of Abnormal Psychology 101, Goldberg TE, Dodge M, Aloia M, Egan MF, Weinberger DR (2000). Effects of neuroleptic medications on speech disorganization in schizophrenia : biasing associative networks towards meaning. Psychological Medicine 30, Green MF, Kern RS, Braff DL, Mintz J (2000). Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the right stuff? Schizophrenia Bulletin 26, Harvey PD, Keefe RS (1997). Cognitive impairment in schizophrenia and implication of atypical neuroleptic treatment. CNS Spectrums 2, Harvey PD, Meltzer H, Simpson GM, Potkin SG, Loebel A, Siu C, Romano SJ (2004a). Improvement in cognitive function following a switch to ziprasidone from conventional antipsychotics, olanzapine, or risperidone in outpatients with schizophrenia. Schizophrenia Research 66, Harvey PD, Siu CO, Romano S (2004b). Randomized, controlled, double-blind, multicenter comparison of the cognitive effects of ziprasidone versus olanzapine in acutely ill inpatients with schizophrenia or schizoaffective disorder. Psychopharmacology (Berlin) 172, Heinrichs DW, Hanlon TE, Carpenter WTJ (1984). The quality of life scale: an instrument for rating the schizophrenic deficit syndrome. Schizophrenia Bulletin 10, Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O Laughlin IA, Meltzer HY (2001). 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5- HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. Journal of Neurochemistry 76, McGurk SR, Lee MA, Jayathilake K, Meltzer HY (2004). Cognitive effects of olanzapine treatment in schizophrenia. Medscape General Medicine 6, 27. Mckay PA, McKenna PJ, Bentham P, Mortimer AM, Holbery A, Hodges JR (1995). Semantic memory impaired in schizophrenia. Biological Psychiatry 39,

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