Brainsci 1204494

1
1 Article
2 Reaction time and visual memory in connection to alcohol use

3 in schizophrenia and schizoaffective disorder
4 Atiqul Haq Mazumder1*, Jennifer Barnett2, Nina Lindberg3, Minna Holm4, Markku Lähteenvuo5,6** , Kaisla
5 Lahdensuo6**,7, Martta Kerkelä1, Jarmo Hietala8,9, Erkki Isometsä3 , Olli Kampman10,11, Tuula Kieseppä3,6**,7, Tuomas
6 Jukuri1,6**, Katja Häkkinen5,6**, Erik Cederlöf4, Willehard Haaki6**,8, Risto Kajanne6, Asko Wegelius3,4,6**, Teemu
7 Männynsalo6**,12, Jussi Niemi-Pynttäri6**,12, Kimmo Suokas6**,10, Jouko Lönnqvist4,13, Solja Niemelä8,9, Jari
8 Tiihonen5,14,15, Tiina Paunio3,4,13, Annamari Tuulio-Henriksson16, Aarno Palotie6**,7,17,1816,17, Jaana Suvisaari4 and Juha
9 Veijola1,1918
10 1
Department of Psychiatry, University of Oulu, FI-90014 Oulu, Finland.
11 2
University of Cambridge, Cambridge CB25 9TU, UK.
12 3
University of Helsinki, Helsinki University Hospital, Psychiatry, FI-00029 Helsinki, Finland.
13 4
Mental Health Unit, Finnish Institute for Health and Welfare (THL), FI-00271 Helsinki, Finland.
14 5
Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, FI-70240 Kuopio,
15 Finland.
16 Citation: Mazumder, A. H.; Barnett,
6 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014 Helsinki, Finland, *years
17 2016–2018
J.; Lindberg; Lindberg, N. Reaction
18 7
Mehiläinen, FI-00260 Helsinki, Finland.
time and visual memory in
19 8
Department of Psychiatry, University of Turku, FI-20014 Turku, Finland.
20 connection to alcohol use in 9
Department of Psychiatry, Turku University Hospital, FI-20521 Turku, Finland.
21 schizophrenia and schizoaffective 10
Faculty of Medicine and Health Technology, Tampere University, FI-33014 Tampere, Finland.
22 disorder. Brain Sci. 2021, 11, x. 11
Department of Psychiatry, Pirkanmaa Hospital District, FI-33521 Tampere, Finland.
23 https://doi.org/10.3390/xxxxx
12
Social Services and Health Care Sector, City of Helsinki, FI-00099 Helsinki, Finland.
24 13
Department of Psychiatry, University of Helsinki, FI-00014 Helsinki, Finland.
25 Academic Editor: Firstname
14
Department of Clinical Neuroscience, Karolinska Institutet, SE-17177 Stockholm, Sweden.
26 15
Center for Psychiatry Research, Stockholm City Council, SE-11364 Stockholm, Sweden.
Lastname
27 16
Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki,
28 Finland.
29 Received: date 17 16
Stanley Center for Psychiatric Research, The Broad Institute of MIT (Massachusetts Institute of Technology)
30 Accepted: date and Harvard, MA-02142 Cambridge, Massachusetts, USA.
31 Published: date 18 17
Analytical and Translational Genetics Unit, Massachusetts General Hospital, MA-02114 Boston,
32 Massachusetts, USA.
33 Publisher’s Note: MDPI stays
19 18
Department of Psychiatry, Oulu University Hospital, FI-90220 Oulu, Finland.
34 neutral with regard to jurisdictional * Correspondence: atiqul.mazumder@oulu.fi atiq10@gmail.com
35 claims in published maps and
**Years 2016-2018.
institutional affiliations.
36 Abstract: Purpose of the study was to explore the association of cognition with hazardous
37 drinking, binge drinking and alcohol use disorder in schizophrenia and schizoaffective disorder.
38 Cognitive deficits are common in schizophrenia. Alcohol might be associated with additional
Copyright: © 2021 by the authors.
Submitted for possible open access
publication under the terms and
conditions of the Creative Commons
Attribution (CC BY) license
(https://creativecommons.org/license
s/by/4.0/).
3 Brain Sci. 2021, 11, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/brainsci

4 Brain Sci. 2021, 11, x FOR PEER REVIEW 2 of 46
5
39 cognitive impairment in schizophrenia patients. The study population included 3362 schizophrenia
40 and schizoaffective disorder patients in Finland. Hazardous drinking was screened with the AUDIT-
41 C (Alcohol Use Disorders Identification Test for Consumption) screening tool. Binge drinking
42 was obtained from the AUDIT-C. Alcohol use disorder (AUD) diagnoses were obtained from the
43 national registrar data. Participants performed two computerized tasks from the Cambridge
44 automated neuropsychological test battery (CANTAB) on tablet computer: the 5-choice serial
45 reaction time task (5-CSRTT), or, reaction time (RT) test and the Paired Associative Learning
46 (PAL) test. Association of alcohol use with RT test and PAL test was analyzed with log-linear
47 regression and logistic regression, respectively. After adjustment for age, education and age at
48 first psychotic episode, hazardous drinking in females was associated with lower median RT.
49 Compared to never binge drinkers, male and female participants drinking 6 or more doses of
50 alcohol monthly or less had lower median RT. In the PAL test both first trial memory score
51 (FTMS) and total errors adjusted score (TEAS) were associated with better performance in males
52 drinking 6 or more doses of alcohol weekly or more and in females drinking 6 or more doses
53 monthly or less. Higher PAL TEAS was associated with AUD in females Some positive
54 associations between alcohol and cognition were found in male and female schizophrenia and
55 schizoaffective disorder patients with hazardous drinking and binge drinking. Purpose of the
56 study was to explore the association of cognition with hazardous drinking and alcohol use
57 disorder in schizophrenia and schizoaffective disorder. Cognition is more or less compromised in
58 schizophrenia and schizoaffective disorder and alcohol use might aggravate this phenomenon.
59 The study population included 3,362 individuals from Finland with the diagnoses of
60 schizophrenia and schizoaffective disorder. Hazardous drinking was screened with the AUDIT-C
61 (Alcohol Use Disorders Identification Test for Consumption) screening tool. Alcohol use disorder
62 (AUD) diagnoses were obtained from the national registrar data. Participants performed two
63 computerized tasks from the Cambridge automated neuropsychological test battery (CANTAB) on
64 tablet computer: the 5-choice serial reaction time task (5-CSRTT), or, reaction time (RT) test and
65 the Paired Associative Learning (PAL) test. Association of alcohol use with RT test and PAL test
66 was analyzed with log-linear regression and logistic regression, respectively. After adjustment for
67 age, education, housing status and age of first psychotic episode, hazardous drinking was
68 associated with lower median RT in females and less variable RT in males, and, AUD was
69 associated with poorer PAL test performance in terms of total error adjusted score (TEAS) in
70 females. Findings of positive associations between alcohol and cognition is unique in
71 schizophrenia and schizoaffective disorder.
72 Keywords: Cognition; Visual memory; Reaction time; Alcohol; schizophrenia and schizoaffective
73 disorder
74
75 1. Introduction
7
76 Cognitive dysfunction is a persistent, disabling hallmark of schizophrenia found to

