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Exploration of the associations between neurocognitive function and neuroleptics side effects
Journal of Psychiatric Research 46 (2012) 913e919
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Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/psychires
Exploration of the associations between neurocognitive function and neuroleptics side effects Samuel Suk-Hyun Hwang a, b, Yeni Kim c, Da Young Yun d, Yong Sik Kim b, e, Hee Yeon Jung b, d, * a
Interdisciplinary Study in Brain Science, Seoul National University College of Natural Science, Seoul 110-744, Republic of Korea Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea c Department of Child Psychiatry, Seoul National Hospital, Seoul 143-711, Republic of Korea d Department of Psychiatry, SMG-SNU Boramae Medical Center, College of Medicine Seoul National University, Seoul 156-707, Republic of Korea e Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 October 2011 Received in revised form 3 April 2012 Accepted 3 April 2012
The etiology of side effects of antipsychotic medications can be conceptualized as involving both specific pharmacological actions of a drug and any mental and physical states attributed by the patient. Both factors are likely to be linked with neurocognitive functioning which may largely affect the subjective experience of side effects in patients with schizophrenia. In this study, we examined whether baseline neurocognitive functions, such as IQ, attention, executive functioning, and short-term memory, are associated with baseline and 6-month follow-up measures of self-reported Liverpool University Neuroleptics Side Effects Scale (LUNSERS) and clinician-rated Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). At the baseline, anxiety and depression were significantly associated with LUNSERS red herring (RH) and total side effects (SE) but not with DIEPSS. There was no association between LUNSERS and DIEPSS. Controlling for anxiety and depression, IQ was significantly correlated with DIEPSS, while choice reaction time (CRT) and stop signal task (SST) direction errors correlated with RH, and intra eextradimensional set-shifting (IED) total errors and pre-extradimensional set-shifting (pre-EDs) errors correlated with SE. The baseline SST direction errors further correlated significantly with RH and SE and DIEPSS total score of 6-month follow-up, and CRT mean and SD correct latency also correlated with DIEPSS. The correlations between the 6-month changes (D) in the same side effects measures and baseline neurocognitive measures were also significant, except that between RH and SST direction errors. Such evidences supported association between both self-rated and clinician-rated side effects and selective impairments in attention and executive functioning. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Self-reported side effects Neurocognitive functions LUNSERS CANTAB
1. Introduction Favorable outcome of antipsychotics treatment in patients with schizophrenia is largely dependent on good compliance, which is required for better assessment of efficacy and formulation of new treatment strategy. However, one of the major causes of noncompliance and treatment discontinuation has been found to be side effects of antipsychotic medication (Vorunganti et al., 2008; Kahn et al., 2008). Side effects can be largely conceptualized as comprising effects accountable by the specific pharmacological actions of a drug and by any mental and physical states attributed by the patient. As self-reported or subjective side effects arguably reflect more of the latter component compared to clinician* Corresponding author. Department of Psychiatry, SMG-SNU Boramae Medical Center, Seoul 156-707, Republic of Korea. E-mail addresses: [email protected], [email protected] (H.Y. Jung). 0022-3956/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2012.04.005
assessed measures, they have proven to not only predict treatment compliance (Hogan et al., 1983; Kampman et al., 2002) but correlate significantly with other self-reported measures, such as quality of life (Hwang et al., 2009; Wolters et al., 2009). By the same token, self-reports of side effects have been found to be adversely affected by psychopathology, such as severity of positive and depressive/anxiety symptoms (Hwang et al., 2010), and to be associated with poor overall executive functioning (Hwang et al., 2009; Kim et al., 2002). In most clinical studies, self-reported measures of side effects are accepted as outcome measures without an extensive examination of its validity. However, patients with schizophrenia in particular have been found to report side effects more frequently than the clinicians (Lindström et al., 2001). In addition, significant variability is present in how patients perceive their state of illness and side effects relative to clinical evaluation which may result in the lack of association between patient-rated and clinician-rated
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measures. For example, our recent study (Jung et al., 2010) demonstrated that patients with schizophrenia who show relatively low correspondence between subjective quality of life and the clinician-rated functioning also show weak or no association between subjective quality of life and clinician-rated side effects. Those with high correspondence, in contrast, showed stronger associations between self-report and clinician-rated measures, including side effects. From the etiological viewpoint, it may be important to examine whether such correspondence may be associated with the presence and severity of impairments in neurocognitive function in patients with schizophrenia, particularly in terms of self-reported and clinician-rated side effects. To date, however, no study has investigated how neurocognitive functions may be directly associated with cross-sectional and long-term ratings of side effects by patients and clinicians. In the present study, we therefore examined how neurocognitive functions at baseline are related to the self-reported and clinician-rated side effects of the baseline and 6-month follow-up and the changes (D) therein. 2. Methods 2.1. Participants Fifty-four Korean outpatients were followed for 6-months post baseline assessment with lost-to-follow-up of only 3 female patients. These patients were also included in a recently published study by Yun et al. (2011), which cross-sectionally compared the executive functions of remitted and non-remitted patients of schizophrenia and healthy control. These patients were recruited from the psychiatric outpatient clinic of the Boramae Medical Center of Seoul, Korea, and have been diagnosed by two experienced psychiatrists (YK and HYJ) according the DSM-IV diagnostic criteria. The patients were further assessed with the Structured Clinical Interview for DSM-IV (SCID) by a trained clinical psychologist to exclude other Axis I diagnoses such as schizoaffective disorder and substance abuse. The age, years of education, and duration of illness of all patients at the baseline were 34.2 (SD ¼ 10.4), 13.2 (SD ¼ 2.4), and 8.7 (SD ¼ 8.0), respectively, and 25 (46%) were males. Interested readers may refer to the study by Yun et al. (2011) for more detailed information on patient recruitment and diagnoses. 2.2. Procedure At the time of initial clinical assessment, the Korean versions of the Liverpool University Neuroleptics Side Effects Scale (LUNSERS: Day et al., 1995; Lambert et al., 2003; Jung et al., 2005), the DrugInduced Extrapyramidal Symptoms Scale (DIEPSS: Inada, 1996; Kim et al., 2002), the Beck Anxiety Inventory (BAI: Beck et al., 1988; Kwon, 1997), and Hamilton Depression Rating Scale (HDRS: Hamilton, 1960; Yi et al., 2005) were completed. Then, within 10 days of clinical assessment, neuropsychological assessment that included the short form of the Korean version of the Wechsler Adult Intelligence Scale (K-WAIS: Wechsler, 1981; Yeom et al., 1992) and subtests of the CANTAB (CANTAB eclipse, 2006), a series of computerized tests using a touch-sensitive screen on an IBMcompatible PC, were completed. The patients were followed up 6 months post the baseline assessment, and they once again completed both side effects measures. Written informed consent was obtained from all patients prior to the initiation of study procedures whose protocol had been approved by the Institutional Review Board of Boramae Medical Center and carried out in accordance with the latest version of the Declaration of Helsinki. Detailed descriptions of the procedure and neurocognitive
