Schizophrenia Research 143 (2013) 8489

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Schizophrenia Research
journal homepage: www.elsevier.com/locate/schres

Cannabis use and premorbid functioning as predictors of poorer neurocognition in schizophrenia spectrum disorder
P. Andreas Ringen a,, Ingrid Melle a, b, Akiah O. Berg a, b, Ingrid Agartz a, b, c, Olav Spigset d, e, Carmen Simonsen a, Kjetil Sundet a, f, Ole A. Andreassen a, b
a

KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, N-0424 Oslo, Norway Division of Mental Health and Addiction, Institute for Clinical Medicine, University of Oslo, N-0318 Oslo, Norway Department of Research and Development, Diakonhjemmet Hospital, Box 23, N-0319 Oslo, Norway d Department of Clinical Pharmacology, St. Olav University Hospital, N-7006 Trondheim, Norway e Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, N-7491 Trondheim, Norway f Department of Psychology, University of Oslo, N-0317 Oslo, Norway
b c

a r t i c l e

i n f o

a b s t r a c t
Background: Evidence of associations between neurocognitive function and cannabis use in schizophrenia is inconclusive. However, direct measures of cannabis intake and premorbid function are rarely explored in this context. We investigated the relation between cannabis use, determined by its presence in urine, and neurocognitive functioning in schizophrenia controlling for the potential bias of premorbid functioning. Methods: Naturalistic study of 364 patients with schizophrenia spectrum disorder from catchment areas in Oslo, Norway. Hierarchical multiple regression analyses were used to assess the relationship between cannabis in urine and measures of neurocognitive functioning, with adjustment for confounders, including premorbid functioning. Results: Cannabis was detected in the urine of 21 patients, who had signicant dysfunction in several neurocognitive domains independent of a current diagnosis of cannabis abuse. However, level of premorbid functioning explained the associations for all measures. Conclusion: Differences in premorbid functioning may explain apparent differences in neurocognitive function between schizophrenia spectrum patients using cannabis or not. The ndings suggest that illness-related traits present early in life can affect both later cannabis use and neurocognition, probably by complex mechanisms. 2012 Elsevier B.V. All rights reserved.

Article history: Received 23 December 2011 Received in revised form 30 September 2012 Accepted 27 October 2012 Available online 22 November 2012 Keywords: Schizophrenia Cannabis Urine samples Neurocognitive functioning Premorbid functioning

1. Introduction Cannabis is the most prevalent substance of abuse, next to alcohol, in the western world (SAMHSA, 2011), and its use is also common among individuals with psychotic disorders (Green et al., 2007). Substance use is generally related to poorer course and outcome in schizophrenia (Dixon et al., 1991; Linszen et al., 1994; Salyers and Mueser, 2001; Margolese et al., 2004; Lambert et al., 2005; Barak et al., 2008). Longitudinal epidemiological studies have suggested that early exposure to cannabis is related to an increased risk for developing psychosis (Moore et al., 2007), but establishing casual relationships is difcult as reverse causality and interactions with other
Corresponding author at: KG Jebsen Centre for Psychosis Research - TOP Program, Building 49, Division of Mental Health and Addiction, Oslo University Hospital - Ulleval, Kirkeveien 166, N-0407 Oslo, Norway. Tel.: +47 23 02 73 50; fax: +47 23 02 73 33. E-mail addresses: p.a.ringen@medisin.uio.no (P.A. Ringen), ingrid.melle@medisin.uio.no (I. Melle), a.o.berg@medisin.uio.no (A.O. Berg), ingrid.agartz@medisin.uio.no (I. Agartz), Olav.Spigset@legemidler.no (O. Spigset), c.e.simonsen@medisin.uio.no (C. Simonsen), k.s.sundet@psykologi.uio.no (K. Sundet), o.a.andreassen@medisin.uio.no (O.A. Andreassen). 0920-9964/$ see front matter 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2012.10.021