77 be present in about 75% of schizophrenia patients [1]. It is associated with the severity of
78 illness in schizophrenia [2]. Schizophrenia patients with comorbid AUD demonstrate
79 marked impairment in multiple cognitive domains [3,4,5,6,7]. Most affected cognitive
80 domains are sustained attention, concept formation and non-verbal cognitive flexibility
81 [8].
82 Individuals with schizophrenia have three times more risk of heavy alcohol use
83 than general population [10]. AUD is the second most common comorbidity in patients
84 with schizophrenia, after nicotine dependence [11]. Systematic review and meta-analysis
85 of 123 research papers published during 1990-2017 revealed 24.3% lifetime prevalence of
86 AUD among subjects with schizophrenia [12].
87 About 90% of people who drink excessively would not be expected to meet the
88 clinical diagnostic criteria for having AUD [13], rather could be screening-positive for
89 hazardous drinking or binge (heavy episodic) drinking.
90 Hazardous drinking is a pattern of alcohol consumption that increases the risk of
91 harmful consequences for the user or others. Hazardous drinking patterns are of public
92 health significance despite the absence of any current disorder in the individual alcohol
93 user [14,15,16,17].
94 Binge drinking, or, heavy episodic drinking (HED) is the most common pattern of
95 excessive alcohol use [13,18,19,20].
96 In general population males drink more alcohol than females [2118]. However, in
97 recent years male to female ratios for alcohol use, problematic alcohol use and alcohol-
98 related harm have declined considerably [22,2319,20].
99 Studies in general populations suggest that mild to moderate alcohol drinking
100 might not decline cognition [24,25,26,2721,22,23,24]. In schizophrenia patients,
101 association of cognition with different drinking patterns has not been fully studied yet.
102 The main aim of the present study was to explore the association of reaction time
103 and visual memory with different drinking patterns in persons with schizophrenia and
104 schizoaffective disorder diagnoses.
105 The specific research aims are to study:
106 1. The association of hazardous drinking with reaction time and visual memory
107 in persons with schizophrenia and schizoaffective disorder.
108 2. The association of binge drinking with reaction time and visual memory in
109 persons with schizophrenia and schizoaffective disorder.
110 32. The association of alcohol use disorder with reaction time and visual memory
111 in persons with schizophrenia and schizoaffective disorder.
112 2. Materials and Methods
113 2.1. Participants

9
114 The participants of this study were part of the study population of the SUPER
115 (Suomalainen psykoosisairauksien perinnöllisyysmekanismien tutkimus/ Finnish study
116 for the hereditary mechanisms behind psychotic illnesses)- study, which is part of the
117 international Stanley Global Neuropsychiatric Genomics Initiative, USA. The SUPER-
118 study collected data during the period 2016-2019 from people with a lifetime diagnosis
119 of psychosis in Finland to identify gene loci and gene variations predisposing to
120 psychotic illnesses and comorbid diseases. Voluntary subjects with a diagnosis of
121 schizophrenia spectrum psychotic disorder, bipolar I disorder or major depressive
122 disorder with psychotic features were recruited from psychiatric inpatient and
123 outpatient departments, general health care centers and supported housings.
124 Participants were identified through local healthcare centers throughout the country
125 from all levels of healthcare to ensure inclusive sampling. Subjects had also been
126 recruited via advertisements on local newspapers.
127 Out of the original sample of 10,555 participants, 6,769 had clinical diagnosis of
128 schizophrenia and schizoaffective disorder. Among those, 228 had missing information
129 on alcohol use or education. Of the remaining 6,541 participants, 1,435 did not complete
130 the cognitive tests or had duplicate test results. Finally, we had 3362 participants after
131 excluding 1,744 who did not live independently (living in supported housing, hospital
132 or unknown residence) as alcohol use is restricted in those places. (Figure 1).
133 Research manuscripts reporting large datasets that are deposited in a publicly
134 available database should specify where the data have been deposited and provide the
135 relevant accession numbers. If the accession numbers have not yet been obtained at the
136 time of submission, please state that they will be provided during review. They must be
137 provided prior to publication.
138 Interventionary studies involving animals or humans, and other studies that
139 require ethical approval, must list the authority that provided approval and the
140 corresponding ethical approval code.
141 2.2. Schizophrenia and schizoaffective disorder diagnoses

142 The diagnoses of schizophrenia and schizoaffective disorder were obtained from
143 the Care Register for Health Care (CRHC) of the Finnish Institute for Health and
144 Welfare. Upon fulfilling diagnostic criteria, clinical diagnoses were made by clinicians,
145 mostly in specialized care by psychiatrists, and the validity of the CRHC-based
146 psychosis diagnoses have shown good validity [25]. In Finland the International
147 Classification of Disease (ICD) system has been used in psychiatric diagnoses. In this
148 study schizophrenia diagnoses included the code 295 according to ICD-8; and ICD-9 and
149 F20 according to ICD-10 and schizoaffective disorder diagnoses included the code 295.7
150 according to ICD-8; and ICD-9 and F25 according to ICD-10. ICD-8 was used during
151 1968-1986, ICD-9 during 1987-1995 and ICD-10 since 1996 in Finland.
11
152 2.3. Hazardous drinking screening

153 Hazardous drinking was screened using the AUDIT-C questionnaire to assess an
154 individual’s alcohol consumption frequency (‘how often do you have a drink containing
155 alcohol?’), quantity (‘how many drinks containing alcohol do you have on a typical day
156 when you are drinking?’), and bingeing (‘how often do you have six or more drinks on
157 one occasion?’). AUDIT-C is derived from the hazardous alcohol use domain of the
158 Alcohol Use Disorders Identification Test (AUDIT) questionnaire [2826]. It has three
159 questions and is scored on a scale of 0-12. Each AUDIT-C question has 5 answer choices
160 valued from 0 points to 4 points.
161 Cutoff scores for hazardous drinking vary considerably [19,2926,27]. In the present
162 study we used cutoff scores recommended by Finnish National Guidelines; a score of 6
163 or more in males, and 5 or more in females [3028].
164 2.4. Binge drinking screening

165 There exist several definitions of binge drinking [31,32]. In the present study binge
166 drinking was screened using the bingeing question (‘how often do you have six or more
167 drinks on one occasion?’) of the AUDIT C screening questionnaire.
168 2.54. Alcohol use disorder diagnoses

169 The diagnoses of alcohol use disorder were obtained from the CRHC data
170 following ICD-8 291, 303, ICD-9 291, 3030, 3050A, ICD-10 F10 during 1969-2018.
171 2.6. Cognitive measures

172 Participants performed two computerized tasks from The Cambridge
173 neuropsychological test automated battery (CANTAB) on tablet computer; the 5-choice
174 serial reaction time task (5-CRTT) and the paired associative learning (PAL) task for the
175 assessment of reaction time (RT) and visual memory respectively. Processing speed and
176 visual learning are the two core cognitive domains compromised in schizophrenia [31]
177 hence we selected the 5-choice serial reaction time task (5-CRTT) and the paired
178 associative learning (PAL) task from the Cambridge neuropsychological test automated
179 battery (CANTAB) test battery for schizophrenia for the assessment of reaction time (RT)
180 and visual memory respectively.
181 The PAL test is sensitive to the integrity of the frontal and medial temporal lobes, in
182 particular the hippocampal and para-hippocampal regions, which corresponds to the
183 changes seen in Alzheimer’s Disease (AD). The PAL test provides markers for impaired
184 visual memory in first-episode psychosis [33], normal variation in midlife cognitive
185 function as well as earliest signs of Alzheimer’s related decline [34,35].
186 These tasks were chosen to produce relevant information of cognition in psychotic
187 disorders in the very restricted assessment schedule. The instructions to both tests were
13
188 translated into Finnish. The CANTAB tests were performed before venipuncture in
189 order to avoid malfunction of the arm due to pain or bandaging. The study nurses were
190 given standardized instructions on how to guide the study subjects in performing the
191 CANTAB test beforehand.
192 In the RT-test, the participant must select and hold a button at the bottom of the
193 screen. Circles are presented above; five for the five-choice mode. A yellow dot will
194 appear in one of the circles, and the participant must react as soon as possible, releasing
195 the button at the bottom of the screen, and selecting the circle in which the dot appeared
196 (Cambridge Cognition, Reaction time). In the RT-test we used two continuous
197 measurements: median of the five-choice reaction time and standard deviation (SD) of
198 the five-choice reaction time. Median of the five-choice reaction time is the median
199 duration between the onset of the stimulus and the release of the button. Standard
200 deviation of the five-choice reaction time is the standard deviation of the time taken to
201 touch the stimulus after the button has been released. Both variables were calculated for
202 correct, assessed trials where the stimulus could appear in any of five locations.
203 In the PAL-test we assessed visual memory using the primary outcome variable of
204 ‘total errors adjusted’. Here we assessed two different dichotomized variables, using
205 data from Northern Finland Birth Cohort 1966 (NFBC 1966) as a reference data [3632].
206 The NFBC 1966 consists of all born with expected date in the year 1966. The data used in
207 this study consist of a 46-year follow-up when cohort members took the PAL-test during
208 clinical examination (N=5,608). For the first trial memory score, the 15th percentile
209 (score of 17 or more) was used as a cut-off for good performance in PAL test in the
210 recent study, meaning the SUPER study population did better performance than 15% of
211 NFBC 1966 study population. Scores for total errors adjusted of NFBC66, the 50th
212 percentile (10 error score or less) was used as a cut-off for good performance in PAL test
213 in the recent study, meaning the SUPER study population made better error score than a
214 50% of NFBC 1966 study population . The distribution of PAL-test is problematic with
215 multiple peaks. It does not follow any known distribution hence we could not use
216 continuous distribution of PAL test Firstvariables. First Trial Memory Score is how
217 many patterns the participant correctly places on the first attempt at each problem, while
218 Total Errors Adjusted Score reflects how quickly the participant learns when the
219 participant has multiple attempts at each problem.
220 2.7. Confounding factors