measures used in this study are provided in the previous study by Yun et al. (2011). 2.3. Measures 2.3.1. Clinical measures To assess the overall level of depression, the HDRS which includes items such as overall depression, guilt, suicide, insomnia, problems related to work, psychomotor retardation, agitation, anxiety, loss of weight, and loss of insight (Hamilton, 1960; Yi et al., 2005) was completed. As an interviewer-administered and rated measuring scale, a higher score signifies more severe levels of depression. The level of subjective anxiety of the patients was assessed with the BAI, a 21-item self-reported measure containing items such as numbness or tingling, feeling hot, wobbliness in legs, and inability to relax (Beck et al., 1988; Kwon, 1997). 2.3.2. Side-effects measures All patients completed Korean version of the LUNSERS, a selfreported measure which consists of 41 items pertaining to various subscales of neuroleptics-related side effects (SE: psychic, extrapyramidal, anticholinergic, other autonomic, allergic, and hormonal) and 10 red herring (RH) items not directly related to known antipsychotic side effects. The RH subscale, which includes items such as runny nose, chilblains, hair loss, and urine darker than usual, has shown to be useful for detecting over-reporting patients (Lambert et al., 2003). Two experienced psychiatrists (YK and HYJ) assessed the severity of side effects with the Korean version of the DIEPSS. It contains 8 individual items, i.e., gait, bradykinesia, sialorrhea, rigidity, tremor, akathisia, dystonia, and dyskinesia, and one global item which considers the overall severity and frequency of the individual items and their negative influence on subjective distress and daily activity (Inada, 1996; Kim et al., 2002). 2.3.3. Neurocognitive measures The short form of the K-WAIS is the Korean version of the WAISRevised (Wechsler, 1981). The composite score was derived from the four subtests from the K-WAIS (Vocabulary, Arithmetic, Picture Arrangement, and Block Design) to estimate current intellectual functioning. The correlation between the estimated IQ scores derived from the K-WAIS-short form and the full battery of the KWAIS was reported to be 0.95 (Kim and Lee, 1995). Also, the Vocabulary subtest was additionally used as the estimation of premorbid IQ. The subtests of the CANTAB were used to assess the domains of attentional ability, as reflected by processing speed and accuracy, executive function, including set-shifting and response inhibition, and spatial short-term memory. Specifically, Choice Reaction Time (CRT), a 2-choice reaction-time task, provided the measures of processing accuracy (no. of correct trials based on two assessment sets of 50 trials each following 24 practice trials), and motor speed (mean correct latency) and its variability (SD correct latency). Intradimensional/Extradimensional Shift (IED), a computer touchscreen adaptation of the Wisconsin Card Sorting Test (WCST), tested the ability to maintain attention on a reinforced stimulus (intradimensional shift, IDS) and then to shift attention to the previously irrelevant stimulus (extradimensional shift, EDS) through 9 stages of increasing complexity. Its outcome variables were the number of stages completed, total errors, preextradimensional shift errors (pre-ED errors), and errors at the extradimensional shift (EDS errors). Stop Signal Task (SST) measured an individual’s ability to inhibit a prepotent response. We obtained direction errors, proportion of successful stops, reaction time on GO trials, and the processing time required to inhibit a prepotent motor
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response (SSRT). Lastly, Spatial Span (SSP), a computerized version of the Corsi block-tapping test, assessed the spatial short-term memory capacity with the maximum span length as the outcome measure. 2.4. Statistical analysis The baseline neurocognitive function measures were correlated with the side effects measures of the baseline and 6-month assessments after investigating the correlations among the measures of side effects and HDRS and BAI to determine the necessity to control for the effects of depression and subjective anxiety. Then, partial correlation analyses were carried out as necessary. All analyses were conducted using SPSS version 15 for Windows (SPSS Inc. Chicago IL, USA SPSS, Inc: SPSS for Windows. Chicago, IL, USA: Rel 13.0; 2004.SPSS, Inc., Chicago, IL, USA). 3. Results 3.1. Baseline correlations among the LUNSERS, DIEPSS, HDRS, and BAI Presented in Table 1 are the correlations among the baseline measures of side effects and HDRS and BAI. Significant positive correlations were found among the LUNSERS subscales, HDRS, and BAI, but none of them were significantly associated with the DIEPSS. Both RH and SE of the LUNSERS were more strongly correlated with the BAI than HDRS. 3.2. Relationship between the baseline side effects and neurocognitive measures Significant associations between the baseline side effects measures and depression and anxiety symptoms signified the need to control their effects in further correlation analyses between side effects measures of the LUNSERS and neurocognitive measures. In Table 2 are the results of correlation and partial correlation analyses controlling for HDRS, BAI, or both. The RH subscale of the LUNSERS was significantly associated with the CRT mean correct latency and the SST direction errors of the CATAB and these correlations remained significant in all partial correlations. Our post hoc partial correlation analyses controlling for depression and anxiety showed that mean correct latency was significantly associated with runny nose, chilblains, and painful joints (r ¼ 0.39, p < 0.01; r ¼ 0.32, p < 0.05; r ¼ 0.32, p < 0.05, respectively). On the other hand, SST direction errors was significantly associated with chilblains, weak nails, and painful joints items of the baseline RH (r ¼ 0.55, p < 0.001; r ¼ 0.34, p < 0.05; r ¼ 0.37, p < 0.01, respectively). As for the total side effects score attributable to the effects due to medication (SE), it was significantly associated with the premorbid IQ derived from the vocabulary subtest of the K-WAIS and pre-ED errors of the CANTAB IED subtest. These correlations remained significant in all partial correlations. As for the side effects subscales Table 1 Baseline correlations among the LUNSERS, DIEPSS, HDRS, and BAI (n ¼ 54).
LUNSERS HDRS BAI
RH SE
LUNSERS SE
HDRS
BAI
DIEPSS
0.82***
0.31* 0.36**
0.66*** 0.79*** 0.54***
0.10 0.02 0.08 0.08
*p < 0.05, **p < 0.01, ***p < 0.001. LUNSERS, Liverpool University Neuroleptic Side Effects Rating Scale; SE, side effects; RH, red herring; HDRS, Hamilton Depression Rating Scale; BAI, Beck’s Anxiety Inventory.
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of the LUNSERS, the premorbid IQ significantly correlated with all but miscellaneous side effects subscale (psychic, r ¼ 0.27, p < 0.05; extrapyramidal, r ¼ 0.31, p < 0.05; hormonal, r ¼ 0.28, p < 0.05; anticholinergic, r ¼ 0.36, p < 0.01; other autonomic, r ¼ 0.38, p < 0.01; allergic, r ¼ 0.38, p < 0.01, respectively). In partial correlations, when controlling for HDRS, the premorbid IQ significantly correlated with the extrapyramidal, hormonal, anticholinergic, other autonomic, and allergic side effects subscales (r ¼ 0.29, p < 0.05; r ¼ 0.28, p < 0.05; r ¼ 0.34, p < 0.01; r ¼ 0.36, p < 0.05; r ¼ 0.37, p < 0.01, respectively). When controlling for BAI, premorbid IQ was significantly correlated with the anticholinergic, other autonomic, and allergic side effects subscales (r ¼ 0.28, p < 0.05; r ¼ 0.31, p < 0.05; r ¼ 0.31, p < 0.05, respectively). Lastly, when both HDRS and BAI were partialled out, the premorbid IQ still remained significantly correlated with the anticholinergic, other autonomic, and allergic side effects (r ¼ 0.28, p < 0.05; r ¼ 0.31, p < 0.05; r ¼ 0.32, p < 0.05, respectively). The pre-ED errors of the CANTAB IED subtest was significantly correlated with only psychic and hormonal side effects subscales of the LUNSERS (r ¼ 0.38, p < 0.05; r ¼ 0.38, p < 0.001, respectively) and these correlations remained significant when only HDRS was partialled out (r ¼ 0.31, p < 0.05; r ¼ 0.46, p < 0.001, respectively). However, the pre-ED errors significantly correlated with only hormonal side effects subscale when BAI (r ¼ 0.45, p < 0.01) or both BAI and HDRS (r ¼ 0.44, p < 0.01) were partialled out. Interestingly, partialling out HDRS resulted in significantly correlations between the LUNSERS SE and the EDS errors of the IED subtest which could be attributed to significant partial correlations with the hormonal and other autonomic symptoms subscales (r ¼ 0.31, p < 0.05; r ¼ 0.30, p < 0.05, respectively), and partialling out both BAI and HDRS had the effect of revealing significant correlation between the SE and total errors of the same subtest attributable to significant partial correlations with the hormonal and allergic side effects (r ¼ 0.31, p < 0.05; r ¼ 0.28, p < 0.05, respectively). Lastly, the estimated IQ of the K-WAIS was significantly associated with the DIEPSS with significant correlations with items such as bradykinesia, tremor, akathesia, and global score (r ¼ 0.37, p < 0.01; r ¼ 0.30, p < 0.05; r ¼ 0.30, p < 0.05; r ¼ 0.34, p < 0.05, respectively). 