The TIPS study is a prospective, longitudinal follow-up of a large, clinical epidemiological cohort recruited consecutively over 4 years from four Scandinavian health care sectors during 1997–2000. These include two sectors in Rogaland County, Norway, the Ullevål sector in Oslo County, Norway, and a sector from Roskilde County, Denmark. The combined estimated population at the start of the study period was 665,000 inhabitants. Health care services were catchment area based and publicly funded in all sectors. The areas were similar sociodemographically (e.g. urbanicity, mean educational and income levels, and opportunities for employment) (51). Patients from all areas were treated according to a 2-year standard treatment protocol that included antipsychotic medication, supportive psychotherapy, and multi-family psycho-education.

The sample consisted of FEP patients with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition schizophrenia, schizophreniform disorder or schizoaffective disorder (“narrow schizophrenia spectrum”), delusional disorder, mood disorder with mood-incongruent psychotic features, brief psychotic disorder, or psychosis not otherwise specified (“broad schizophrenia spectrum”) (51, 52). Participants had to reside in one of the participating sites and were 15–65 years of age in Rogaland or 18–65 years in Oslo/Roskilde and within the normal range of intellectual capacity (Wechsler Adult Intelligence Scale—Revised-based IQ estimate >70). Participants were included between 1997 and 2001 (baseline) and followed up at 1-, 2-, 5-, and 10 years. Twenty-three percent of those who were eligible declined participation. Within the group of 301 who consented to participate, the current sample consists of those who completed cognitive testing at baseline (n = 218) who had data for substance-use grouping (n = 195). There were no statistically significant differences in symptom levels, age, gender, premorbid functioning, or diagnostic distribution between those who did and those who did not complete testing at baseline. A total of 87% completed at least two neuropsychological tests, and 22% completed all five follow-ups. There were 138, 137, 82, and 85 participants who completed neurocognitive testing at each follow-up point. Dropout analyses did not show any statistical differences with regard to diagnoses, gender, duration of untreated psychosis (DUP), substance use, symptom levels, premorbid functioning, or age at 1-, 2-, 5-, or 10-year follow-up. However, 5- and 10-year follow-up dropouts had higher excitative symptom component scores at baseline. Also, participants who dropped out in the course of the study had better scores on the trail making tests (visuomotor processing) compared with those who only completed one test (t = 3.7; df: 44.4; p < .001).

The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (severe combined immunodeficiency) (53) was used for diagnostic purposes. All included patients were assessed using the global assessment of functioning (GAF) split into symptom and function scores (54). Demographic data, including family history of mental illness, was collected for all study-eligible patients. DUP was measured as weeks from the emergence of positive psychotic symptoms to the start of adequate treatment, defined as structured treatment with antipsychotic medication or the admission to psychiatric wards for psychosis. A few non-admitted patients started outpatient psychotherapy structured and directed toward psychosis but did not want medication initially. For these patients, start of psychotherapy was regarded as the start of adequate treatment. Symptom levels were measured by the positive and negative syndrome scale (PANSS) (53), scored on five symptom domains: positive, negative, cognitive, depressive, and excitative symptoms (55). Items constituting these components are as follows: positive component items P1 delusions, P3 hallucinatory behavior, P5 grandiosity, P6 suspiciousness, and general scale item G9 unusual thought content; negative component N1 blunted affect; N2 emotional withdrawal; N3 poor rapport; N4 passive withdrawal; and general scale items G7 motor retardation, G13 disturbance of volition, and G16 active social withdrawal; cognitive component items P2 conceptual disorganization, N5 difficulty in abstract thinking, N6 lack of spontaneity and flow of conversation and general scale items G10 disorientation, G11 poor attention and G15 preoccupation; depressive component general scale items G1 somatic concern, G2 anxiety, G3 guilt feelings, G4 tension and G6 depression; and excitative component items P4 excitement, P7 hostility, and general scale items G8 uncooperativeness and G14 poor impulse control. Onset of FEP positive symptoms was defined as a PANSS score of 4 or higher on any of the PANSS positive component items; not previously receiving adequate treatment for psychosis defined as antipsychotic medication of 3.5 haloperidol equivalents for 12 weeks or until remission of psychotic symptoms. Remission was defined as subthreshold symptoms for at least 7 days, whereas relapse involved reappearance of positive symptoms (items 1, 3, 5, 6, or general scale item 9) for at least 7 days. Stable remission was defined as no relapse in the first year after admission (53–55).

Premorbid functioning was measured by the premorbid adjustment scale (56), covering two areas of functioning—school adaptation and socialization—described through initial childhood level and subsequent change (57). Scores ranged from 1 through 6 with higher scores indicating more impairment. A premorbid adjustment scale change score was calculated as the difference between childhood scores and the last score available, to indicate decline or improvement over time (56, 57).

Length of treatment was split into number of weeks of antipsychotic medication and the number of weeks of psychosocial treatments measured as the sum of weeks with uninterrupted psychosocial treatments with a frequency of once every fortnight or more for the first 5 years or once a month between 5 and 10 years.

Neurocognitive tests were administered by clinical psychologists trained in standardized assessments or by research assistants supervised by a senior psychologist.

The five domains of neurocognitive functioning were:

For all tests, a z score was calculated based on mean scores at baseline. Except for finger tapping, indices were moderately correlated. The four indices (CVLT, TM, Wisconsin card sorting test, and controlled oral word association task) were therefore added together and averaged to form a composite index.

All cognitive ratings were done blind to the substance-use group affiliation of the participants. Reliability of GAF, DUP, and diagnosis was found satisfactory throughout the study. The results of the reliability assessments have been reported previously (62, 63).