221 Age, education [3733], living without spouse [34] and age of first psychotic episode
222 [4] have effects on cognitive functioning, hence we considered them be the confounding
223 variables in this study.
224 2.7.1. Age

15
225 Cognition is negatively associated with increased age in healthy populations [3835]
226 and debatably in alcohol users [3936]. Age of the participants was calculated using
227 participation date and year of birth of the participant. Age was used as continues
228 variable.
229 2.7.2. Education

230 Education is strongly associated with cognitive performance [4037]. The questions
231 and possible answers addressing education of the participants were: ‘What is your basic
232 education?’ (1= less than the primary school, 2= matriculation examination, 3= middle
233 school, 4= part of general upper secondary school or general upper secondary education
234 certificate, 5= part of a middle school or primary school less than 9 years, 6= primary
235 school, 7= Four year elementary school). During the analysis we combined classes 1, 3, 4,
236 5, 6 and 7 as ‘No matriculation examination’ versus class 2 (‘Matriculation examination’).
237
238 2.7.3. Age of first psychotic episodeHousehold pattern

239 We used age at first psychotic episode as a marker of severity of the illness.
240 Research shows that the earlier is the schizophrenia and schizoaffective disorder
241 development, the mores severe is the illness in terms of the disease pattern and cognitive
242 decline [41,42]. The data of age at first psychotic episode were obtained form the CRHC
243 and were used in this research as continuous variable. Household patterns, specially
244 living without spouse might affect cognition [34, 38] hence we considered household
245 patterns as confounder.
246 2.7.4. Age of first psychotic episode

247 We used age at first psychotic episode as a marker of severity of the illness.
248 Research shows that the earlier is the schizophrenia and schizoaffective disorder
249 development, the mores severe is the illness in terms of the disease pattern and cognitive
250 decline [39,40]. The data of age at first psychotic episode were obtained from the CRHC
251 and were used in this research as continuous variable.
252
253 2.8. Statistical methods

254 We evaluated the association between cognition and alcohol use by using four
255 different cognition variables; median and standard deviation of RT, PAL FTMS and PAL
256 total errors adjusted. Alcohol use was measured by different variables; dichotomous
257 hazard drinking variable derived from AUDIT score; classified variable of binge
258 drinking obtained from AUDIT questionnaire; and dichotomous variable indicating, if
259 the study subject had had alcohol use disorder diagnosis. We assessed crude models and
17
260 also adjusted models with age, education, household pattern and age of first psychosis
261 episode and education. Association between RT-test and alcohol use was analyzed with
262 log-linear regression, and eβ with 95% confidence intervals (CI) are reported.
263 Association between PAL-test and alcohol use was analyzed with logistic regression and
264 odds ratios (OR) with 95% CI are reported.
265 All analyses were conducted separately in males and females. Males and females
266 have differences in performing selected cognitive tests [43,44,4541,42,43]. Also, males
267 and females have differences in alcohol use patterns [18,46,47,4844].
268 3. Results
269 This section may be divided by subheadings. It should provide a concise and
270 precise description of the experimental results, their interpretation, as well as the
271 experimental conclusions that can be drawn.
272 3.1. Background factors and alcohol use patterns

273 Of the participants 51% were males and 49 % were females. Mean age was 45 years
274 for males and 46 years for females. One third of the males and two fifth of the females
275 had highest basic educational of 12 years (matriculation). Mean age at of first psychotic
276 episode was 27 years for male and 28 for female. Four fifth of the males and three fifth of
277 the females were living alone. One-tenth of males and one-fourth of the males were
278 living with spouse. Most of the participants were on psychotropic medication (Table 1).
279 All types of alcohol use patterns were more common in males than in females.
280 Every fifth fourth male and every tenth sixth female schizophrenia and schizoaffective
281 disorder patients had positive screening for hazardous drinking. About half of the male
282 and one third of the female were screened as binge drinkers, mostly binge drinking
283 monthly or less frequently. About one third of male and one sixth of female
284 schizophrenia and schizoaffective disorder patients had a lifetime diagnosis of AUD
285 (Table 1).
286 Lower age was associated with hazardous drinking both in males and females. In
287 females lower age of onset and types of household associated with hazardous drinking
288 (Supplementary table 1).
289 Median RT was 435 milliseconds (SD 50 milliseconds), PAL median FTMS was 8
290 and median total errors adjusted was 33 (Supplementary table 2).
291 Association between background factors and AUD with RT P-values are has
292 reportedbeen reported in supplementary table 3. Association between background
293 factors and alcohol use patterns with PAL scores are reported in supplementary table 4
294 and supplementary table 5.
295 Cohen's d Measure of Effect Size has been shown in supplementary table 7. Effect
296 sizes were in line with our results (significant results on Male hazardous drinking RTI
19
297 SD (p=0.008), Cohen's d = 0.22, Female RTI median (p=0.016), Cohen's d = 0.31 (0.18-
298 0.44), Female PAL TEA alcohol use disorder (p= 0.048), Cohen's d = 0.12.
299 3.2. Association of reaction time and visual memory with hazardous drinking in schizophrenia
300 and schizoaffective disorder patients
301 Crude median reaction time was shorter and less divers in male and female
302 schizophrenia and schizoaffective disorder patients with hazardous drinking compared
303 to those without hazardous drinking. After adjustment for age, education, household
304 pattern and age at of first psychotic episode, hazardous drinking was associated in
305 females associated with lower median RT (OR 0.97, 95% CI 0.95-0.99). After adjustment,
306 reaction time was less diverse, and in males schizophrenia and schizoaffective disorder
307 patients with hazardous drinking compared to male schizophrenia patients without
308 hazardous drinking with less variable reaction time (Table 2). Association between
309 hazardous drinking and RT scores are has been reported in supplementary table 6.
310 Crude PAL first trial memory score was higher in male and crude PAL total errors
311 adjusted score were higher in both female schizophrenia and schizoaffective disorder
312 patients with hazardous drinking compared to those without hazardous drinking (Table
313 2).
314 3.3. Association of reaction time and visual memory with binge drinking in schizophrenia and
315 schizoaffective disorder patients
316 Crude median reaction time was shorter and less diverse in male schizophrenia and
317 schizoaffective disorder patients binge drinking weekly compared to those binge-
318 drinking monthly or less and in male schizophrenia and schizoaffective disorder
319 patients binge drinking monthly or less compared to those never binge drinking.
320 Adjusted median reaction time was shorter in male schizophrenia patients binge
321 drinking monthly or less compared to those binge-drinking never (OR 0.98, CI 0.96-0.99).
322 After adjustment, reaction time was less diverse in male schizophrenia and
323 schizoaffective disorder patients binge drinking weekly compared to those binge-
324 drinking monthly or less. Crude median reaction time was shorter in female
325 schizophrenia and schizoaffective disorder patients binge drinking weekly compared to
326 those binge-drinking monthly or less and in female schizophrenia and schizoaffective
327 disorder patients binge drinking monthly or less compared to those never binge
328 drinking (OR 0.98, CI 0.96-1.00). Both crude and adjusted median reaction time were less
329 diverse in female schizophrenia and schizoaffective disorder patients binge drinking
330 monthly or less compared to those binge-drinking drinking never (Table 3).
331 Crude PAL FTMS and crude PAL total errors adjusted score were higher in male
332 schizophrenia and schizoaffective disorder patients binge drinking weekly (for FTMS
333 OR 2.09, CI 1.17-3.62; for total errors adjusted OR 0.63, CI 0.43-0,95) compared to those
334 binge drinking monthly or less and in male schizophrenia and schizoaffective disorder
21
335 patients binge drinking monthly or less compared to those never binge drinking. Crude
336 PAL first trial memory score and crude PAL total errors adjusted score were higher in
337 female schizophrenia and schizoaffective disorder patients binge drinking monthly or
338 less compared to those never binge drinking (for FTMS OR 1.64, CI 1.08-2.49; for total
339 errors adjusted OR 0.74, CI 0.56-0.97) and crude PAL total errors adjusted score was
340 higher in female schizophrenia and schizoaffective disorder patients binge drinking
341 weekly compared to those binge drinking monthly or less (Table 3).
342 3.43. Association of reaction time and visual memory with alcohol use disorder in schizophrenia
343 and schizoaffective disorder patients
344 There was no significant difference in crude or adjusted reaction time in male and
345 female schizophrenia and schizoaffective disorder patients with or without a lifetime
346 history of alcohol use disorder (Table 43).
347 Crude Females performed poorer in PAL test in terms of total errors adjusted score
348 after adjustment for age, education, household pattern and age at of first psychotic
349 episode after was higher in female schizophrenia and schizoaffective disorder patients
350 with a lifetime history of alcohol use disorder compared to those without alcohol use
351 disorder (OR 1.51, CI 1.06-2.171.34, CI 1.02-1.93) (Table 43).
352 3.5. Figures, Tables and Schemes