3.3. Relationships between the baseline neurocognitive and 6month side effects measures and their change (D) scores The baseline measures of neurocognitive functions were correlated with the 6-month side effects measures and with their changes (D) before and after partialling out their respective baseline scores (Table 3). The baseline HDRS and BAI were not partialled out in this analysis because they were not significantly correlated with the neurocognitive measures, except proportion of successful stops of the CANTAB IED subtest (r ¼ 0.31, p < 0.05). The baseline SST direction errors of the CANTAB was significantly correlated with the 6-month follow-up rating of the LUNSERS RH with significant correlations with chilblains, hair loss greasy skin, flushing face, and painful joints (r ¼ 0.78, p < 0.001; r ¼ 0.41, p < 0.01; r ¼ 0.39, p < 0.01; r ¼ 0.37, p < 0.05; r ¼ 0.47, p < 0.001, respectively). It also correlated significantly with SE, particularly with psychic, extrapyramidal, anticholinergic, miscellaneous, and other autonomic side effects subscales (r ¼ 0.46, p < 0.01; r ¼ 0.42, p < 0.01; r ¼ 0.37, p < 0.01; r ¼ 0.36, p < 0.05; r ¼ 0.38, p < 0.01, respectively). The SST direction errors showed further significant correlations with the 6-month follow-up of the DIEPSS global score and the gait, bradykinesia, and rigidity items (r ¼ 0.67, p < 0.001; r ¼ 0.76, p < 0.001; r ¼ 0.67, p < 0.001; r ¼ 0.78, p < 0.001, respectively). The CRT mean correct latency was significantly
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Table 2 Correlations and partial correlations between the baseline side effects measures and neurocognitive measures (n ¼ 54). HDRS partialled out LUNSERS
K-WAIS CANTAB CRT IED
SST
SSP
Estimated IQ Premorbid IQ Mean correct latency Total correct trials Stages completed Total errors pre-ED errors EDS errors Direction errors Successful stops % GO trial RT SSRT Span length
RH
SE
0.18 0.27 0.29* 0.05 0.11 0.03 0.14 0.18 0.31* 0.13 0.20 0.06 0.22
0.26 0.36** 0.13 0.09 0.11 0.10 0.31* 0.25 0.19 0.10 0.11 0.05 0.20
DIEPSS
LUNSERS RH
SE
0.32* 0.25 0.10 0.13 0.02 0.06 0.07 0.04 0.03 0.19 0.16 0.05 0.04
0.15 0.24 0.30* 0.00 0.13 0.02 0.14 0.20 0.32* 0.10 0.19 0.10 0.24
0.22 0.33* 0.13 0.04 0.15 0.09 0.33* 0.27* 0.2 0.05 0.08 0.11 0.21
BAI partialled out DIEPSS
LUNSERS RH
SE
0.34* 0.26 0.10 0.16 0.01 0.06 0.07 0.04 0.03 0.18 0.15 0.07 0.04
0.07 0.15 0.34* 0.01 0.04 0.11 0.05 0.01 0.28* 0.10 0.07 0.10 0.23
0.16 0.28* 0.15 0.07 0.04 0.26 0.31* 0.07 0.12 0.26 0.12 0.12 0.22
HDRS and BAI partialled out DIEPSS
LUNSERS
DIEPSS
RH
SE
0.35* 0.27* 0.10 0.13 0.03 0.05 0.08 0.02 0.02 0.17 0.15 0.06 0.03
0.07 0.15 0.34* 0.02 0.03 0.12 0.04 0.00 0.28* 0.1 0.07 0.09 0.22
0.17 0.29* 0.15 0.09 0.02 0.28* 0.30* 0.05 0.12 0.27 0.13 0.11 0.21
0.35* 0.27* 0.10 0.13 0.02 0.05 0.08 0.03 0.02 0.17 0.15 0.06 0.03
*p < 0.05, **p < 0.01. LUNSERS, Liverpool University Neuroleptic Side Effects Rating Scale; SE, side effects; RH, red herring; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale; HDRS, Hamilton Depression Rating Scale; BAI, Beck’s Anxiety Inventory; K-WAIS, Korean Wechsler Adult Intelligence Scale; CRT, Choice Reaction Time; IED, Intradimensional/Extradimensional Shift; pre-ED, pre-Extradimensional shift; EDS, Extradimensional shift; SST, Stop Signal Task; RT, reaction time; SSRT, stop signal reaction time; SSP, Spatial Span.
correlated with the DIEPSS gait and rigidity items (r ¼ 0.29, p < 0.05; r ¼ 0.42, p < 0.01, respectively) and SD correct latency with DIEPSS global score, gait, bradykinesia, and rigidity (r ¼ 0.32, p < 0.05; r ¼ 0.36, p < 0.01; r ¼ 0.32, p < 0.05; rigidity, r ¼ 0.42, p < 0.01, respectively). There were no indications of sialorrhea, tremor, dystonia, and dyskinesia among the patients at 6-month follow-up. In terms of the changes (D) in the side effects scores during the 6-months, significant positive correlation was found between the baseline SST GO trial reaction time of the CANTAB and the changes in LUNSERS RH (Table 3). When the baseline scores of the RH and SE were partialled out respectively, however, such a correlation became non-significant. Instead, the SST direction errors became significantly correlated with the LUNSERS SE. It showed significant partial correlations particularly with psychic, extrapyramidal, and anticholinergic side effects subscales (r ¼ 0.34, p < 0.05; r ¼ 0.34, p < 0.05; r ¼ 0.29, p < 0.05, respectively).
The CANTAB CRT SD correct latency and SST direction errors correlated negatively with the changes (D) in the DIEPSS. Specifically, the SD correct latency was significantly associated with the DIEPSS measures of global score, gait, bradykinesia, and rigidity (r ¼ 0.32, p < 0.05; r ¼ 0.32, p < 0.05; r ¼ 0.38, p < 0.01; r ¼ 0.29, p < 0.05, respectively) as was SST direction (r ¼ 0.52, p < 0.001; r ¼ 0.56, p < 0.001; r ¼ 0.68, p < 0.001; r ¼ 0.34, p < 0.05, respectively). However, when the baseline DIEPSS total score was partialled out, CRT mean correct latency became significantly correlated with the changes in the DIEPSS total score. This was likely to be attributable to the significant partial correlations with the changes in the DIEPSS global score, bradykinesia, and rigidity (r ¼ 0.31, p < 0.05; r ¼ 0.31, p < 0.05; r ¼ 0.35, p < 0.05, respectively). Furthermore, the change in the DIEPSS total score retained its significant associations with the CANTAB CRT SD correct and SST direction errors even after partialling out the baseline DIEPSS total score. Specifically, the CANTAB CRT SD correct
Table 3 Correlations between baseline neurocognitive measures and 6-month side effects measures (n ¼ 51) and between baseline neurocognitive measures and changes (D) in side effects measures before and after partialling out for baseline scores. Changes (D) (Baseline e 6-month)
6-month LUNSERS
K-WAIS CANTAB CRT
IED
SST
SSP
Estimated IQ Premorbid IQ Mean correct latency SD correct latency Total correct trials Stages completed Total errors Pre-ED errors EDS errors Direction errors Successful stops % GO trial RT SSRT Span length
LUNSERS
LUNSERS
RH
SE
DIEPSS
RH (D)
SE (D)
DIEPSS(D)
RH (D) Baseline RH partialled out
SE (D) Baseline SE partialled out
DIEPSS (D) Baseline DIEPSS partialled out
0.11 0.08 0.12
0.13 0.14 0.09
0.23 0.13 0.28*
0.04 0.19 0.25
0.03 0.15 0.06
0.15 0.13 0.26
0.05 0.06 0.07
0.08 0.03 0.03
0.22 0.12 0.29*
0.15 0.14 0.10 0.03 0.04 0.03 0.38** 0.07 0.08 0.09 0.03
0.12 0.19 0.11 0.05 0.04 0.02 0.40** 0.15 0.09 0.08 0.04
0.34* 0.24 0.10 0.08 0.11 0.11 0.72*** 0.02 0.02 0.09 0.23
0.14 0.07 0.22 0.02 0.20 0.22 0.03 0.23 0.32* 0.02 0.26
0.08 0.08 0.22 0.08 0.27 0.19 0.14 0.24 0.18 0.02 0.17
0.32* 0.24 0.07 0.00 0.01 0.10 0.47*** 0.14 0.14 0.01 0.17
0.02 0.14 0.2 0.01 0.15 0.15 0.25 0.19 0.25 0.07 0.15
0.04 0.17 0.18 0.00 0.11 0.08 0.35* 0.22 0.15 0.07 0.06
0.36* 0.25 0.10 0.07 0.10 0.11 0.72*** 0.01 0.02 0.09 0.23
*p < 0.05, **p < 0.01, ***p < 0.001. LUNSERS, Liverpool University Neuroleptic Side Effects Rating Scale; SE, side effects; RH, red herring; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale; HDRS, Hamilton Depression Rating Scale; BAI, Beck’s Anxiety Inventory; K-WAIS, Korean Wechsler Adult Intelligence Scale; CRT, Choice Reaction Time; IED, Intradimensional/Extradimensional Shift; pre-ED, pre-Extradimensional shift; EDS, Extradimensional shift; SST, Stop Signal Task; RT, reaction time; SSRT, stop signal reaction time; SSP, Spatial Span.
