WEB-ONLY CONTENT Influence of NOS1 on Verbal and Working in Both Patients With Schizophrenia and Healthy Control Subjects

Gary Donohoe, DClinPsych, PhD; James Walters, MRCPsych, BM; Derek W. Morris, PhD; Emma M. Quinn, MSc; Ro´isı´n Judge, BA; Nadine Norton, PhD; Ina Giegling, PhD; Annette M. Hartmann, PhD; Hans-Jürgen Möller, MD; Pierandrea Muglia, MD; Hywel Williams, PhD; Valentina Moskvina, PhD; Rosemary Peel, MSc; Therese O’Donoghue, MSc; Michael J. Owen, FRCPsych, PhD; Michael C. O’Donovan, FRCPsych, PhD; Michael Gill, MRCPsych, MD; Dan Rujescu, MD; Aiden Corvin, MRCPsych, PhD

Arch Gen Psychiatry. 2009;66(10):1045-1054

FULL DESCRIPTION OF COGNITIVE MEASURES samples, was also assessed using 2 work- OF MEMORY AND ATTENTIONAL CONTROL ing memory scores. The first was the composite digit span and spatial span score from the Wechsler Memory Scale– Episodic Memory Revised. The digit span and spatial span subtests re- quire the ability to maintain a sequence of numbers or Verbal episodic memory was assessed in the Irish samples spatial moves in both a forward and a reverse direction. using the logical memory subtest from the Wechsler The second was an N-back task (National Institutes of Memory Scale, third edition.1 This task assesses the pa- Mental Health version),5 which involved attending to the tient’s ability to remember the details of 2 short stories numbers 2, 4, 6, and 8 presented on a screen and recall- both in terms of immediate recall and after a brief ing the number presented just before the number on the (20-minute) delay. Visual memory was assessed using the screen. Only the 1-back condition was used as the 2-back Wechsler Memory Scale, third edition, faces subtest, which condition is typically too difficult for patients, leading requires participants to accurately recognize 25 previ- to a floor effect. ously presented faces from a series of face pairs (1 cor- rect, 1 foil). In the German samples, the German ver- Attentional Control sion of the Wechsler Memory Scale–Revised2,3 was used. The logical memory subtest was again used as an index In the Irish samples, attentional control was assessed using of verbal memory. One of the changes between the Wechs- the continuous performance test, identical pairs ver- ler Memory Scale–Revised and the newer Wechsler sion.6 This computer-generated test of attentional con- Memory Scale, third edition, is that the faces subtest re- trol requires patients to respond to pairs of numbers that placed the figural memory subtest as an index of visual appear sequentially in an array of 2, 3, or 4 numbers. A memory. As it was therefore not possible to match ex- signal detection index dЈ is calculated for each of these actly the same subtest, we used the Wechsler Memory numbers; dЈ for the 3-number condition and dЈ for the Scale–Revised visual memory score in the German samples 4-number condition were the dependent measures used as the comparison score. in this study. In the German samples, the 3-7 Continu- ous Performance Test was used.7 This computer task re- Working Memory quires participants to attend a continuous series of num- bers presented individually and to respond by button press Verbal working memory was assessed in the Irish samples each time the number 7 appears preceded immediately using the letter-number sequencing task of the Wechs- by the number 3. Accuracy on this task was again cal- ler Memory Scale, third edition. Strings of alternating let- culated using dЈ. ters and numbers of increasing length are presented and participants must order them alphabetically and numeri- NOS1 AND CLINICAL SYMPTOM SEVERITY cally before verbally repeating them. The dependent vari- IN THE IRISH SAMPLE able was the number of total correct responses. Spatial working memory was assessed using the spatial work- Each of the global scale score items from the Scale for ing memory task from the Cambridge Neuropsychologi- the Assessment of Positive Symptoms and the Scale cal Test Automated Battery, Expedio Version.4 This com- for the Assessment of Negative Symptoms was sub- puterized task requires participants to “open” a set of jected to a principal components analysis with varimax boxes with the aim of locating a “token.” As each box rotation. Based on a review of the subsequent scree plot, only ever contains 1 token, the dependent variable is a 3-factor solution appeared to fit the data best. These counted in terms of returning to a box where a token had accounted for 62% variance in global Scale for the As- previously been found (ie, errors made). In the German sessment of Positive Symptoms and Scale for the Assess-