23
353
354 Figure 1. flowchart showing selection of study population
355 Table 1. Background factors and alcohol use patterns in schizophrenia and schizoaffective
356 disoderdisorder.
Male Female
N = 1711 N = 1651
25
Age (mean (SD)) 44.5 (12.8) 46.3 (13.2

Education
No matriculation examination (%) 1191 (69.6) 981 (59.4)
Matriculation examination (%) 520 (30.4) 670 (40.6)
Age at first psychotic episode (Mean (SD)) 26.84 (8.25) 28.01 (9.51)
Household pattern
Alone (%) 1338 (78.2) 1065 (64.5)
With children without spouse (%) 7 (0.4) 63 (3.8)
With parents or siblings (%) 166 (9.7) 82 (5.0)
With spouse (%) 140 (8.2) 339 (20.5)
With spouse and children (%) 60 (3.5) 102 (6.2)
Current Psychotrophic medications
No (%) 42 (2.45) 33 (2.00)
Yes (%) 1668 (97.49) 1614 (97.76)
Missing (%) 1 (0.06) 4 (0.24)
Hazardous drinking*
No (%) 1276 (74.6) 1390 (84.2)
Yes (%) 435 (25.4) 261 (15.8)
Binge drinking**
Never (%) 903 (52.8) 1134 (68.7)
Monthly or less frequently (%) 596 (34.8) 434 (26.3)
Weekly or more frequently (%) 212 (12.4) 83 (5.0)
Alcohol use disorder
No (%) 1212 (70.8) 1395 (84.5)
Yes (%) 499 (29.2) 256 (15.5)
357 *AUDIT-C cutoff scores for hazardous drinking were ≥6 for males and ≥5 for females.
358 **≥6 doses in single occasion .
Male Female
N = 1711 N = 1651
Age (mean (SD)) 44.5 (12.8) 46.3 (13.2)
Education
No matriculation examina-
1191 (69.6) 981 (59.4)
tion (%)
Matriculation examina-
520 (30.4) 670 (40.6)
tion (%)
Age at first psychotic
26.84 (8.25) 28.01 (9.51)
episode (Mean (SD))
Household pattern
With spouse 200 (11.7) 441 (26.7)
Other 1511 (88.3) 1210 (73.3)
Current Psychotropic medi-
cations
27
No (%) 42 (2.45) 33 (2.00)

Yes (%) 1668 (97.49) 1614 (97.76)
Missing (%) 1 (0.06) 4 (0.24)
Hazardous drinking*
No (%) 1276 (74.6) 1390 (84.2)
Yes (%) 435 (25.4) 261 (15.8)
Alcohol use disorder
No (%) 1212 (70.8) 1395 (84.5)
Yes (%) 499 (29.2) 256 (15.5)
359 *AUDIT-C cutoff scores for hazardous drinking were ≥6 for males and ≥5 for females.
360
361 Table 2. Association of RT test and PAL test with hazardous drinking in schizophrenia and
362 schizoaffective disorder.
363
Five choice reaction time* Five choice reaction time*
Median SD
Crude Adjusteda Crude Adjusteda
OR (95% p- OR (95% OR (95% p- OR (95%
p-value p-value
CI) value CI) CI) value CI)
Male
0.97
Hazardous drink- 0.99 (0.97- 0.86 (0.81- 0.92 (0.87-
(0.95- 0.002 0.323 <.001 0.005
ing 1.01) 0.91) 0.98)
0.99)
Female
0.94
Hazardous drink- 0.97 (0.95- 0.89 (0.83- 0.98 (0.92-
(0.92- <.001 0.010 0.002 0.606
ing 0.99) 0.96) 1.05)
0.97)
PAL first trial memory score** PAL total errors adjusted score**
Better performance than 15% of Higher error scores than 50% of
NFBC 1966 members NFBC 1966 members
p- OR (95% p- OR (95% OR (95%
OR (95% CI) p-value p-value
value CI) value CI) CI)
Male
Hazardous drink- 1.76 (1.13- 1.21 (0.77- 0.56 (0.43- 0.79 (0.60-
0.001 0.397 <.001 0.106
ing 2.66) 1.86) 0.73) 1.05)
Female
Hazardous drink- 1.58 (0.95- 1.07 (0.63- 0.58 (0.43- 0.88 (0.64-
0.064 0.798 <.001 0.440
ing 2.52) 1.74) 0.80) 1.22)
29
364
Median SD
OR (95% p- OR (95% p- OR (95% p- OR (95%
p-value
CI) value CI) value CI) value CI)
Male
0.97
Hazardous (0.95- 0.002
0.99 (0.97-
0.379
0.86 (0.81-
<.001
0.93 (0.88-
0.008
drinking 1.01) 0.91) 0.98)
0.99)
Female
0.94
Hazardous (0.92- <.001
0.97 (0.95-
0.016
0.89 (0.83-
0.002
0.99 (0.92-
0.760
drinking 0.99) 0.96) 1.06)
0.97)
Better performance than 15% of Higher error scores than 50% of NFBC
NFBC 1966 members 1966 members
p- OR (95% p- OR (95% p- OR (95%
OR (95% CI) p-value
value CI) value CI) value CI)
Male
Hazardous 1.76 (1.13-
0.001
1.24 (0.74-
0.399
0.56 (0.43-
<.001
0.92 (0.67-
0.253
drinking 2.66) 2.02) 0.73) 1.28)
Female
Hazardous 1.58 (0.95-
0.064
1.02 (0.60-
0.893
0.58 (0.43-
<.001
0.97 (0.75-
0.743
drinking 2.52) 1.71) 0.80) 1.34)
365 a
Adjusted with age, education, household pattern and age at first psychotic episode.
366 * Analyzed with log-linear regression.
367 ** Analyzed with logistic regression.
368 Table 3. Association of RT test and PAL test with binge drinking in schizophrenia and

Median SD
OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value
Binge drinking
Male
Monthly or less fre- 0.98 (0.96- 0.85 (0.81- 0.94 (0.89-
0.95 (0.93-0.96) <.001 0.009 <.001 0.040
quently 0.99) 0.90) 1.00)
31
Weekly or more fre- 0.98 (0.96- 0.83 (0.77- 0.89