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latency was significantly correlated with the changes in the global score, gait, bradykinesia, and rigidity (r ¼ 0.31, p < 0.05; r ¼ 0.30, p < 0.05; r ¼ 0.36, p < 0.05; r ¼ 0.36, p < 0.05, respectively). The SST direction errors were also strongly correlated with the DIEPSS global score, gait, bradykinesia, and rigidity (r ¼ 0.66, p < 0.001; r ¼ 0.67, p < 0.001; r ¼ 0.70, p < 0.001; r ¼ 0.63, p < 0.001, respectively). 3.4. Post hoc analysis of the correlations between the side effects measures One of the factors that we did not include in our main analyses was the longitudinal relationship between the measures of the side effects. To date, there has been no report on even the crosssectional associations between the LUNSERS and the DIEPSS to our knowledge and it was necessary to examine their longitudinal associations to account for their convergence with SST direction errors. Hence, we carried out post hoc analyses on the correlations between the 6-month LUNSERS and DIEPSS as well as between their changes (D). As the result, we found significant cross-sectional correlations of the LUNSERS SE and RH total scores (r ¼ 0.48, p < 0.001; r ¼ 0.35, p < 0.05, respectively) with the DIEPSS total score and between selective LUNSERS subscales of the LUNSERS and the DIEPSS items related with motor side effects (Table 4). The changes (D) in the total scores of the LUNSERS SE and RH and DIEPSS over the 6 months did not correlate significantly. 4. Discussion In this study, we examined the relationships between the baseline neurocognitive functions and the side effects measures at baseline and 6-month follow-up and their changes (D) in patients with schizophrenia by conducting partial correlation analyses to control for the effects of baseline anxiety and depression. As a result, we have found some significant associations between the measures of the neurocognitive functions and both self-reported and clinician-rated side effects measures that may have important implications for future clinical and pharmacological research. The cross-sectional correlations at the baseline revealed that over-reporting of side effects as reflected by the LUNSERS RH was significantly positively correlated with the CANTAB CRT mean correct latency, or the slower reaction time, and SST direction errors, or failure to discriminate between left and right signal under inhibition condition. The patients who performed poorly on these neurocognitive measures were likely to over-attribute their symptoms to the effects of medication by reporting RH items such as chilblains and painful joints. The SST direction errors further correlated with 6-month assessment of the RH and SE of the LUNSERS and the DIEPSS, indicating long-term associations with side effects measures. High correlation of the SST direction errors with the DIEPSS was attributable to the strong associations with the items related to
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motor side effects, such as gait, bradykinesia, rigidity. These items were also associated with baseline reaction speed (i.e., CRT mean correct latency) and its variability (CRT SD correct latency). The changes (D) in scores over the 6-month period were largely consistent with and reflected such associations whereby poor levels of baseline SST direction errors and CRT mean and SD correct latency were significantly associated with less improvement in both self-reported and clinician-rated side effects. Interestingly, CRT mean correct latency and SST direction errors were not significantly correlated, implicating independent cognitive processes, with the former involving alertness and motor function and the latter involving signal discrimination under response inhibition condition, or executive control. Such a distinction is important because SST mainly differs from the CRT subtest in that it involves the presence of auditory signal to differentiate between “go” and “stop” trials. A study by Aron and Poldrack (2006) has identified involvement of different pathways for these trials, with “going” involving frontal, striatal, pallidal, and motor cortical regions and “stopping” involving right inferior frontal cortex and subthalamic nucleus. While these processes are not completely independent (Boehler et al., 2010), our results suggest that side effects are likely to be associated with the impairment in the neurobiological mechanism involving the switching of these pathways and that these measures warrant further examination for their utility in predicting outcomes in side effects. Other neurocognitive measures associated with the side effects at the baseline were the K-WAIS estimated IQ and premorbid IQ scores and the CANTAB IED pre-ED errors. The K-WAIS estimated IQ, derived from verbal and performance components of mental ability, was positively correlated with DIEPSS total score, and such a result can be attributed to negative effect of more severe levels of motor side effects on timed subtests such as block design and picture arrangement. On the other hand, the premorbid IQ, derived from the vocabulary subtest, largely reflects verbal ability which is considered to be more crystallized compared with other cognitive abilities. It is unclear how this subtest relates to the self-reported side effects of the LUNSERS but one key contributing factor may be the frequency of side effects endorsed, rather than their severity (Lindström et al., 2001). In fact, our post hoc analysis revealed that the premorbid IQ was significantly correlated with the total number of endorsed SE items (r ¼ 0.33, p < 0.05), but not that of RH items. Furthermore, the significance of the correlation between the premorbid IQ and the LUNSERS SE total score disappeared once the number of endorsed SE items was partialled out. As to why patients with lower premorbid intellectual functioning as measured by the vocabulary subtest are prone to report a wider range of side effects, it may be hypothesized that some impairments in cognitive processes involved in generating precise spoken definition, such as auditory-verbal working memory, generative ability, oral fluency, and semantic retrieval (Lezak, 2004), may also cause over-generalizing of subjective discomfort. The measure of IED pre-ED errors, on the other hand, reflects
Table 4 The correlations between LUNSERS side effects subscales and DIEPSS items at 6-month follow-up (n ¼ 51). LUNSERS
DIEPSSa
Gait Bradykinesia Rigidity Akathesia Global score
Psychic
EPS
Hormonal
Anticholinergic
Autonomic
Allergic
Miscellaneous
0.54*** 0.57*** 0.40** 0.26 0.56***
0.48*** 0.51*** 0.43** 0.23 0.51***
0.04 0.09 0.08 0.08 0.09
0.29* 0.34* 0.41** 0.08 0.34*
0.36** 0.44** 0.46*** 0.02 0.44**
0.24 0.46** 0.35* 0.06 0.46**
0.30* 0.37** 0.24 0.09 0.37**
*p < 0.05, **p < 0.01, ***p < 0.001. LUNSERS, Liverpool University Neuroleptic Side Effects Rating Scale; EPS, Extrapyramidal; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale. a There were no side effects reported for sialorrhea, tremor, dystonia, and dyskinesia.
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the failure to maintain attention to a reinforced stimulus prior to set-shifting and it was also significantly correlated with SE of the LUNSERS. Our post hoc analysis revealed the same pattern of results as the premorbid IQ, where pre-ED errors were significantly correlated with the total number of endorsed SE items (r ¼ 0.35, p < 0.05), but not RH items. Accordingly, the association between the pre-ED errors and the LUNSERS SE total score became non-significant after partialling out the frequency of endorsement of SE items. However, as pre-ED errors significantly correlated with only hormonal side effects subscale while the premorbid IQ correlated with the anticholinergic, other autonomic, and allergic side effects after partialling out depression and anxiety, it is likely that pre-ED errors may be selectively related with specific side effects and premorbid IQ with more overall global discomfort. Our study did not consider the level of psychopathology as one of our variables while there has been inconsistent results regarding the associations between side effects and psychopathology. Day et al. (1995) found no association between LUNSERS SE and the subscales of the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) among hospitalized patients while we previously found positive and anxiety/depressive symptoms to contribute to SE among outpatients, using the symptoms derived from the factor analysis of the PANSS (Hwang et al., 2010). While a strong consensus is yet to be reached on the effects of psychopathology on neurocognitive functioning in patients with schizophrenia, we have previously found no associations between psychopathology and executive functioning in chronic patients of schizophrenia (Hwang et al., 2009) and no difference in CRT mean correct latency and SST direction errors between the schizophrenia remitted and nonremitted patients (Yun et al., 2011). As such, the significant associations found between the baseline CANTAB measures and side effects in this study are likely to be mostly independent from the severity of psychopathology. Lastly, emergence of significant cross-sectional correlations at 6month follow-up between the measures of side effects, which did not show at the baseline, suggested that self-report measures and clinician-rated measures of side effects better converge with time. While we suggested above that baseline associations between the CANTAB measures and side effects are likely to be independent of psychopathology, it is possible that improvement in side effects and psychopathology over time may be significantly associated, and that they may share some common etiological grounds which may be tabbed by SST direction errors. Further examination of the utility of this measure in predicting long-term outcome of neuroleptic side effects is warranted along with possible connections with other relevant clinical variables, such as insight, compliance, and drug attitude. Author contributions Samuel Suk-Hyun Hwang was involved in the analysis of the data and drafting and editing of the manuscript. Yeni Kim was involved in the designing of the study and data collection. Da Young Yun was involved in data collection and analysis of the data. Yong Sik Kim was involved in the designing of the study and drafting and editing of the manuscript. Hee Yeon Jung was involved in the designing of the study and data collection and analysis, as well as in the drafting and editing of the manuscript. Conflict of interest None of the authors of this manuscript report any conflict of interest.