environmental and genetic factors cannot be excluded (Minozzi et al., 2010). In experimental studies, the main active constituent of cannabis, 9-tetrahydrocannabinol (THC) has been shown to transiently increase symptoms and impair neurocognitive functioning in healthy individuals (D'Souza et al., 2004), with even more pronounced effects in patients with schizophrenia (D'Souza et al., 2005; Morrison et al., 2009). Several cross-sectional clinical studies have, however, found cannabis users with schizophrenia to have less negative symptoms (Dixon et al., 1991; Salyers and Mueser, 2001) and better neurocognitive functioning than non-users (Yucel et al., 2012; Rabin et al., 2011). This apparent inconsistency in ndings may reect the existence of different mechanisms behind associations between cannabis use, symptoms and functional levels in schizophrenia. It is e.g. suggested that schizophrenia patients using cannabis could represent a subgroup with a less severe form of illness (Loberg and Hugdahl, 2009; Yucel et al., 2012). The direct pharmacological effects of THC found in the experimental studies are mediated by cannabinoid receptor activation leading to downstream neuronal changes causing clinical symptoms and cognitive dysfunction (D'Souza et al., 2005). However, the underlying psychopathology of the associations revealed in clinical studies may be other than direct

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pharmacological effects, including overlapping neurobiological substrates for psychosis and cannabis use, and effects of cannabis exposure on brain maturation (Murray et al., 2007). The inconsistencies in the literature could also, among others, be due to methodological problems, such as bias in sample recruitment, suboptimal methods for determining cannabis use, failure to account for other types of substance use, and lack of control for susceptibility traits. The clinical studies have determined cannabis exposure according to self-reported use over a dened level (quantity, frequency, duration, recency/abstinence), or according to ICD or DSM diagnostic criteria. Denitions of use thus differ between studies. Although the validity of self-reports of illicit drug use is generally reported to be acceptable, there are several limitations to self-reports compared to objective markers of use (Del Boca and Noll, 2000). Cannabinoids can be easily measured in urine and is a robust evidence of cannabis use. In general, cannabis (and its metabolites) is cleared from urine within a few days after a single intake. It may however remain traceable in urine for several weeks after a period of chronic daily exposure, depending on dose, duration and individual metabolic factors (Lowe et al., 2009). A mere presence of cannabis in urine is therefore not necessarily evidence for a very recent intake of cannabis use. The diagnostic categories of abuse or addiction in DSM-IV are broad entities. Full remission is not achieved until after 12 months without fullling criteria, and in this period the person may be totally abstinent. Furthermore, patterns of use need some time to evolve in order to cause substantially reduced functioning as required in the criteria. Thus, a diagnosis of current abuse or addiction is associated with long-term use and not necessarily with current. The notion that schizophrenia patients using cannabis represent a subgroup with a different severity is difcult to explore, since schizophrenia is a broad clinical syndrome with a complex etiology and several mutually interacting risk factors. However, assessment of premorbid functioning could be of help to explore if premorbid factors may be associated with both cannabis use and clinical sub-groups of schizophrenia. Poor premorbid functioning is associated with a more severe course of schizophrenia, and this measure is often used as a susceptibility trait and a proxy for a more severe form of the disorder. Investigation of the possible role for susceptibility traits is of special interest, as there is evidence pointing to gene-environment interactions between cannabis and schizophrenia symptoms, including neurocognition (Ho et al., 2011). Assessment of premorbid functioning is therefore of importance in the study of overlapping psychopathological factors leading to cannabis intake and outcome in schizophrenia. The current study aimed at investigating the relationship between objective urine measures of cannabis use, neurocognition and premorbid functioning in a large, consecutively selected and thoroughly described sample of patients with schizophrenia from a catchment area based hospital setting. This recruitment design has shown to give the subjects a high degree of representativity with the general schizophrenia population in the city of Oslo, Norway (Ringen et al., 2008). The following hypotheses were postulated for the study: 1) Recent cannabis intake as determined by urine analyses is associated with altered cognitive functioning in patients with schizophrenia; 2) Long-term cannabis intake or poor premorbid function inuence these relationships. 2. Materials and methods 2.1. Overview The study was part of the Thematically Organized Psychosis (TOP) Study. Recruitment to the current part of the study was carried out from 2004 until 2011 from the three major hospitals in Oslo, Norway, covering a catchment area of 485 000 inhabitants. Patients were recruited consecutively from in- and outpatient psychiatric units.