0.96 (0.94-0.99) 0.002 0.102 <.001 0.003
quently 1.00) 0.90) (0.83.0.96)
Female
0.94 (0.93-0.96) <.001 0.015 <.001 0.001
quently 1.00) 0.86) 0.96)
Weekly or more fre- 0.97 (0.93- 0.87 (0.77- 0.94 (0.84-
0.95 (0.91-0.99) 0.007 0.114 0.027 0.307
quently 1.01) 0.98) 1.06)
Better performance than 15% of NFBC 1966 mem- Higher error scores than 50% of NFBC 1966 mem-
bers bers
Binge drinking
Male
1.80 (1.17-2.77) 0.008 0.876 <.001 0.170
quently 1.55) 0.62) 1.09)
2.99 (1.70-5.07) <.001 0.010 <.001 0.023
quently 3.62) 0.65) 0.95)
Female
2.56 (1.71-3.81) <.001 0.019 <.001 0.029
quently 2.49) 0.59) 0.97)
1.43 (0.49-3.33) 0.456 0.983 0.001 0.071
quently 2.41) 0.74) 1.06)
370 a
Adjusted with age, education and age at first psychotic episode
373 Table 43. Association of RT test and PAL test with alcohol use disorder in schizophrenia and
375
Median SD
Male
Alcohol use disor- 1.01 (0.99- 1.00 (0.99- 1.02 (0.96- 1.00 (0.95-
0.545 0.785 0.482 0.833
der 1.02) 1.02) 1.08) 1.06)
Female
Alcohol use disor- 0.99 (0.96- 0.99 (0.96- 1.03 (0.96- 1.03 (0.96-
0.246 0.228 0.413 0.371
der 1.01) 1.00) 1.11) 1.11)
PAL first trial memory score** PAL total errors adjusted**
33
Better performance than 15% of NFBC 1966 members Higher error scores than 50% of NFBC 1966 members
Crude Adjusted Crude Adjusted
Male
Alcohol use disor-
0.71 (0.45-1.09) 0.131 0.88 (0.55-1.36) 0.567 1.36 (1.05-1.77) 0.021 1.14 (0.86-1.51) 0.364
der
Female
Alcohol use disor-
0.53 (0.28-0.94) 0.043 0.57 (0.29-1.02) 0.076 1.57 (1.13-2.22) 0.009 1.51 (1.06-2.17) 0.024
der
Median SD
Male
Alcohol use 1.01 (0.99-
0.545
1.00 (0.99-
0.871
1.02 (0.96-
0.482
1.00 (0.95-
0.899
disorder 1.02) 1.02) 1.08) 1.06)
Female
Alcohol use 0.99 (0.96-
0.246
0.99 (0.96-
0.225
1.03 (0.96-
0.413
1.04 (0.97-
0.324
disorder 1.01) 1.01) 1.11) 1.11)
PAL first trial memory score** PAL total errors adjusted**
Better performance than 15% of NFBC 1966 members Higher error scores than 50% of NFBC 1966 members
Crude Adjusted Crude Adjusted
Male
Alcohol use 0.71 (0.45-1.09) 0.131 0.83 (0.46-1.45) 0.543 1.36 (1.05-1.77) 0.021 1.18 (0.84-1.67) 0.358
disorder
Female
Alcohol use 0.53 (0.28-0.94) 0.043 0.62 (0.29-1.17) 0.102 1.57 (1.13-2.22) 0.009 1.34 (1.02-1.93) 0.048
disorder
376
377 a
Adjusted with age, education, household pattern and age at of first psychotic episode .episode.
380 Supplementary table 1 Association between background factors and hazardous drinking in
381 schizophrenia and schizoaffective disorder.
Male Female
Hazardous drink- Hazardous drink-
35
ing ing
No Yes p No Yes p
n 1276 435 1390 261
45.79 40.84 47.45 40.19
Age <0.001 <0.001
(13.03) (11.54) (13.11) (11.97)
No matriculation 889 302 818 163
Education examination (69.7) (69.4) (58.8) (62.5)
Matriculation exam- 387 133 572
0.971 98 (37.5) 0.308
ination (30.3) (30.6) (41.2)
Age at first psy- 26.77 27.04 28.36 26.14
0.561 0.001
chotic episode (8.48) (7.57) (9.71) (8.13)
986 352 895 170
Household pattern Alone 0.307 0.045
(77.3) (80.9) (64.4) (65.1)
With children with-
6 (0.5) 1 (0.2) 60 (4.3) 3 (1.1)
out spouse
With parents or 132
34 (7.8) 73 (5.3) 9 (3.4)
siblings (10.3)
275
With spouse 103 (8.1) 37 (8.5) 64 (24.5)
(19.8)
With spouse and
49 (3.8) 11 (2.5) 87 (6.3) 15 (5.7)
children
Psychotropic
No 35 (2.7) 7 (1.6) 30 (2.2) 3 (1.1)
medication
1240 428 1356 258
Yes
(97.2) (98.4) (97.6) (98.9)
Missing 1 (0.1) 0 (0.0) 0.352 4 (0.3) 0 (0.0) 0.385
Male Female
Hazardous drink- Hazardous drink-
ing ing
No Yes p No Yes p
n 1276 435 1390 261
Age (Mean 45.79 40.84
<0.001
47.45 40.19
<0.001
(SD)) (13.03) (11.54) (13.11) (11.97)
Education No matriculation 889 302 818 163
0.308
N(%) examination (69.7) (69.4) (58.8) (62.5)
Matriculation exam- 387 133 572
0.971 98 (37.5)
ination (30.3) (30.6) (41.2)
Age at first 26.77 27.04 0.561 28.36 26.14 0.001
(8.48) (7.57) (9.71) (8.13)
psychotic
episode (Mean
37
(SD))
Household pat- With spouse
152
48 (11.0) 0.685
362
79 (30.3) 0.180
tern N(%) (11.9) (26.0)
1124 387 1028 182
Other
(88.1) (89.0) (74.0) (69.7)
Psychotropic
medication No 35 (2.7) 7 (1.6) 30 (2.2) 3 (1.1)
N(%)
1240 428 1356 258
Yes
(97.2) (98.4) (97.6) (98.9)
Missing 1 (0.1) 0 (0.0) 0.352 4 (0.3) 0 (0.0) 0.385
382
383 Supplementary table 2 Distribution of RT median, RT SD, PAL first trial memory scores (FTMS)
384 and PAL total errors adjusted in study population.
Min 1st Qu, Median Mean 3rd Qu. Max