Acknowledgments This research was supported by the Seoul National University Hospital (SNUH) Research Fund (Grant Number: 04-2009-93) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Grant Number: 2010-0010274). The SNUH and NRF had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
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Contents lists available at SciVerse ScienceDirect
Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/psychires
Exploration of the associations between neurocognitive function and neuroleptics side effects Samuel Suk-Hyun Hwang a, b, Yeni Kim c, Da Young Yun d, Yong Sik Kim b, e, Hee Yeon Jung b, d, * a
Interdisciplinary Study in Brain Science, Seoul National University College of Natural Science, Seoul 110-744, Republic of Korea Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea c Department of Child Psychiatry, Seoul National Hospital, Seoul 143-711, Republic of Korea d Department of Psychiatry, SMG-SNU Boramae Medical Center, College of Medicine Seoul National University, Seoul 156-707, Republic of Korea e Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 October 2011 Received in revised form 3 April 2012 Accepted 3 April 2012
The etiology of side effects of antipsychotic medications can be conceptualized as involving both specific pharmacological actions of a drug and any mental and physical states attributed by the patient. Both factors are likely to be linked with neurocognitive functioning which may largely affect the subjective experience of side effects in patients with schizophrenia. In this study, we examined whether baseline neurocognitive functions, such as IQ, attention, executive functioning, and short-term memory, are associated with baseline and 6-month follow-up measures of self-reported Liverpool University Neuroleptics Side Effects Scale (LUNSERS) and clinician-rated Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). At the baseline, anxiety and depression were significantly associated with LUNSERS red herring (RH) and total side effects (SE) but not with DIEPSS. There was no association between LUNSERS and DIEPSS. Controlling for anxiety and depression, IQ was significantly correlated with DIEPSS, while choice reaction time (CRT) and stop signal task (SST) direction errors correlated with RH, and intra eextradimensional set-shifting (IED) total errors and pre-extradimensional set-shifting (pre-EDs) errors correlated with SE. The baseline SST direction errors further correlated significantly with RH and SE and DIEPSS total score of 6-month follow-up, and CRT mean and SD correct latency also correlated with DIEPSS. The correlations between the 6-month changes (D) in the same side effects measures and baseline neurocognitive measures were also significant, except that between RH and SST direction errors. Such evidences supported association between both self-rated and clinician-rated side effects and selective impairments in attention and executive functioning. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Self-reported side effects Neurocognitive functions LUNSERS CANTAB
1. Introduction Favorable outcome of antipsychotics treatment in patients with schizophrenia is largely dependent on good compliance, which is required for better assessment of efficacy and formulation of new treatment strategy. However, one of the major causes of noncompliance and treatment discontinuation has been found to be side effects of antipsychotic medication (Vorunganti et al., 2008; Kahn et al., 2008). Side effects can be largely conceptualized as comprising effects accountable by the specific pharmacological actions of a drug and by any mental and physical states attributed by the patient. As self-reported or subjective side effects arguably reflect more of the latter component compared to clinician* Corresponding author. Department of Psychiatry, SMG-SNU Boramae Medical Center, Seoul 156-707, Republic of Korea. E-mail addresses: [email protected], [email protected] (H.Y. Jung). 0022-3956/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2012.04.005
assessed measures, they have proven to not only predict treatment compliance (Hogan et al., 1983; Kampman et al., 2002) but correlate significantly with other self-reported measures, such as quality of life (Hwang et al., 2009; Wolters et al., 2009). By the same token, self-reports of side effects have been found to be adversely affected by psychopathology, such as severity of positive and depressive/anxiety symptoms (Hwang et al., 2010), and to be associated with poor overall executive functioning (Hwang et al., 2009; Kim et al., 2002). In most clinical studies, self-reported measures of side effects are accepted as outcome measures without an extensive examination of its validity. However, patients with schizophrenia in particular have been found to report side effects more frequently than the clinicians (Lindström et al., 2001). In addition, significant variability is present in how patients perceive their state of illness and side effects relative to clinical evaluation which may result in the lack of association between patient-rated and clinician-rated
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measures. For example, our recent study (Jung et al., 2010) demonstrated that patients with schizophrenia who show relatively low correspondence between subjective quality of life and the clinician-rated functioning also show weak or no association between subjective quality of life and clinician-rated side effects. Those with high correspondence, in contrast, showed stronger associations between self-report and clinician-rated measures, including side effects. From the etiological viewpoint, it may be important to examine whether such correspondence may be associated with the presence and severity of impairments in neurocognitive function in patients with schizophrenia, particularly in terms of self-reported and clinician-rated side effects. To date, however, no study has investigated how neurocognitive functions may be directly associated with cross-sectional and long-term ratings of side effects by patients and clinicians. In the present study, we therefore examined how neurocognitive functions at baseline are related to the self-reported and clinician-rated side effects of the baseline and 6-month follow-up and the changes (D) therein. 2. Methods 2.1. Participants Fifty-four Korean outpatients were followed for 6-months post baseline assessment with lost-to-follow-up of only 3 female patients. These patients were also included in a recently published study by Yun et al. (2011), which cross-sectionally compared the executive functions of remitted and non-remitted patients of schizophrenia and healthy control. These patients were recruited from the psychiatric outpatient clinic of the Boramae Medical Center of Seoul, Korea, and have been diagnosed by two experienced psychiatrists (YK and HYJ) according the DSM-IV diagnostic criteria. The patients were further assessed with the Structured Clinical Interview for DSM-IV (SCID) by a trained clinical psychologist to exclude other Axis I diagnoses such as schizoaffective disorder and substance abuse. The age, years of education, and duration of illness of all patients at the baseline were 34.2 (SD ¼ 10.4), 13.2 (SD ¼ 2.4), and 8.7 (SD ¼ 8.0), respectively, and 25 (46%) were males. Interested readers may refer to the study by Yun et al. (2011) for more detailed information on patient recruitment and diagnoses. 2.2. Procedure At the time of initial clinical assessment, the Korean versions of the Liverpool University Neuroleptics Side Effects Scale (LUNSERS: Day et al., 1995; Lambert et al., 2003; Jung et al., 2005), the DrugInduced Extrapyramidal Symptoms Scale (DIEPSS: Inada, 1996; Kim et al., 2002), the Beck Anxiety Inventory (BAI: Beck et al., 1988; Kwon, 1997), and Hamilton Depression Rating Scale (HDRS: Hamilton, 1960; Yi et al., 2005) were completed. Then, within 10 days of clinical assessment, neuropsychological assessment that included the short form of the Korean version of the Wechsler Adult Intelligence Scale (K-WAIS: Wechsler, 1981; Yeom et al., 1992) and subtests of the CANTAB (CANTAB eclipse, 2006), a series of computerized tests using a touch-sensitive screen on an IBMcompatible PC, were completed. The patients were followed up 6 months post the baseline assessment, and they once again completed both side effects measures. Written informed consent was obtained from all patients prior to the initiation of study procedures whose protocol had been approved by the Institutional Review Board of Boramae Medical Center and carried out in accordance with the latest version of the Declaration of Helsinki. Detailed descriptions of the procedure and neurocognitive