There were no other treatment organizations serving these areas, allowing for a high degree of representativity for participating patients. For details, see Ringen et al. (2008). To be eligible for inclusion in the present part of the study the patients had to be between 18 and 65 years, to have a DSM-IV diagnosis of schizophrenia, schizophreniform disorder or schizoaffective disorder, and be willing and able to give informed consent. Exclusion criteria were the presence of a diagnosis of developmental disorder, serious brain damage or not speaking Norwegian. Emphasis was put on recruiting all patients regardless of level of involvement in their respective treatment programs. Data on the rst 364 consecutively recruited patients with valid urine tests and complete data sets on relevant outcome variables are included in the current analyses. This number represents the available data in the most recent updating of the on-going inclusions in the TOP database in April 2012. Mean age was 31.2 years (SD = 9.6), and 43.1% (N = 157) were female. All assessments were conducted by trained clinicians working as research fellows (psychiatrists, psychiatric residents or clinical psychologists). The TOP study is approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate. 2.2. Assessments of diagnosis Diagnosis was established using the Structural Clinical Instrument of Diagnosis for DSM-IV axis I disorders (SCID I), modules A-E. Subjects with schizophrenia counted 278 (76.4%), subjects with schizophreniform disorder 30 (8.2%) and subjects with schizoaffective disorder 56 (15.4%). All interviewers participated in regularly diagnostic consensus meetings led by a clinically and scientically well experienced supervisor. In addition, all raters nished a training course in SCID assessment based on the training program at the UCLA (Ventura et al., 1998). The reliability of diagnoses has been assessed to be high, with a Kappa value of 0.77. For further details, see Ringen et al. (2008). 2.3. Assessments of substance use Urine samples for drugs of abuse were collected in the morning the same day as the neuropsychological testing took place. Standard methods for the detection of illegal substances in urine were used, including enzyme immunoassay (CEDIA, Microgenics Corporation, Fremont, CA, USA) and liquid chromatography-mass spectrometry (LC-MS) (Bagoien et al., 2009). Cut-off levels were in the range 20-40 ng/mL for the THC metabolite THC-carboxylic acid (THC-COOH). For the amphetamines and ecstasy the maximum cut-off level was 500 ng/mL whereas for cocaine it was 150 ng/mL. Diagnosis of abuse/addiction of any substance was established using the SCID-E module. 57 patients had a lifetime DSM-IV diagnosis of cannabis abuse or addiction (15.7%), in 43 (11.8%) of the patients this condition was current (not in full remission). Prevalence of current abuse/addiction was 38 (10.4%) for alcohol and 16 (4.4%) for stimulants (amphetamines, cocaine or ecstasy). Information on daily tobacco use was recorded. 2.4. Assessment of sociodemographic characteristic, symptoms and functioning Premorbid functioning was assessed by the Premorbid Adjustment Scale (PAS) (Cannon-Spoor et al., 1982). PAS scores were divided into premorbid academic and social functioning according to premorbid age intervals (Larsen et al., 2004). The childhood age intervals were used in order to have a uniform premorbid measure for all participants. High scores on the PAS signify poor functioning. Data were collected about ethnicity (European versus not European), years of education, occupational status, marital/civil status, type of

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health care (inpatient or outpatient), duration of illness and current psychopharmacological medication. Symptoms and functioning levels are reported here for better description of the sample only and are not intended for testing of hypotheses. These measures were recorded within a few weeks from the urine tests and the neuropsychological evaluations (median 12.5 days, range 0-33). The measures used were the Global Assessment of Functioning Scale (GAF), using the split version of GAF (Pedersen et al., 2007) and the Positive and Negative Symptoms Scale (PANSS) (Kay et al., 1987). The inter-rater reliability of the symptom assessments in the TOP study have been shown to be good with an Intraclass Coefcient (ICC)(Shrout and Fleiss, 1979) for PANSS positive symptoms of 0.82 and GAF of 0.86 (Ringen et al., 2008). 2.5. Neurocognitive assessment A comprehensive neuropsychological test battery was administered to all participants by trained assessment personnel (psychologists trained by a specialist in clinical neuropsychology). Tests from domains previously found to be sensitive to dysfunction in groups with cannabis use, bipolar disorder and/or schizophrenia were included, all tests are standard tests in validated translations (Simonsen et al., 2009). All subjects showed adequate neuropsychological test effort as indicated by the forced recognition trial of the California Verbal Learning Task (CVLT-II) (Delis et al., 2004). General cognitive functioning / Current IQ was assessed with the Wechsler Abbreviated Scale of Intelligence (WASI) (Wechsler, 2007). Domains: 2.5.1. Psychomotor speed The Digit Symbol test from Wechsler Adult Intelligence Scale (WAIS-III) (Wechsler, 2003) was used as a measure of psychomotor speed. Symbols must be lled in manually in a form according to a number-key. The score is the number of symbols correctly lled in within a time limit. 2.5.2. Attention With the Digit Span Test (forward version), from the Wechsler Adult Intelligence Scale (WAIS-III) (Wechsler, 2003), the maximum number of digits repeated in the same order as presented was used as a measure of focused attention. 2.5.3. Working memory We used the 2-back version of the Bergen n-back task (Haatveit et al., 2010) in which pairs of numbers are presented on a computer screen, and the participant is instructed to press a key whenever the pair of numbers corresponds to the pair of numbers presented two trials before. The session consists of 100 pairs divided on 20 target pairs and 80 non-target pairs. We used the sensitivity index d-prime to gather information regarding how a participant is able to discriminate targets from non-targets as a measure of working memory. 2.5.4. Executive functioning / interference control From the third trial in the ColorWord Interference Test, part of the Delis Kaplan Executive Functioning System (D-KEFS)(Delis et al., 2005), the time taken to name the color of the ink on a list of written color names incongruent with the color of the ink was used to measure interference control. 2.5.5. Verbal memory From the California Verbal Learning Task (CVLT-II) (Delis et al., 2004) the total number of words repeated immediately after ve reading trials of a list of 16 words was used as a measure of verbal memory (List A).