RT Median 288 298 434.5 450.2 482 1610
RT SD 14.78 37.98 49.95 66.50 69.87 922.02
PAL FTMS 0.0 4.0 8.0 8.3 12 20
PAL Total
errors ad- 0.0 14 35 33.16 50 70
justed
385 Supplementary table 3. RT median and RT SD P-values for background factors and alcohol use
386 disorder in schizophrenia and schizoaffective disorder.
P-values
Male Female
RT RT
median SD median SD Test
Age <.001 <.001 <.001 <.001 Spearman
Education 0.563 0.104 <.001 <.001 Spearman
Age at first
psychotic <.001 <.001 <.001 <.001 Spearman
episode
Alcohol use
0.445 0.245 0.178 0.211 Point biserial
disorder
387 Supplementary table 4. PAL first trial memory scores (FTMS) for background factors and alcohol
388 use patterns in schizophrenia and schizoaffective disorder.
39
Male Female
PAL FTMS PAL FTMS
0 1 p 0 1 p
n 1462 79 1361 100
44.86 46.28 37.44
Age 33.77 (9.41) <0.001 <0.001
(12.58) (12.97) (10.87)
Matriculation exami-
Education 452 (30.9) 35 (44.3) 0.018 564 (41.4) 58 (58.0) 0.002
nation
No matriculation 1010
44 (55.7) 797 (58.6) 42 (42.0)
examination (69.1)
Age at first
26.90 28.11 25.93
psychotic 24.38 (5.93) 0.008 0.028
(8.26) (9.69) (7.69)
episode
Household 1162
Alone 50 (63.3) 0.002 888 (65.2) 49 (49.0) <0.001
pattern (79.5)
With children without
5 (0.3) 1 (1.3) 45 (3.3) 10 (10.0)
spouse
With parents or sib-
137 (9.4) 12 (15.2) 66 (4.8) 7 (7.0)
lings
With spouse 109 (7.5) 8 (10.1) 277 (20.4) 20 (20.0)
With spouse and
49 (3.4) 8 (10.1) 85 (6.2) 14 (14.0)
children
Psychotropic
No 34 (2.3) 7 (8.9) 26 (1.9) 5 (5.0)
medication
1427 1334
Yes 72 (91.1) 94 (94.0)
(97.6) (98.0)
Missing 1 (0.1) 0 (0.0) 0.002 1 (0.1) 1 (1.0) 0.006
Hazardous 1101 1146
No 51 (64.6) 0.044 80 (80.0) 0.335
drinking (75.3) (84.2)
Yes 361 (24.7) 28 (35.4) 215 (15.8) 20 (20.0)
Binge
Never 784 (53.6) 30 (38.0) 937 (68.8) 53 (53.0)
drinking
Monthly or less fre-
505 (34.5) 31 (39.2) 0.004 352 (25.9) 44 (44.0) <0.001
quently
Weekly or more
173 (11.8) 18 (22.8) 72 (5.3) 3 (3.0)
frequently
Alco-
1037 1143
hol use disor- No 62 (78.5) 0.188 90 (90.0) 0.145
(70.9) (84.0)
der
Yes 425 (29.1) 17 (21.5) 218 (16.0) 10 (10.0)
Male Female
PAL FTMS PAL FTMS
41
0 1 p 0 1 p
n 1462 79 1361 100
Age Mean 44.86
33.77 (9.41) <0.001
46.28 37.44
<0.001
(SD) (12.58) (12.97) (10.87)
Education Matriculation exami-
452 (30.9) 35 (44.3) 0.018
564
58 (58.0) 0.002
N(%) nation (41.4)
No matriculation 1010 797
44 (55.7) 42 (42.0)
examination (69.1) (58.6)
Age of first
psychotic 26.90
24.38 (5.93) 0.008
28.11 25.93
0.028
episode Mean (8.26) (9.69) (7.69)
(SD)
Household With spouse 158 (10.8) 16 (20.3) 0.016
362
34 (34.0) 0.136
pattern N(%) (26.6)
1304 999
Other 63 (79.7) 66 (66.0)
(89.2) (73.4)
Psychotropic
medication No 34 (2.3) 7 (8.9) 26 (1.9) 5 (5.0)
N(%)
1427 1334
Yes 72 (91.1) 94 (94.0)
(97.6) (98.0)
Missing 1 (0.1) 0 (0.0) 0.002 1 (0.1) 1 (1.0) 0.006
Hazardous
1101 1146
drinking N(% No
(75.3)
51 (64.6) 0.044
(84.2)
80 (80.0) 0.335
)
215
Yes 361 (24.7) 28 (35.4) 20 (20.0)
(15.8)
Alcohol use No
1037
62 (78.5) 0.188
1143
90 (90.0) 0.145
disorder (70.9) (84.0)
N(%)
218
Yes 425 (29.1) 17 (21.5) 10 (10.0)
(16.0)
389
390 Supplementary table 5. PAL total errors adjusted sores for background factors and alcohol use
391 patterns in schizophrenia and schizoaffective disorder.
43
Male Female
PAL total errors PAL total errors
adjusted adjusted
0 1 0 1
n 241 1300 297 1164
35.46 45.93 <0.00 37.82 47.68 <0.00
Age
(10.11) (12.43) 1 (10.90) (12.76) 1
Education 925 (71.2) 710 (61.0)
examination (53.5) (43.4)
Matriculation exami- 112 <0.00 168 <0.00
375 (28.8) 454 (39.0)
nation (46.5) 1 (56.6) 1
Age at first psy- 24.34 27.23 <0.00 25.94 28.47 <0.00
chotic episode (5.99) (8.45) 1 (7.70) (9.94) 1
174 1038 167 <0.00
Household pattern Alone 0.031 770 (66.2)
(72.2) (79.8) (56.2) 1
1 (0.4) 5 (0.4) 23 (7.7) 32 (2.7)
spouse
30 (12.4) 119 (9.2) 19 (6.4) 54 (4.6)
lings
With spouse 20 (8.3) 97 (7.5) 56 (18.9) 241 (20.7)
With spouse and
16 (6.6) 41 (3.2) 32 (10.8) 67 (5.8)
children
Psychotropic
No 11 (4.6) 30 (2.3) 10 (3.4) 21 (1.8)
medication
230 1269 286 1142
Yes
(95.4) (97.6) (96.3) (98.1)
Missing 0 (0.0) 1 (0.1) 0.124 1 (0.3) 1 (0.1) 0.143
Hazardous 166 239
No 986 (75.8) 0.027 987 (84.8) 0.085
drinking (68.9) (80.5)
Yes 75 (31.1) 314 (24.2) 58 (19.5) 177 (15.2)
Binge 100 170
Never 714 (54.9) 820 (70.4)
drinking (41.5) (57.2)
Monthly or less fre- 106 111 <0.00
430 (33.1) 0.001 285 (24.5)
quently (44.0) (37.4) 1
Weekly or more fre-
35 (14.5) 156 (12.0) 16 (5.4) 59 (5.1)
quently
Alcohol 186 259
No 913 (70.2) 0.035 974 (83.7) 0.160
use disorder (77.2) (87.2)
Yes 55 (22.8) 387 (29.8) 38 (12.8) 190 (16.3)
392
Male Female
45
PAL total errors PAL total errors

adjusted adjusted
0 1 0 1
n 241 1300 297 1164
35.46 45.93 <0.00 37.82 47.68 <0.00
Age (10.11) (12.43) 1 (10.90) (12.76) 1
Education examination (53.5)
925 (71.2)
(43.4)
710 (61.0)
Matriculation exami- 112 <0.00 168 <0.00
375 (28.8) 454 (39.0)
nation (46.5) 1 (56.6) 1
Age at first
24.34 27.23 <0.00 25.94 28.47 <0.00
psychotic (5.99) (8.45) 1 (7.70) (9.94) 1
episode
Household Alone
174 1038
0.031
167
770 (66.2)
<0.00
pattern (72.2) (79.8) (56.2) 1
1 (0.4) 5 (0.4) 23 (7.7) 32 (2.7)
spouse
30 (12.4) 119 (9.2) 19 (6.4) 54 (4.6)
lings
With spouse 20 (8.3) 97 (7.5) 56 (18.9) 241 (20.7)
With spouse and
16 (6.6) 41 (3.2) 32 (10.8) 67 (5.8)
children
Psy-
chotropic med- No 11 (4.6) 30 (2.3) 10 (3.4) 21 (1.8)
ication
230 1269 286 1142
Yes
(95.4) (97.6) (96.3) (98.1)
Missing 0 (0.0) 1 (0.1) 0.124 1 (0.3) 1 (0.1) 0.143
166 239
Hazardous No
(68.9)
986 (75.8) 0.027
(80.5)
987 (84.8) 0.085
drinking
Yes 75 (31.1) 314 (24.2) 58 (19.5) 177 (15.2)
100 170
Never 714 (54.9) 820 (70.4)
Binge drinking (41.5) (57.2)
Monthly or less fre- 106 111 <0.00
430 (33.1) 0.001 285 (24.5)
quently (44.0) (37.4) 1
Weekly or more fre-
35 (14.5) 156 (12.0) 16 (5.4) 59 (5.1)
quently
Al- No 186 913 (70.2) 0.035 259 974 (83.7) 0.160
47
cohol use dis- (77.2) (87.2)

order
Yes 55 (22.8) 387 (29.8) 38 (12.8) 190 (16.3)
393
394 Supplementary table 6. RT median and RT SD for hazardous drinking in schizophrenia and
Male Female
Hazardous drinking Hazardous drinking
0 1 p 0 1 p
n 1276 435 1390 261
Median (Mean 453 438.30 455.75 426.66
RT 0.004 <.001
(SD)) (96.06) (79.04) (98.50) (64.39)
67.93 53.65 70.60 59.26
SD (Mean (SD)) <.001 0.021
(71.75) (32.57) (75.62) (54.18)
396 Supplementary table 7. Cohen's d Measure of Effect.
Female Male
Hazardous drinking
0.16 (0.05-0.27) 0.22 (0.11, 0.33) RTI SD
0.31 (0.18-0.44) 0.16 (0.05, 0.27) RTI Median
0.12 (0.03, 0.26) 0.08 (0.03, 0.19) PAL FTMS
0.13 (0.00, 0.27) 0.13 (0.02, 0.25) PAL TEA
Alcohol disorder
0.02 (-0.12, 0.15) 0.02 (-0.05, 0.12) RTI SD
0.08 (0.00-0.19) 0.02 [-0.01, 0.10) RTI median
0.08 (-0.03, 0.19) -0.11 (-0.25, 0.03) PAL FTMS
0.12 (0.01, 0.26) -0.12 (-0.23, -0.01) PAL TEA
397
398 Supplementary table 6. RT median and RT SD for hazardous drinking in schizophrenia and
Male Female
Hazardous drinking Hazardous drinking
49
0 1 p 0 1 p
n 1276 435 1390 261
438.30 455.75 426.66
RT Median 453 (96.06) 0.004 <.001
(79.04) (98.50) (64.39)
67.93 53.65 70.60 59.26
SD <.001 0.021
(71.75) (32.57) (75.62) (54.18)
400 4. Discussion
401 4.1. Main findings