measures used in this study are provided in the previous study by Yun et al. (2011). 2.3. Measures 2.3.1. Clinical measures To assess the overall level of depression, the HDRS which includes items such as overall depression, guilt, suicide, insomnia, problems related to work, psychomotor retardation, agitation, anxiety, loss of weight, and loss of insight (Hamilton, 1960; Yi et al., 2005) was completed. As an interviewer-administered and rated measuring scale, a higher score signifies more severe levels of depression. The level of subjective anxiety of the patients was assessed with the BAI, a 21-item self-reported measure containing items such as numbness or tingling, feeling hot, wobbliness in legs, and inability to relax (Beck et al., 1988; Kwon, 1997). 2.3.2. Side-effects measures All patients completed Korean version of the LUNSERS, a selfreported measure which consists of 41 items pertaining to various subscales of neuroleptics-related side effects (SE: psychic, extrapyramidal, anticholinergic, other autonomic, allergic, and hormonal) and 10 red herring (RH) items not directly related to known antipsychotic side effects. The RH subscale, which includes items such as runny nose, chilblains, hair loss, and urine darker than usual, has shown to be useful for detecting over-reporting patients (Lambert et al., 2003). Two experienced psychiatrists (YK and HYJ) assessed the severity of side effects with the Korean version of the DIEPSS. It contains 8 individual items, i.e., gait, bradykinesia, sialorrhea, rigidity, tremor, akathisia, dystonia, and dyskinesia, and one global item which considers the overall severity and frequency of the individual items and their negative influence on subjective distress and daily activity (Inada, 1996; Kim et al., 2002). 2.3.3. Neurocognitive measures The short form of the K-WAIS is the Korean version of the WAISRevised (Wechsler, 1981). The composite score was derived from the four subtests from the K-WAIS (Vocabulary, Arithmetic, Picture Arrangement, and Block Design) to estimate current intellectual functioning. The correlation between the estimated IQ scores derived from the K-WAIS-short form and the full battery of the KWAIS was reported to be 0.95 (Kim and Lee, 1995). Also, the Vocabulary subtest was additionally used as the estimation of premorbid IQ. The subtests of the CANTAB were used to assess the domains of attentional ability, as reflected by processing speed and accuracy, executive function, including set-shifting and response inhibition, and spatial short-term memory. Specifically, Choice Reaction Time (CRT), a 2-choice reaction-time task, provided the measures of processing accuracy (no. of correct trials based on two assessment sets of 50 trials each following 24 practice trials), and motor speed (mean correct latency) and its variability (SD correct latency). Intradimensional/Extradimensional Shift (IED), a computer touchscreen adaptation of the Wisconsin Card Sorting Test (WCST), tested the ability to maintain attention on a reinforced stimulus (intradimensional shift, IDS) and then to shift attention to the previously irrelevant stimulus (extradimensional shift, EDS) through 9 stages of increasing complexity. Its outcome variables were the number of stages completed, total errors, preextradimensional shift errors (pre-ED errors), and errors at the extradimensional shift (EDS errors). Stop Signal Task (SST) measured an individual’s ability to inhibit a prepotent response. We obtained direction errors, proportion of successful stops, reaction time on GO trials, and the processing time required to inhibit a prepotent motor
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response (SSRT). Lastly, Spatial Span (SSP), a computerized version of the Corsi block-tapping test, assessed the spatial short-term memory capacity with the maximum span length as the outcome measure. 2.4. Statistical analysis The baseline neurocognitive function measures were correlated with the side effects measures of the baseline and 6-month assessments after investigating the correlations among the measures of side effects and HDRS and BAI to determine the necessity to control for the effects of depression and subjective anxiety. Then, partial correlation analyses were carried out as necessary. All analyses were conducted using SPSS version 15 for Windows (SPSS Inc. Chicago IL, USA SPSS, Inc: SPSS for Windows. Chicago, IL, USA: Rel 13.0; 2004.SPSS, Inc., Chicago, IL, USA). 3. Results 3.1. Baseline correlations among the LUNSERS, DIEPSS, HDRS, and BAI Presented in Table 1 are the correlations among the baseline measures of side effects and HDRS and BAI. Significant positive correlations were found among the LUNSERS subscales, HDRS, and BAI, but none of them were significantly associated with the DIEPSS. Both RH and SE of the LUNSERS were more strongly correlated with the BAI than HDRS. 3.2. Relationship between the baseline side effects and neurocognitive measures Significant associations between the baseline side effects measures and depression and anxiety symptoms signified the need to control their effects in further correlation analyses between side effects measures of the LUNSERS and neurocognitive measures. In Table 2 are the results of correlation and partial correlation analyses controlling for HDRS, BAI, or both. The RH subscale of the LUNSERS was significantly associated with the CRT mean correct latency and the SST direction errors of the CATAB and these correlations remained significant in all partial correlations. Our post hoc partial correlation analyses controlling for depression and anxiety showed that mean correct latency was significantly associated with runny nose, chilblains, and painful joints (r ¼ 0.39, p < 0.01; r ¼ 0.32, p < 0.05; r ¼ 0.32, p < 0.05, respectively). On the other hand, SST direction errors was significantly associated with chilblains, weak nails, and painful joints items of the baseline RH (r ¼ 0.55, p < 0.001; r ¼ 0.34, p < 0.05; r ¼ 0.37, p < 0.01, respectively). As for the total side effects score attributable to the effects due to medication (SE), it was significantly associated with the premorbid IQ derived from the vocabulary subtest of the K-WAIS and pre-ED errors of the CANTAB IED subtest. These correlations remained significant in all partial correlations. As for the side effects subscales Table 1 Baseline correlations among the LUNSERS, DIEPSS, HDRS, and BAI (n ¼ 54).
LUNSERS HDRS BAI
RH SE
LUNSERS SE
HDRS
BAI
DIEPSS
0.82***
0.31* 0.36**
0.66*** 0.79*** 0.54***
0.10 0.02 0.08 0.08
*p < 0.05, **p < 0.01, ***p < 0.001. LUNSERS, Liverpool University Neuroleptic Side Effects Rating Scale; SE, side effects; RH, red herring; HDRS, Hamilton Depression Rating Scale; BAI, Beck’s Anxiety Inventory.
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of the LUNSERS, the premorbid IQ significantly correlated with all but miscellaneous side effects subscale (psychic, r ¼ 0.27, p < 0.05; extrapyramidal, r ¼ 0.31, p < 0.05; hormonal, r ¼ 0.28, p < 0.05; anticholinergic, r ¼ 0.36, p < 0.01; other autonomic, r ¼ 0.38, p < 0.01; allergic, r ¼ 0.38, p < 0.01, respectively). In partial correlations, when controlling for HDRS, the premorbid IQ significantly correlated with the extrapyramidal, hormonal, anticholinergic, other autonomic, and allergic side effects subscales (r ¼ 0.29, p < 0.05; r ¼ 0.28, p < 0.05; r ¼ 0.34, p < 0.01; r ¼ 0.36, p < 0.05; r ¼ 0.37, p < 0.01, respectively). When controlling for BAI, premorbid IQ was significantly correlated with the anticholinergic, other autonomic, and allergic side effects subscales (r ¼ 0.28, p < 0.05; r ¼ 0.31, p < 0.05; r ¼ 0.31, p < 0.05, respectively). Lastly, when both HDRS and BAI were partialled out, the premorbid IQ still remained significantly correlated with the anticholinergic, other autonomic, and allergic side effects (r ¼ 0.28, p < 0.05; r ¼ 0.31, p < 0.05; r ¼ 0.32, p < 0.05, respectively). The pre-ED errors of the CANTAB IED subtest was significantly correlated with only psychic and hormonal side effects subscales of the LUNSERS (r ¼ 0.38, p < 0.05; r ¼ 0.38, p < 0.001, respectively) and these correlations remained significant when only HDRS was partialled out (r ¼ 0.31, p < 0.05; r ¼ 0.46, p < 0.001, respectively). However, the pre-ED errors significantly correlated with only hormonal side effects subscale when BAI (r ¼ 0.45, p < 0.01) or both BAI and HDRS (r ¼ 0.44, p < 0.01) were partialled out. Interestingly, partialling out HDRS resulted in significantly correlations between the LUNSERS SE and the EDS errors of the IED subtest which could be attributed to significant partial correlations with the hormonal and other autonomic symptoms subscales (r ¼ 0.31, p < 0.05; r ¼ 0.30, p < 0.05, respectively), and partialling out both BAI and HDRS had the effect of revealing significant correlation between the SE and total errors of the same subtest attributable to significant partial correlations with the hormonal and allergic side effects (r ¼ 0.31, p < 0.05; r ¼ 0.28, p < 0.05, respectively). Lastly, the estimated IQ of the K-WAIS was significantly associated with the DIEPSS with significant correlations with items such as bradykinesia, tremor, akathesia, and global score (r ¼ 0.37, p < 0.01; r ¼ 0.30, p < 0.05; r ¼ 0.30, p < 0.05; r ¼ 0.34, p < 0.05, respectively). 