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 CORRELATIONS BETWEEN eTable 1. Principal Components Analysis of Positive WORKING MEMORY AND IQ and Negative Symptom Severity in the Irish Patient Sample Correlations of verbal and spatial working memory with Component, r verbal, performance, and full-scale IQ were determined Global Symptom Rating Negative Disorganized Positive for the total Irish sample (n=579) (eTable 3) and for Severity of delusion .092 .194 .812 the Irish patient sample (n=349) (eTable 4). Severity of hallucinations .080 .042 .850 The relationship between NOS1 and working memory Severity of bizarre behavior .236 .720 .071 was reanalyzed with verbal IQ covaried for and vice versa. Severity of positive formal −.082 .795 .305 Multivariate analysis of variance was performed for NOS1 disorder and verbal working memory (letter-number sequencing Severity of affective flattening .843 .006 .098 Severity of alogia .776 .207 .062 task) or spatial working memory (Cambridge Neuropsy- Avolition-apathy .631 .253 .031 chological Test Automated Battery, Expedio Version spa- Anhedonia-asociality .751 .082 .066 tial working memory task) using verbal IQ as an addi- Attention .365 .581 −.035 tional covariate. To rerun these analyses covarying for verbal IQ, scores on the letter-number sequencing task and the spatial working memory task were entered as the ment of Negative Symptoms scores and yielded eigen- dependent variables, NOS1 and diagnosis were entered values of 3.58, 1.53, and 1.01. Based on a review of the as the independent variables, and verbal IQ and sex were items loading onto each factor, the factors were labeled entered as covariables. On this basis, the association be- as negative (including affective flattening, alogia, avolition- tween NOS1 and working memory became nonsignifi- apathy, and anhedonia-asociality), disorganized (includ- cant for both verbal working memory (F=2.0; P=.13) and ing bizarre behavior, formal thought disorder, and at- spatial working memory (F=1.3; P=.27). tention), and positive (including delusions and Multivariate analysis of variance was performed for hallucinations). The rotated component matrix is repro- NOS1 and verbal IQ using verbal working memory (letter- duced in eTable 1. number sequencing task) as an additional covariate. To rerun this analysis covarying for verbal working memory, NOS1 AND CLINICAL SYMPTOM SEVERITY verbal IQ was entered as the dependent variable, NOS1 IN THE GERMAN SAMPLE and diagnosis were entered as the independent vari- ables, and verbal working memory and sex were en- Each of the individual items from the Positive and Nega- tered as covariables. On this basis, the association be- tive Syndrome Scale was subjected to a principal com- tween NOS1 and working memory became nonsignificant ponents analysis with varimax rotation. Based on a re- for verbal working memory (F=2.6; P=.75). view of the subsequent scree plot, a 5-factor solution appeared to fit the data best. These accounted for 54% REFERENCES variance in Positive and Negative Syndrome Scale scores and yielded eigenvalues of 8.1, 4.2, 2.1, 1.9, and 1.1. Based 1. Wechsler D. Wechsler Memory Scale, Third Edition (WMS-III). New York, NY: Psy- on a review of the items loading onto each factor, the fac- chological Corp; 1998. tors were labeled as negative (emotional withdrawal, poor 2. Wechsler D. Wechsler Memory Scale–Revised. San Antonio, TX: Psychological Corp; 1987. rapport, social withdrawal, lack of spontaneity, motor re- 3. Härting C, Markowitsch HJ, Neufeld H, Calabrese P, Deisinger K, Kessler J. Wechs- tardation, and avoidance), positive (delusions, halluci- ler Memory Scale–Revised, German Version: Wechsler Gedächtnistest; Revidi- nations, grandiosity, unusual , and poor in- erte Fassung. Bern, Switzerland: Huber; 2000. sight), disorganized (conceptual disorganization, poor 4. Cambridge . Cambridge Neuropsychological Test Automated Battery, Ex- abstract thinking, and poor attention), hostility (hostil- pedio Version (CANTABexpedio). Cambridge, England: Cambridge Cognition Ltd; 2003. 5. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Gold- ity, uncooperativeness, and poor impulse control), and man D, Weinberger DR. Effect of COMT Val108/158 Met genotype on frontal lobe depression (anxiety, guilt, and somatic concerns). The function and risk for schizophrenia. Proc Natl Acad SciUSA. 2006;98(12):6917- rotated component matrix is reproduced in eTable 2. 6922. To compare symptom severity in a manner comparable 6. Cornblatt BA, Risch NJ, Faris G, Friedman D, Erlenmeyer-Kimling L. The continu- ous performance test, identical pairs version (CPT-IP): new findings about sus- to that in the Irish sample, differences in negative, dis- tained attention in normal families. Psychiatry Res. 1988;26(2):223-238. organized, and positive symptoms associated with NOS1 7. Nuechterlein K, Asarnow R. 3-7 Continuous Performance Test. Los Angeles: Uni- were analyzed. versity of California; 2004.