402 Our findings did not support our hypothesis that alcohol use is associated with
403 additional cognitive impairment in schizophrenia and schizoaffective disorder patients.
404 In contrast, crude median reaction time was significantly shorter in female schizophrenia
405 and schizoaffective disorder patients with hazardous drinking. Crude PAL total errors
406 adjusted score were significantly higher in male and female schizophrenia and
407 schizoaffective disorder patients with hazardous drinking. Crude PAL first trial memory
408 score and crude PAL total errors adjusted score were significantly higher in male and
409 female schizophrenia and schizoaffective disorder patients binge drinking monthly or
410 less compared to those never binge drinking. Our findings did not support our
411 hypothesis that problematic drinking was associated with impaired cognitive function in
412 schizophrenia and schizoaffective disorder. Rather, some positive association was found
413 between hazardous drinking and reaction time scores both in males and females.
414 4.2. Comparison with other studies

415 There hardly exist any studies investigating association of different alcohol use
416 patterns in schizophrenia and schizoaffective disorder patients hence it is difficult to
417 compare our findings with other studies.
418 Most studies investigating cognitive impact of alcohol in schizophrenia patients
419 with comorbid AUD revealed negative association between alcohol use and cognitive
420 function [6,7,49,50,51,5245,46,47,48]. On the other hand, some studies suggested that
421 AUD had no additive effects on cognitive impairment in schizophrenia patients
422 [53,54,5549.50,51], or had positive associations with social cognition
423 [56,57,58,5952,53,54,55], task making and the speed processing domains [6056].
424 Meta-analysis of 6 research findings published during 1996-2009 revealed that
425 younger (<30 years) schizophrenia patients with comorbid alcohol use disorders had
426 better cognition than schizophrenia patients without AUD. In contrast, older (> 40 years)
427 schizophrenia patients with comorbid alcohol use disorders had worse cognition than
428 their non-comorbid counterparts [5]. A systematic review of research papers published
429 during 1990-2012 revealed that cognition was more preserved in schizophrenia patients
430 with comorbid substance/ alcohol use disorders compared schizophrenia patients
51
431 without comorbidity [6157]. It is likely that unmeasured confounding contributes to the
432 discrepant findings in previous studies.
433 General population cross-sectional studies investigating effects of alcohol on
434 cognitive function revealed that moderate to heavy drinking was associated with
435 cognitive decline [62,63,64,6558,59,60,61] and mild to moderate drinking was associated
436 with either no effects on cognition [66,6762,63] or cognitive enhancement
437 [65,68,69,70,7161,64,65,66,67].
438 Most cohort studies in the general population addressing the same issue revealed a
439 positive correlation between light / light to moderate alcohol use and cognitive function
440 [26,27,72,73,7423,24,68,69,70] whereas other cohort study found no association between
441 light to moderate alcohol consumption and better or worse cognitive functions
442 [75,76,7771,72,73]. One study reported a positive association between moderate to heavy
443 drinking and cognitive function [7874]. In contrast, another cohort study revealed
444 negative association between heavy alcohol use and cognitive function in normal
445 population [7975]. One cohort study found dose-response positive association of alcohol
446 use and cognitive function compared to abstainers and former drinkers [8076]. Another
447 cohort study revealed significant cognitive impairment in low functioning non-drinkers
448 and light to moderate drinkers and high functioning non-drinkers [8177].
449 A brief review of 29 studies (2003-2013) revealed that acute alcohol mostly impaired
450 executive function in normal population [8278]. In contrast, A systematic review of 143
451 studies (1977-2011) revealed that light to moderate alcohol use did not impair cognition
452 in young male and female individuals and reduced the risk of all forms of dementia and
453 cognitive decline in older individuals [8379]. Another systematic review of 28 reviews
454 (2000-2017) revealed that light to moderate alcohol use in middle to late adulthood was
455 associated with a decreased risk of cognitive impairment and dementia [2522]. Meta-
456 analysis of 27 cohort studies (2007-2018) revealed that moderate alcohol use improved
457 cognition insignificantly among male and slightly among female compared to current
458 non-drinkers [2421]. Moderate alcohol has been found to be associated with reduced
459 amyloid-beta deposition in human brain [8480].
460 Study findings suggesting positive association between alcohol and cognition could
461 be attributed by unmeasured or residual confounding factors [85,8681,82] like: smoking
462 [8783], drink type [8884], drink pattern [8985], personality [87,9083,86], intelligence
463 [76,91,9272,87,88], educational attainment [93,9489,90], potential abstainer errors
464 [95,96,97,9891,92,93,94], reverse causality bias [9995], recall error [10096] within person
465 temporal variation [101,10297,98], ascertainment of diseases [10399] and sociability effect
466 of alcohol [104100]. Study findings suggesting positive association between alcohol and
467 cognition could be attributed by poor motivation [105,106,107101,102,103].
468 Animal-model studies suggested alcohol to be associated with cognition negatively
469 through decreasing cell density in the cerebral cortex [108104], altering accumbal
470 cholinergic interneurons [109105] and positively through enhancing brain metabolite
53
471 clearance [110106], activating vagus nerve [111107], anti-oxidant system

472 [112,113,114,115108,109,110,111] and other biological processes [116,117,118112,113,114].
473 However, none of these findings have so far been confirmed to be causally important.
474 Epidemiological studies suggested that apparent befitting effects of alcohol might
475 largely be non-causal [27,119,120,121,12224,115,116,117,118]. More research is needed for
476 further clarification [123119].
477 4.3. Strength

478 We were able to use a very large sample of schizophrenia and schizoaffective
479 disorder patients to investigate cognitive impact of different alcohol use patterns. We
480 studied multiple alcohol use patterns in the same study population, and used age,
481 education and age of onset of schizophrenia and schizoaffective disorder as potential
482 confounding variables.
483 Although long-term antipsychotic medication might be associated with additional
484 loss of both gray and white matters in schizophrenia [124120], in our study we did not
485 confound antipsychotic medication because 98% of the study population was on
486 antipsychotic medication hence it would not make any statistically significant
487 differences. First generation antipsychotics have been found to be associated with
488 increased volume of basal ganglia, namely globes pallidus, which might be reversed on
489 switching into second-generation antipsychotics and clozapine [121,122]. However,
490 antipsychotic induced brain volume loss has never been established to be associated
491 with additional cognitive decline [123]. It was beyond the scope of this study to consider
492 different types and different doses of psychotropic medication because it would be
493 extremely laborious to extract detailed data on medication and translate the prescription
494 from Finnish to English. Use of drug combinations was a further problem. In the original
495 self-reporting questionnaire of the SUPER Study, only using or not using antipsychotic
496 medication were included.
497 We have included all schizophrenia and schizoaffective disorder patients living
498 independently and excluded those whose living circumstances might affect their alcohol
499 use.
500 4.4. Limitations

501 We used only two tests from CANTAB. Our study was cross-sectional, not
502 longitudinal. Our study was cross-sectional, not longitudinal. We did not use
503 information about the onset of alcohol use, any recent changes in drinking habits or any
504 previous history of abstinence. We also did not differentiate previous alcohol users from
505 never-alcohol users.
506 We did not use information about poly-substance use and smoking. We did not
507 include daily smoking as a covariate because of multicollinearity; approximately 3/4 of
508 those with hazardous alcohol use in this sample also were daily smokers.We did specify
55
509 psychotropic medications. First generation antipsychotics have been found to be

510 associated with increased volume of basal ganglia, namely globes pallidus, which might
511 be reversed on switching into second-generation antipsychotics and clozapine [125,126].
512 However, antipsychotic induced brain volume loss has never been established to be
513 associated with additional cognitive decline [12].
514 4.5. What is already known on this subject?