3.3. Relationships between the baseline neurocognitive and 6month side effects measures and their change (D) scores The baseline measures of neurocognitive functions were correlated with the 6-month side effects measures and with their changes (D) before and after partialling out their respective baseline scores (Table 3). The baseline HDRS and BAI were not partialled out in this analysis because they were not significantly correlated with the neurocognitive measures, except proportion of successful stops of the CANTAB IED subtest (r ¼ 0.31, p < 0.05). The baseline SST direction errors of the CANTAB was significantly correlated with the 6-month follow-up rating of the LUNSERS RH with significant correlations with chilblains, hair loss greasy skin, flushing face, and painful joints (r ¼ 0.78, p < 0.001; r ¼ 0.41, p < 0.01; r ¼ 0.39, p < 0.01; r ¼ 0.37, p < 0.05; r ¼ 0.47, p < 0.001, respectively). It also correlated significantly with SE, particularly with psychic, extrapyramidal, anticholinergic, miscellaneous, and other autonomic side effects subscales (r ¼ 0.46, p < 0.01; r ¼ 0.42, p < 0.01; r ¼ 0.37, p < 0.01; r ¼ 0.36, p < 0.05; r ¼ 0.38, p < 0.01, respectively). The SST direction errors showed further significant correlations with the 6-month follow-up of the DIEPSS global score and the gait, bradykinesia, and rigidity items (r ¼ 0.67, p < 0.001; r ¼ 0.76, p < 0.001; r ¼ 0.67, p < 0.001; r ¼ 0.78, p < 0.001, respectively). The CRT mean correct latency was significantly
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Table 2 Correlations and partial correlations between the baseline side effects measures and neurocognitive measures (n ¼ 54). HDRS partialled out LUNSERS
K-WAIS CANTAB CRT IED
SST
SSP
Estimated IQ Premorbid IQ Mean correct latency Total correct trials Stages completed Total errors pre-ED errors EDS errors Direction errors Successful stops % GO trial RT SSRT Span length
RH
SE
0.18 0.27 0.29* 0.05 0.11 0.03 0.14 0.18 0.31* 0.13 0.20 0.06 0.22
0.26 0.36** 0.13 0.09 0.11 0.10 0.31* 0.25 0.19 0.10 0.11 0.05 0.20
DIEPSS
LUNSERS RH
SE
0.32* 0.25 0.10 0.13 0.02 0.06 0.07 0.04 0.03 0.19 0.16 0.05 0.04
0.15 0.24 0.30* 0.00 0.13 0.02 0.14 0.20 0.32* 0.10 0.19 0.10 0.24
0.22 0.33* 0.13 0.04 0.15 0.09 0.33* 0.27* 0.2 0.05 0.08 0.11 0.21
BAI partialled out DIEPSS
LUNSERS RH
SE
0.34* 0.26 0.10 0.16 0.01 0.06 0.07 0.04 0.03 0.18 0.15 0.07 0.04
0.07 0.15 0.34* 0.01 0.04 0.11 0.05 0.01 0.28* 0.10 0.07 0.10 0.23
0.16 0.28* 0.15 0.07 0.04 0.26 0.31* 0.07 0.12 0.26 0.12 0.12 0.22
HDRS and BAI partialled out DIEPSS
LUNSERS
DIEPSS
RH
SE
0.35* 0.27* 0.10 0.13 0.03 0.05 0.08 0.02 0.02 0.17 0.15 0.06 0.03
0.07 0.15 0.34* 0.02 0.03 0.12 0.04 0.00 0.28* 0.1 0.07 0.09 0.22
0.17 0.29* 0.15 0.09 0.02 0.28* 0.30* 0.05 0.12 0.27 0.13 0.11 0.21
0.35* 0.27* 0.10 0.13 0.02 0.05 0.08 0.03 0.02 0.17 0.15 0.06 0.03
*p < 0.05, **p < 0.01. LUNSERS, Liverpool University Neuroleptic Side Effects Rating Scale; SE, side effects; RH, red herring; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale; HDRS, Hamilton Depression Rating Scale; BAI, Beck’s Anxiety Inventory; K-WAIS, Korean Wechsler Adult Intelligence Scale; CRT, Choice Reaction Time; IED, Intradimensional/Extradimensional Shift; pre-ED, pre-Extradimensional shift; EDS, Extradimensional shift; SST, Stop Signal Task; RT, reaction time; SSRT, stop signal reaction time; SSP, Spatial Span.
correlated with the DIEPSS gait and rigidity items (r ¼ 0.29, p < 0.05; r ¼ 0.42, p < 0.01, respectively) and SD correct latency with DIEPSS global score, gait, bradykinesia, and rigidity (r ¼ 0.32, p < 0.05; r ¼ 0.36, p < 0.01; r ¼ 0.32, p < 0.05; rigidity, r ¼ 0.42, p < 0.01, respectively). There were no indications of sialorrhea, tremor, dystonia, and dyskinesia among the patients at 6-month follow-up. In terms of the changes (D) in the side effects scores during the 6-months, significant positive correlation was found between the baseline SST GO trial reaction time of the CANTAB and the changes in LUNSERS RH (Table 3). When the baseline scores of the RH and SE were partialled out respectively, however, such a correlation became non-significant. Instead, the SST direction errors became significantly correlated with the LUNSERS SE. It showed significant partial correlations particularly with psychic, extrapyramidal, and anticholinergic side effects subscales (r ¼ 0.34, p < 0.05; r ¼ 0.34, p < 0.05; r ¼ 0.29, p < 0.05, respectively).
The CANTAB CRT SD correct latency and SST direction errors correlated negatively with the changes (D) in the DIEPSS. Specifically, the SD correct latency was significantly associated with the DIEPSS measures of global score, gait, bradykinesia, and rigidity (r ¼ 0.32, p < 0.05; r ¼ 0.32, p < 0.05; r ¼ 0.38, p < 0.01; r ¼ 0.29, p < 0.05, respectively) as was SST direction (r ¼ 0.52, p < 0.001; r ¼ 0.56, p < 0.001; r ¼ 0.68, p < 0.001; r ¼ 0.34, p < 0.05, respectively). However, when the baseline DIEPSS total score was partialled out, CRT mean correct latency became significantly correlated with the changes in the DIEPSS total score. This was likely to be attributable to the significant partial correlations with the changes in the DIEPSS global score, bradykinesia, and rigidity (r ¼ 0.31, p < 0.05; r ¼ 0.31, p < 0.05; r ¼ 0.35, p < 0.05, respectively). Furthermore, the change in the DIEPSS total score retained its significant associations with the CANTAB CRT SD correct and SST direction errors even after partialling out the baseline DIEPSS total score. Specifically, the CANTAB CRT SD correct
Table 3 Correlations between baseline neurocognitive measures and 6-month side effects measures (n ¼ 51) and between baseline neurocognitive measures and changes (D) in side effects measures before and after partialling out for baseline scores. Changes (D) (Baseline e 6-month)
6-month LUNSERS
K-WAIS CANTAB CRT
IED
SST
SSP
Estimated IQ Premorbid IQ Mean correct latency SD correct latency Total correct trials Stages completed Total errors Pre-ED errors EDS errors Direction errors Successful stops % GO trial RT SSRT Span length
LUNSERS
LUNSERS
RH
SE
DIEPSS
RH (D)
SE (D)
DIEPSS(D)
RH (D) Baseline RH partialled out
SE (D) Baseline SE partialled out
DIEPSS (D) Baseline DIEPSS partialled out
0.11 0.08 0.12
0.13 0.14 0.09
0.23 0.13 0.28*
0.04 0.19 0.25
0.03 0.15 0.06
0.15 0.13 0.26
0.05 0.06 0.07
0.08 0.03 0.03
0.22 0.12 0.29*
0.15 0.14 0.10 0.03 0.04 0.03 0.38** 0.07 0.08 0.09 0.03
0.12 0.19 0.11 0.05 0.04 0.02 0.40** 0.15 0.09 0.08 0.04
0.34* 0.24 0.10 0.08 0.11 0.11 0.72*** 0.02 0.02 0.09 0.23
0.14 0.07 0.22 0.02 0.20 0.22 0.03 0.23 0.32* 0.02 0.26
0.08 0.08 0.22 0.08 0.27 0.19 0.14 0.24 0.18 0.02 0.17
0.32* 0.24 0.07 0.00 0.01 0.10 0.47*** 0.14 0.14 0.01 0.17
0.02 0.14 0.2 0.01 0.15 0.15 0.25 0.19 0.25 0.07 0.15
0.04 0.17 0.18 0.00 0.11 0.08 0.35* 0.22 0.15 0.07 0.06
0.36* 0.25 0.10 0.07 0.10 0.11 0.72*** 0.01 0.02 0.09 0.23
*p < 0.05, **p < 0.01, ***p < 0.001. LUNSERS, Liverpool University Neuroleptic Side Effects Rating Scale; SE, side effects; RH, red herring; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale; HDRS, Hamilton Depression Rating Scale; BAI, Beck’s Anxiety Inventory; K-WAIS, Korean Wechsler Adult Intelligence Scale; CRT, Choice Reaction Time; IED, Intradimensional/Extradimensional Shift; pre-ED, pre-Extradimensional shift; EDS, Extradimensional shift; SST, Stop Signal Task; RT, reaction time; SSRT, stop signal reaction time; SSP, Spatial Span.