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 eTable 2. Principal Components Analysis of Positive and Negative Symptom Severity in the German Patient Sample

Component, r

Symptom Negative Positive Disorganized Hostility Depression Delusions .058 .723 .145 .121 .421 Conceptual disorganization .254 .327 .600 .278 .094 Hallucinations .140 .546 .083 .064 .323 Excitement −.150 .291 .509 .369 .068 Grandiosity −.023 .738 .026 .006 −.058 Suspiciousness .195 .403 .044 .365 .476 Hostility .056 .064 .027 .844 .009 Blunted affect .806 −.051 .233 .117 .137 Emotional withdrawal .804 .173 .080 .050 .205 Poor rapport .687 .065 .261 .284 .030 Social withdrawal .770 .257 .110 .077 .089 Abstract thinking .364 −.038 .659 .182 .042 Spontaneity .707 .021 .410 −.073 −.055 Stereotyped thinking .143 .397 .408 .343 .247 Somatic concerns .026 .285 .129 .230 .414 Anxiety .025 −.004 .381 −.005 .724 Guilt .107 .054 .038 −.049 .662 Posturing .176 .226 .605 .189 .180 Mannerisms .209 .271 .487 −.095 −.011 Depression .385 .049 .091 −.108 .511 Motor retardation .674 −.007 .264 −.222 −.060 Uncooperative .181 .189 .056 .694 −.237 Unusual thoughts .092 .793 .215 .171 .150 Disorientation .085 −.012 .513 −.219 .184 Attention .268 .140 .653 .119 .123 Insight .098 .719 .182 .259 −.139 Volition .326 .070 .554 .040 .102 Impulse control −.056 .230 .110 .667 .246 Preoccupation .257 .443 .253 .367 .025 Social avoidance .666 .096 .116 .169 .285

eTable 3. Correlations of Verbal and Spatial Working Memory With Verbal, Performance, and Full-Scale IQ Based on the 579 Participants in the Total Irish Sample

Pearson Correlation Coefficient

Letter-Number Between-Errors Measure Full-Scale IQ Verbal IQ Performance IQ Sequencing Task Score Standard Score Full-scale IQ 1 0.917a 0.910a 0.673a 0.495a Verbal IQ 0.917a 1 0.680a 0.597a 0.378a Performance IQ 0.910a 0.680a 1 0.637a 0.540a Letter-number sequencing task score 0.673a 0.597a 0.637a 1 0.529a Between-errors standard score 0.495a 0.378a 0.540a 0.529a 1

a Correlation is significant at the PϽ.001 level (2-tailed).

eTable 4. Correlations of Verbal and Spatial Working Memory With Verbal, Performance, and Full-Scale IQ Based on the 349 Participants in the Irish Patient Sample

Pearson Correlation Coefficient

Letter-Number Between-Errors Measure Full-Scale IQ Verbal IQ Performance IQ Sequencing Task Score Standard Score Full-scale IQ 1 0.884a 0.879a 0.552a 0.328a Verbal IQ 0.884a 1 0.581a 0.432a 0.202a Performance IQ 0.879a 0.581a 1 0.570a 0.420a Letter-number sequencing task score 0.552a 0.432a 0.570a 1 0.402a Between-errors standard score 0.328a 0.202a 0.420a 0.402a 1

a Correlation is significant at the PϽ.001 level (2-tailed).

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