Higher scores on the neuropsychological tests signify better performance on all tests except for the D-KEFS interference tests where higher scores signify poorer performance. 2.6. Statistical procedures All analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 19.0. Statistical signicance was determined using the .05 level and 2-tailed tests of signicance. Below follows a step-by step description of the procedure. 2.6.1. Group comparisons T-tests were used to compare the cannabis-positive urine and the cannabis-negative urine groups on continuous variables; dichotomous variables were analyzed with Chi-square tests/Fisher exact tests when cell counts allowed (> 5). Since differences in group sizes were large, equal variances were not assumed for the t-tests. Normal distribution for continuous variables was assessed based on histograms and normal probability plots. One variable without normal distribution (interference control) was analyzed with a non-parametrical test and logarithmically transformed to achieve a normal distribution of the values used in correlation and regression analyses. 2.6.2. Bivariate associations Pearson correlations were used to assess bivariate associations between cannabis in urine, clinical and sociodemographic variables found to be signicantly associated with cannabis in urine and the neuropsychological test results. 2.6.3. Evaluation of the effect of possible confounders A series of multiple linear regression analyses was used to evaluate the possible confounders of the signicant associations in the group comparisons between cannabis in urine and the neurocognitive variables. A hierarchical stepwise approach was selected in order to discern the effects of the different variables in the associations. The neurocognitive variables were chosen as dependent variables and cannabis in urine was entered as independent variable in the last step. Gender and age were chosen as a priori independent variables and entered as the rst step. The other independent variables were chosen independently for each dependent variable if signicantly associated (p b .05) with both the dependent variable and the presence of cannabis in urine in the bivariate analyses, and were entered in the model in separate intermediate steps. These variables included a current DSM-IV diagnosis of cannabis abuse and/or addiction, premorbid academic functioning and a nding of amphetamines and/or cocaine in urine. 3. Results Cannabis was found in the urine in 21 patients (5.8%). Group comparisons of demographic and clinical characteristics according to presence of cannabis in urine or not are shown in Table 1. Subjects who were positive for cannabis in urine had signicantly lower premorbid academic functioning, fewer years of education and more often a diagnosis of abuse or addiction. The sample size in the cannabis positive group with current use of antipsychotics (n = 16) was too small to analyze differences with regard to type, dosage and duration of use (Table 1). Group differences in neuropsychological test results are shown in Table 2. A positive urine test for cannabis was signicantly associated with poorer scores on measures for digit span forwards (attention), d-prime (working memory) and interference control (executive functioning) (Table 2). Signicant correlations between cannabis in urine, neuropsychological variables and clinical and sociodemographic variables are shown in Table 3. All correlations indicated more negative conditions