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latency was significantly correlated with the changes in the global score, gait, bradykinesia, and rigidity (r ¼ 0.31, p < 0.05; r ¼ 0.30, p < 0.05; r ¼ 0.36, p < 0.05; r ¼ 0.36, p < 0.05, respectively). The SST direction errors were also strongly correlated with the DIEPSS global score, gait, bradykinesia, and rigidity (r ¼ 0.66, p < 0.001; r ¼ 0.67, p < 0.001; r ¼ 0.70, p < 0.001; r ¼ 0.63, p < 0.001, respectively). 3.4. Post hoc analysis of the correlations between the side effects measures One of the factors that we did not include in our main analyses was the longitudinal relationship between the measures of the side effects. To date, there has been no report on even the crosssectional associations between the LUNSERS and the DIEPSS to our knowledge and it was necessary to examine their longitudinal associations to account for their convergence with SST direction errors. Hence, we carried out post hoc analyses on the correlations between the 6-month LUNSERS and DIEPSS as well as between their changes (D). As the result, we found significant cross-sectional correlations of the LUNSERS SE and RH total scores (r ¼ 0.48, p < 0.001; r ¼ 0.35, p < 0.05, respectively) with the DIEPSS total score and between selective LUNSERS subscales of the LUNSERS and the DIEPSS items related with motor side effects (Table 4). The changes (D) in the total scores of the LUNSERS SE and RH and DIEPSS over the 6 months did not correlate significantly. 4. Discussion In this study, we examined the relationships between the baseline neurocognitive functions and the side effects measures at baseline and 6-month follow-up and their changes (D) in patients with schizophrenia by conducting partial correlation analyses to control for the effects of baseline anxiety and depression. As a result, we have found some significant associations between the measures of the neurocognitive functions and both self-reported and clinician-rated side effects measures that may have important implications for future clinical and pharmacological research. The cross-sectional correlations at the baseline revealed that over-reporting of side effects as reflected by the LUNSERS RH was significantly positively correlated with the CANTAB CRT mean correct latency, or the slower reaction time, and SST direction errors, or failure to discriminate between left and right signal under inhibition condition. The patients who performed poorly on these neurocognitive measures were likely to over-attribute their symptoms to the effects of medication by reporting RH items such as chilblains and painful joints. The SST direction errors further correlated with 6-month assessment of the RH and SE of the LUNSERS and the DIEPSS, indicating long-term associations with side effects measures. High correlation of the SST direction errors with the DIEPSS was attributable to the strong associations with the items related to
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motor side effects, such as gait, bradykinesia, rigidity. These items were also associated with baseline reaction speed (i.e., CRT mean correct latency) and its variability (CRT SD correct latency). The changes (D) in scores over the 6-month period were largely consistent with and reflected such associations whereby poor levels of baseline SST direction errors and CRT mean and SD correct latency were significantly associated with less improvement in both self-reported and clinician-rated side effects. Interestingly, CRT mean correct latency and SST direction errors were not significantly correlated, implicating independent cognitive processes, with the former involving alertness and motor function and the latter involving signal discrimination under response inhibition condition, or executive control. Such a distinction is important because SST mainly differs from the CRT subtest in that it involves the presence of auditory signal to differentiate between “go” and “stop” trials. A study by Aron and Poldrack (2006) has identified involvement of different pathways for these trials, with “going” involving frontal, striatal, pallidal, and motor cortical regions and “stopping” involving right inferior frontal cortex and subthalamic nucleus. While these processes are not completely independent (Boehler et al., 2010), our results suggest that side effects are likely to be associated with the impairment in the neurobiological mechanism involving the switching of these pathways and that these measures warrant further examination for their utility in predicting outcomes in side effects. Other neurocognitive measures associated with the side effects at the baseline were the K-WAIS estimated IQ and premorbid IQ scores and the CANTAB IED pre-ED errors. The K-WAIS estimated IQ, derived from verbal and performance components of mental ability, was positively correlated with DIEPSS total score, and such a result can be attributed to negative effect of more severe levels of motor side effects on timed subtests such as block design and picture arrangement. On the other hand, the premorbid IQ, derived from the vocabulary subtest, largely reflects verbal ability which is considered to be more crystallized compared with other cognitive abilities. It is unclear how this subtest relates to the self-reported side effects of the LUNSERS but one key contributing factor may be the frequency of side effects endorsed, rather than their severity (Lindström et al., 2001). In fact, our post hoc analysis revealed that the premorbid IQ was significantly correlated with the total number of endorsed SE items (r ¼ 0.33, p < 0.05), but not that of RH items. Furthermore, the significance of the correlation between the premorbid IQ and the LUNSERS SE total score disappeared once the number of endorsed SE items was partialled out. As to why patients with lower premorbid intellectual functioning as measured by the vocabulary subtest are prone to report a wider range of side effects, it may be hypothesized that some impairments in cognitive processes involved in generating precise spoken definition, such as auditory-verbal working memory, generative ability, oral fluency, and semantic retrieval (Lezak, 2004), may also cause over-generalizing of subjective discomfort. The measure of IED pre-ED errors, on the other hand, reflects
Table 4 The correlations between LUNSERS side effects subscales and DIEPSS items at 6-month follow-up (n ¼ 51). LUNSERS
DIEPSSa
Gait Bradykinesia Rigidity Akathesia Global score
Psychic
EPS
Hormonal
Anticholinergic
Autonomic
Allergic
Miscellaneous
0.54*** 0.57*** 0.40** 0.26 0.56***
0.48*** 0.51*** 0.43** 0.23 0.51***
0.04 0.09 0.08 0.08 0.09
0.29* 0.34* 0.41** 0.08 0.34*
0.36** 0.44** 0.46*** 0.02 0.44**
0.24 0.46** 0.35* 0.06 0.46**
0.30* 0.37** 0.24 0.09 0.37**
*p < 0.05, **p < 0.01, ***p < 0.001. LUNSERS, Liverpool University Neuroleptic Side Effects Rating Scale; EPS, Extrapyramidal; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale. a There were no side effects reported for sialorrhea, tremor, dystonia, and dyskinesia.
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the failure to maintain attention to a reinforced stimulus prior to set-shifting and it was also significantly correlated with SE of the LUNSERS. Our post hoc analysis revealed the same pattern of results as the premorbid IQ, where pre-ED errors were significantly correlated with the total number of endorsed SE items (r ¼ 0.35, p < 0.05), but not RH items. Accordingly, the association between the pre-ED errors and the LUNSERS SE total score became non-significant after partialling out the frequency of endorsement of SE items. However, as pre-ED errors significantly correlated with only hormonal side effects subscale while the premorbid IQ correlated with the anticholinergic, other autonomic, and allergic side effects after partialling out depression and anxiety, it is likely that pre-ED errors may be selectively related with specific side effects and premorbid IQ with more overall global discomfort. Our study did not consider the level of psychopathology as one of our variables while there has been inconsistent results regarding the associations between side effects and psychopathology. Day et al. (1995) found no association between LUNSERS SE and the subscales of the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) among hospitalized patients while we previously found positive and anxiety/depressive symptoms to contribute to SE among outpatients, using the symptoms derived from the factor analysis of the PANSS (Hwang et al., 2010). While a strong consensus is yet to be reached on the effects of psychopathology on neurocognitive functioning in patients with schizophrenia, we have previously found no associations between psychopathology and executive functioning in chronic patients of schizophrenia (Hwang et al., 2009) and no difference in CRT mean correct latency and SST direction errors between the schizophrenia remitted and nonremitted patients (Yun et al., 2011). As such, the significant associations found between the baseline CANTAB measures and side effects in this study are likely to be mostly independent from the severity of psychopathology. Lastly, emergence of significant cross-sectional correlations at 6month follow-up between the measures of side effects, which did not show at the baseline, suggested that self-report measures and clinician-rated measures of side effects better converge with time. While we suggested above that baseline associations between the CANTAB measures and side effects are likely to be independent of psychopathology, it is possible that improvement in side effects and psychopathology over time may be significantly associated, and that they may share some common etiological grounds which may be tabbed by SST direction errors. Further examination of the utility of this measure in predicting long-term outcome of neuroleptic side effects is warranted along with possible connections with other relevant clinical variables, such as insight, compliance, and drug attitude. Author contributions Samuel Suk-Hyun Hwang was involved in the analysis of the data and drafting and editing of the manuscript. Yeni Kim was involved in the designing of the study and data collection. Da Young Yun was involved in data collection and analysis of the data. Yong Sik Kim was involved in the designing of the study and drafting and editing of the manuscript. Hee Yeon Jung was involved in the designing of the study and data collection and analysis, as well as in the drafting and editing of the manuscript. Conflict of interest None of the authors of this manuscript report any conflict of interest.
Acknowledgments This research was supported by the Seoul National University Hospital (SNUH) Research Fund (Grant Number: 04-2009-93) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Grant Number: 2010-0010274). The SNUH and NRF had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
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