515  Alcohol use disorder decline cognition in schizophrenia and schizoaffective
516 disorder patients
517  Mild alcohol use is not associated with impaired cognition in normal
518 population.
519 4.6. What this study adds?

520  Mild alcohol use is not associated with additional cognitive impairment in
521 schizophrenia and schizoaffective disorder patients. Hazardous drinking
522 was not associated with cognitive deficits in schizophrenia and schizoaffec-
523 tive disorder.
524
525 5. Conclusions
526 Hazardous drinking was not associated with cognitive decline in schizophrenia and
527 schizoaffective disorder. Rather, some positive association was found between
528 hazardous drinking and cognition which was unique to these psychiatric disorders, but,
529 in line with the findings from general population studies.No additional cognitive
530 impairment was associated with both male and female schizophrenia and
531 schizoaffective disorder patients with hazardous drinking, binge drinking and alcohol
532 use disorder. Some positive association between alcohol and cognition were found in
533 terms of shorter crude median reaction time in female and higher crude PAL total errors
534 adjusted score in male and female schizophrenia and schizoaffective disorder patients
535 with hazardous drinking, higher crude PAL first trial memory score and crude PAL total
536 errors adjusted score in male and female schizophrenia and schizoaffective disorder
537 patients binge drinking monthly or less compared to those never binge drinking. Further
538 genetic epidemiological studies could help resolving alcohol and cognition correlation-
539 causality-reverse causality debate.
540 6. Patents
541 This section is not mandatory but may be added if there are patents resulting from
542 the work reported in this manuscript.
57
543 Supplementary Materials: The following are available online at

544 https://drive.google.com/drive/folders/1-9PUv7ZxZ9cSTE8RD_0sAPgV7NZfTsVq ,
545 Supplementary tables 1-6.
546 Author Contributions: All authors have contributed to the conception and design of the study as
547 well as collection of data from various sources. SS performed the analyses. All authors were
548 involved in text editing and discussion of findings. All authors have approved of the final version
549 of the manuscript.
550 Funding: The work was supported by a grant from the Stanley Center for psychiatric research,
551 Broad Institute, Cambridge, USA. (Grant Agreement no. 6045290-5500000710, 6000009-
552 5500000710). . (Grant number 0000-0000).
553 The Principal author was supported by the Marie Skłodowskaja-Curie Action co-funding of
554 regional, national, and international programmes (COFUND) (Grant Agreement no. 713606) for
555 his doctoral programme (MSC-COFUND, I4FUTURE). The Principal author was also supported
556 by the Iso-Mällisen Foundation (Iso-Mällisen Säätiö) through a medical grant of EUR 4,000 for the
557 year 2019 (Grant no. 0400 584622).
558 Institutional Review Board Statement: Prior to seeking study permissions, a statement pertaining
559 to the ethical considerations of the study was requested from the Coordinating Ethics Committee
560 of the The Hospital District of Helsinki and Uusimaa, which is responsible for nationwide ethical
561 statements. After receiving a favorable statement (HUS/1842/2016) the permissions to conduct the
562 study was sought and obtained from all participating healthcare organizations individually.
563 Permissions for use of national registries were obtained from relevant authorities.
564 After receiving a favorable statement, the permissions to conduct the study was sought and
565 obtained from all participating healthcare organizations individually. The Finnish Institute for
566 Health and Welfare gave permission to access individual healthcare records the registry data for
567 which it is responsible (THL/1007/5.05.00/2017).
568 The research was conducted also according to the guidelines of the following research ethics
569 documents: theThe Responsible conduct of research and procedures for handling allegations of
570 misconduct in Finland (http://www.tenk.fi/sites/tenk.fi/files/HTK_ohje_2012.pdf) and,
571 The European Code of Conduct for Research Integrity, revised edition 2017
572 (http://www.tenk.fi/sites/tenk.fi/files/ALLEA-European-Code-of-Conduct-for-Research-Integrity-
573 2017.pdf
574 Informed Consent Statement: Written informed consent was obtained from all participants. They
575 were informed that participating in or abstaining from the study would not affect the treatment of
576 the study patients.
577 Study subjects were also informed that they could withdraw their consent at any time, at which
578 point any samples or data stored from them would be destroyed. Data already used in analysis, if
579 not possible to remove from the completed analyses, would never be used in the future, unless a
580 part of a large summary dataset. If the subject was in involuntary psychiatric care or the study
581 nurse had any doubts on the subject’s ability to give informed consent, permission would be asked
582 to contact the attending physician of the subject to obtain a statement whether the subject was able
59
583 to give informed consent to participate in the study. Patients under guardianship were excluded
584 from the study as well as all minors.
585
586 From all study participants written informed consent for publication of the study results without
587 disclosing their identities have been taken.
588
589 Data Availability Statement: Raw data and materials used for this study are available on request.
590 Acknowledgments: The authors are grateful to the participants and SUPER-Study staffs.
591 Conflicts of Interest: None of the authors has any conflicts of interest associated with this study.
592 All authors have completed the ICMJE uniform disclosure form at
593 www.icmje.org/coi_disclosure.pdf and declare: grant support for the submitted work is detailed
594 above; no financial relationships with any organizations that might have an interest in the
595 submitted work in the previous three years; no other relationships or activities that could appear
596 to have influenced the submitted work. However, Jennifer Barnett has been working in Cambridge
597 Cognition since 2016.
598
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2 Reaction time and visual memory in connection to alcohol use

3 Brain Sci. 2021, 11, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/brainsci

76 Cognitive dysfunction is a persistent, disabling hallmark of schizophrenia found to

112 2. Materials and Methods

113 2.1. Participants

141 2.2. Schizophrenia and schizoaffective disorder diagnoses

152 2.3. Hazardous drinking screening

164 2.4. Binge drinking screening

168 2.54. Alcohol use disorder diagnoses

171 2.6. Cognitive measures

220 2.7. Confounding factors

224 2.7.1. Age

229 2.7.2. Education

238 2.7.3. Age of first psychotic episodeHousehold pattern

246 2.7.4. Age of first psychotic episode

253 2.8. Statistical methods

272 3.1. Background factors and alcohol use patterns

352 3.5. Figures, Tables and Schemes

354 Figure 1. flowchart showing selection of study population

Age (mean (SD)) 44.5 (12.8) 46.3 (13.2

No (%) 42 (2.45) 33 (2.00)

Five choice reaction time* Five choice reaction time*

Weekly or more fre- 0.98 (0.96- 0.83 (0.77- 0.89

Min 1st Qu, Median Mean 3rd Qu. Max

PAL total errors PAL total errors

cohol use dis- (77.2) (87.2)

396 Supplementary table 7. Cohen's d Measure of Effect.

401 4.1. Main findings

414 4.2. Comparison with other studies

471 clearance [110106], activating vagus nerve [111107], anti-oxidant system

477 4.3. Strength

500 4.4. Limitations

509 psychotropic medications. First generation antipsychotics have been found to be

514 4.5. What is already known on this subject?

519 4.6. What this study adds?

543 Supplementary Materials: The following are available online at

600 1. Bosia M, Buonocore M, Bechi M, et al (2018) Improving Cognition to Increase Treatment

617 6. Manning V, Betteridge S, Wanigaratne S, Best D, Strang J, Gossop M (2009) Cognitive

1089 tects Against Acidosis-Induced Neurotoxicity. Mol Neurobiol. 56(5):3326-3340.

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