P.A. Ringen et al. / Schizophrenia Research 143 (2013) 8489 Table 1 Demographic and clinical characteristics of 364 patients with schizophrenia spectrum disorder according to a nding of cannabis in urine or not. Negative for cannabis in urine N = 343 N Age (years) Premorbid academic functioning1 Premorbid social functioning1 Age of onset of psychosis Duration of untreated psychosis (years) Age of onset of cannabis use Number of psychotic episodes Duration of illness Number of alcohol units consumed past 14 days Years of education Full IQ 2 N Female Ethnic non-European Education in Norway Outpatients Schizophrenia Schizophreniform disorder Schizoaffective disorder Alcohol abuse (current) Cannabis abuse (current) Stimulant3 abuse (current) Stimulants3 in urine Current use of antipsychotics 151 60 254 252 263 27 53 36 33 15 3 296 343 307 311 335 322 313 154 337 339 339 336 Mean 31.4 1.7 1.3 24.1 2.6 2.0 18.2 7.2 6.6 12.7 98.5 % 44.0 17.8 81.2 73.7 76.7 7.9 15.5 10.5 9.6 4.4 0.9 86.5 SD 9.7 1.3 1.5 8.3 4.7 2.2 5.4 7.5 17.6 2.7 16.2 N 6 6 13 17 15 3 3 2 10 1 3 16 Positive for cannabis in urine N = 21 N 21 18 19 19 19 20 17 19 20 20 21 Mean 28.6 2.7 1.6 24.2 2.1 2.4 18.2 5.1 7.3 11.3 91.9 % 28.6 31.6 72.2 81.0 71.4 14.3 14.3 9.5 47.6 4.8 14.3 76.2 SD 7.1 1.4 1.3 6.7 3.4 3.4 4.4 5.0 12.9 2.2 16.5 p .182 .135 .359 .611 .584 b .001 .194 p .104 .006 .465 .954 .491 .669 .990 .095 .821 .014 .091

87

while cannabis in urine no longer had a signicant contribution to any of these measures (Table 4b). 4. Discussion The main nding of the present study was that presence of cannabis in urine was not associated with levels of neurocognitive functioning after adjusting for premorbid functioning. We found nominally poorer scores for every neurocognitive measure in the cannabis positive group, and several were statistically signicant associated with cannabis in urine also after controlling for a current diagnosis of cannabis abuse and/or addiction. However, after introducing premorbid functioning in the regression models, these associations were no longer statistically signicant and premorbid functioning was instead highly signicantly associated with the neuropsychological test results. The comparisons between the urine cannabis positive and negative groups are in line with previous reports from experimental studies showing that intake of cannabis causes transient clinical deterioration (D'Souza et al., 2005). They however differ from group comparisons of clinical studies with cannabis use dened by interview, where reported use of cannabis is found to be associated with better functioning and less symptoms (Yucel et al., 2012; Rabin et al., 2011). The current results are difcult to compare directly with previous ndings, as none of the previous studies controlled for premorbid functioning. There may be several explanations to the current ndings, as the underlying mechanisms of cannabis use and psychosis are not known. Poor premorbid functioning could be a susceptibility trait for later cannabis use, which in turn could affect neurocognition. This would be an interpretation in accordance with the ndings of pharmacological effects of THC on neurocognition as reported by D'Souza and colleagues (D'Souza et al., 2005). In this view, it is of interest that cannabis in urine explained the association between a diagnosis of cannabis abuse or addiction and neurocognition in the analyses. A possible alternative interpretation could be that poor premorbid functioning in schizophrenia instead was associated with increased vulnerability for adverse effects of cannabis on neurocognition. Thus, our ndings do not support a direct effect of cannabis on neurocognitive measures, but do neither rule this out. Both mechanisms related to brain maturation and direct pharmacological effects may still be involved (Murray et al., 2007). It could also be that poor premorbid functioning in schizophrenia represents a more serious form of the disorder, including neurocognitive decits. Such decits could, in turn, through an interaction with perceived stress, increase the risk for substance/cannabis use in line with the self-medication hypothesis. However, none of the parameters related to severity of the course of illness showed any association with cannabis in urine in the current study. Alternatively, a more severe form of the disorder could independently lead to both higher risks of an extensive cannabis intake and of poorer cognitive outcome, as suggested e.g. in a model for comorbidity by Chamber and colleagues (Chambers et al., 2001). These interpretations are somewhat in opposition to the previously discussed hypothesis that cannabis-using patients represent a subgroup with a less severe form of the disorder. This is intriguing, and it could be that we are dealing with different co-existent clinical sub-groups. Differences in study populations, and hence also differences in the representation of possible sub-groups, might account for some of the differences of the current ndings compared to earlier studies. Due to the high association between premorbid functioning and current cannabis use, the results obtained after entering premorbid functioning in the regressions might also be cases of statistical interference. The current study has some limitations. The cross-sectional design does not enable conclusions about cause and effect. The small sample size of the cannabis-positive group is a result of the naturalistic design, but gives limitations to statistical power and reduced possibilities to explore subgroups within our sample. Adding independent

t-tests, equal variances not assumed, and Fisher exact tests (levels of signicance below the 0.05 level in bold). 1 Premorbid assessment of functioning (PAS). 2 Wechsler Abbreviated Scale of Intelligence, Full IQ, 4 subtests. 3 Cocaine, amphetamine, methamphetamine or ecstasy. Too small numbers in cells for Fisher tests.

in the group with cannabis in urine. Several neurocognitive measures correlated signicantly with the same background variables as cannabis in urine (Table 3). The results of the hierarchical multiple regression analyses controlling for the variables with signicant bivariate associations to cannabis in urine are shown in Tables 4a4b. The rst series of hierarchical multiple regression analyses indicated that nding cannabis in urine contributed signicantly to the variance in current levels of the Digit Span forward test, the d-prime test and the interference control test (Table 4a). However, when adding premorbid academic functioning to the model in the second series of regression analyses, this turned out to have a statistically highly signicant contribution,

Table 2 Neuropsychological measures in 364 patients with schizophrenia according to cannabis in urine or not. Negative for cannabis in urine N= 345 N Digit Symbol Coding Digit Span forward Working memory; d prime Interference control* CVLT, verbal learning, list A 341 343 273 342 343 Mean 56.3 5.7 2.6 61.0 48.1 SD 15.3 1.1 1.8 34-197 10.9 Positive for cannabis in urine N = 21 N 21 21 16 21 21 Mean 55.8 5.1 1.0 72.0 42.3 SD 21.0 1.0 1.2 36-321 16.4 p 0.910 0.010 0.015 0.031 0.126

t-tests, signicant differences in bold (p values 0.05). *Variable without normal distribution: median and range (minmax); MannWhitney U-test.

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Table 3 Bivariate correlations (Pearson's R) between substance use, sociodemographic factors and neuropsychological variables in 364 patients with schizophrenia spectrum disorder. Cannabis in urine Cannabis in urine Digit Symbol Coding Digit Span forward Working memory; d prime Interference control* Verbal learning. CVLT list A X .246 .138 .182 .142 .119 .166 .107 .146 .136 .237 .208 .243 .184 .271 .289 .128 Age Female gender Ethnicity Premorbid .184 .164 .224 .171 .159 .216 Cannabis abuse/dep. .274 .132 .121 .155 .177 Stimulants in urine .245 .124

Pearson correlation coefcients. Only signicant associations shown (p values 0.05). Cannabis in urine: THC-COOH in urine; Cannabis abuse/dep.: DSM-IV Diagnosis of cannabis abuse or addiction; Premorbid: Premorbid academic functioning (PAS). *log-transformed.

variables to the regression model reduces power and increases risk for type II errors. Although we have argued that the study sample has a high degree of representativity, the general representativity of the sample may be discussed as we cannot rule out any specic regional bias in the Oslo region. However, as our ndings are based on comparisons of patients with cannabis in urine or not from the same region, we argue that it is highly unlikely that there are some geographical factors that specically interact with this effect. The urine measurement can be used to determine intake by very high degree of certainty, but lack specic information concerning the time passed since the intake took place and the amount of cannabis consumed. The measurements also lack information of other constituents of the cannabis than THC as e.g. cannabidiol, which is suggested to have antipsychotic properties (Bhattacharyya

et al., 2010). The urine measurements were performed at different labs and with different methods. However, the sensitivity and specicity are considered adequate for the scope of this paper and as long as the main ndings are based on relative results, i.e. comparison

Table 4b Results of regressions controlling for premorbid functioning. Block model summary for each step Block No. Variable R2 Change Contribution of separate variables for last step t P value 95% CI of B lower 5.934 .021 .328 1.711 upper 6.980 .002 .130 .364

F Beta Change

Table 4a Results of regressions without controlling for premorbid functioning. Block model summary for each step Block No. Variable R2 F Beta Change Change forward .002 .305 Contribution of separate variables for last step t P 95% CI of B value lower upper 24.352 .000 .053 1.009 .314 .019 .366 .714 .016 .013 5.865 .098 1.824 .069 4.841 .119 2.200 .028 1.029 .058 1.711 .064 5.495 .017 .264 6.460 .006 .181

Attention; Digit span Constant 1 Age Female gender 2 Stimulants in urine 3 THC-COOH in urine

Attention; Digit span forward Constant 1 .005 Age Female gender 2 .011 Stimulants in urine 3 .051 Premorbid functioning 4 .003 THC-COOH in urine

.752

24.288 .000 .092 1.691 .092 .047 .848 .397

3.543 .071 1.277 .202 17.579 .222 3.980 .000 1.053 .058 1.026 .306 .770 .242 .266 .090

Working memory; N-back/d-prime Constant 1 .028 4.083 Age Female gender 2 .025 7.536 Cannabis abuse/ dependency 3 .025 7.727 THC-COOH in urine

12.569 .000 .198 3.380 .001 .005 .091 .927 .127 2.115 .035

2.843

3.899

.034 .009 .254 .231 .772 .028

Working memory; N-back/d-prime Constant 1 .035 4.664 Age Female gender 2 .013 3.537 Cannabis abuse/ dependency 3 .033 9.033 Premorbid functioning 4 .004 1.028 THC-COOH in urine

12.233 .000 .227 3.607 .000 .008 .129 .898 .093 1.462 .145

3.044

4.212

.037 .011 .270 .237 .672 .099

.169 2.685 .008

.245 .038

.064 1.014 .311

.888

.284

.163 2.780 .006

1.285 .220

Executive functioning; Interference control Constant 58.961 .000 1 .032 5.926 Age .146 2.814 .005 Female gender .123 2.404 .017 2 .027 10.286 Cannabis abuse/ .140 2.589 .010 dependency 3 .010 3.880 THC-COOH in .105 1.970 .050 urine

3.959

4.232

.001 .008 .136 .014 .031 .229

.000

.270

Executive functioning; Interference control Constant 50.255 .000 1 .024 4.010 Age .158 2.842 .005 Female gender .080 1.450 .148 2 .021 6.900 Cannabis abuse/ .123 2.152 .032 dependency 3 .023 7.786 Premorbid .140 2.517 .012 functioning 4 THC-COOH in .006 1.892 .078 1.375 .170 urine

3.838 .002 .115 .010

4.151 .008 .017 .222

.007

.058

.044

.251

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between patients with positive and negative urine, important bias is unlikely. Historic variables are based on retrospective self-reports and are thus less reliable than would have been the case with a longitudinal study, however both self-reports of substance use (Weiss et al., 1998) and PAS data (Brill et al., 2007) have previously been shown to be valid in this patient group. The validity of several of the neuropsychological tests is associated with the language skills of the subjects, although the current tests have been selected to minimize this kind of unwanted bias. To the best of our knowledge this is the rst study to assess the association between cannabis in urine and neurocognitive variables in a naturalistic clinical sample of patients with schizophrenia. Furthermore, premorbid functioning was controlled for. We found that an apparent association with recent cannabis intake and poorer neurocognition was explained by the level of premorbid academic functioning. This suggests the presence of clinical sub-groups and complex and overlapping multifactorial psychopathological mechanisms. We did not nd cannabis to be associated with any benecial factors. More studies of cannabis use in representative patient samples from different regions and preferably with a longitudinal perspective are warranted to clarify the underlying mechanisms of the current ndings.
Role of funding source The funding sources had no involvement in the authors' work. Contributors Agartz, Andreassen, Berg, Melle, Ringen, Spigset and Sundet contributed to the design of the study. Andreassen, Melle, Ringen, Simonsen and Spigset designed the study. Ringen managed the literature searches. Melle and Ringen did the statistical analysis, and Ringen, Melle and Andreassen wrote the rst draft of the manuscript. All authors contributed to and have approved the nal manuscript. Conicts of interest Dr. Ringen has served as a consultant for Eli Lilly and received speakers' honoraria from Lundbeck. Dr. Andreassen has received speakers honoraria from Eli Lilly, Lundbeck, GSK, Janssen and BMS. The other authors report no competing interests. Acknowledgements The study is part of the Thematically Organized Psychosis (TOP) study and has been funded by grants from the Research Council of Norway (No.147787, 167153 and 164778/V50) and South-East Norway Health Authority (No.123/2004). Dr. Ringen's work is funded by the Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. The funding sources had no involvement in the authors' work.

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