Substance and alcohol use was measured by the alcohol and drug use scale (64) using a scale from 1 to 5 (1 = no use; 2 = use without impairment; 3 = abuse; 4 = dependence; 5 = dependence with institutionalization). All commonly used illegal psychoactive substances were included in the assessment. We did not include tobacco, caffeine, or alcohol in our definition of substance use, as these follow different treatment paths and sequelae.

Patients were dichotomized into users or not users, where “use” was defined as any score >1. Abstinence is a culturally relevant concept in Norway, where substance use is largely restricted to subgroups, with any use being considered harmful. Patients were assessed concerning pattern of substance use at all follow-up points. At 5-year follow-up, we also did a retrospective assessment of substance use at 3 and 4 years based on patient information and medical charts. Patients’ substance use changed most during the first 2 years after inclusion; thus, this interval was chosen for grouping. This interval is consistent with prior studies (65–68).

For analyses, we grouped patients into a) nonusers (NUs), i.e. patients who had never used, b) stop-users (SUs), c) episodic users (EUs), and d) persistent users (PUs). Patients who had only “no-use” measurements during the first 2 years of follow-up were defined as nonusers (NUs). Patients who had used at baseline and then not use for at least two consecutive measurements, i.e. at 1 and 2 years of follow-up, were defined as stop-users (SUs). Persistent users (PUs) used at all follow-up points, and episodic users (EUs) had various other substance-use patterns. This four-group solution was chosen based on recent studies that have shown that around half of substance-using patients who stop using appear to have less severe symptoms than those who continue (45). Merging previous substance users with NUs does not aid in understanding the impact of ceasing substance use on patient trajectories or prognosis.

Statistical analyses were carried out using SPSS version 22.0 (69) and R version 3.4.3 (70).

Differences between groups at baseline were described using frequencies and percentages for categorical variables and means and standard deviations or medians and ranges for continuous variables. Comparisons between groups were made using chi-squared tests for categorical data and student t-tests for independent samples for continuous data. All tests were two-tailed.

To investigate the effect of substance abuse on performance over time, linear mixed effects models were used. The model uses maximum likelihood estimation to manage dropout to a certain degree. This is based on the assumption of dropout at random, that is, the probability of dropout is independent of future but may be dependent on previous history, which may be reasonable in this situation. Separate models were estimated, each with one of the cognitive index scores as the dependent variable and substance-use group as categorical predictor. Covariates were based on baseline differences: age, gender, years of education, and premorbid academic adjustment ( Table 1 ). Furthermore, based on the literature, diagnostic category (narrow schizophrenia spectrum disorder or not) and DUP (log transformed due to skewed distribution) were included. Interaction between time and group was included in order to investigate whether change in neuropsychological test scores developed differently in the different groups. Furthermore, the interaction between narrow schizophrenia spectrum diagnoses and group was examined to determine whether narrow schizophrenia diagnoses are associated with different effects on the neuropsychological tests in the substance-use groups. The large data set justifies the number of parameters in the models. Random intercept and AR (1) was used to achieve a satisfactory model for correlation between longitudinal measurements within individuals. The executive function and TM indices were severely skewed to the left. In order to achieve a robust analysis, these data were log transformed after inverting the scale and adding a constant to assure positive values only.

There were no group differences at baseline for motor speed ( Table 2 ). LME modeling showed that development over time was significantly different between groups. SUs performed better over time (t = 2.20; df 433; p = 0.03) compared with all groups. Females had lower scores over time and at baseline (t = −7.07; df 208; p = 0.001).

There were no significant group differences for executive functioning.

All four groups perform poorer with time on verbal learning. SUs had higher scores across all follow-up points (t = 2.00; df 211; p = 0.05). Poorer premorbid function was associated with lower scores (t = −2.57; df 211; p = 0.01). Women performed significantly better than men at all follow-up points (t = 4.95; df 211; p = 0.001). Patients with narrow schizophrenia diagnoses in the SUs (t = −2.03; df 211; p = 0.04) and EUs (t = −2.76; df 211; p = 0.006) performed poorer than NUs.

The PUs scored significantly poorer than NUs across all time points on visuomotor processing (t = −2.37; df 207; p = 0.020). Performance levels were predicted by education where shorter length (t = −3.58; df 207; p = 0.001) and poorer premorbid adjustment predicted lower scores. Higher age was also a predictor of poorer scores (t = 4.63; df 207; p = 0.001).

The SUs scored significantly higher than the NUs on verbal fluency, although change over time was parallel (t = 2.21; df 210; p = 0.03). There was a significant improvement over time in all groups. Longer education (t = 2.23; df 210; p = 0.03), better premorbid functioning (t = −2.75; df 210; p = 0.006), and female gender (t = 2.68; df 210; p = 0.008) were associated with better scores.

There was no significant change over time and no significant group differences in overall performances. The composite score was significantly associated with longer education (t = 2.73; df 213; p = 0.006), better premorbid functioning (t = −3.98; df 213; p = 0.001), female gender (t = 2.29; df 213; p = 0.022), and lower age (t = −2.24; df 213; p = 0.026). Within the SUs (t = −2.32; df 213; p = 0.022) and EUs (t = −2.34; df 213; p = 0.021), the narrow schizophrenia group performed poorer.

In summary, patients who stopped using substances had higher motor speed, better verbal learning, and better verbal fluency. Persistent users performed significantly worse on visuomotor processing, while participants who had never used substances had significantly better visuomotor processing and poorer verbal fluency. For EUs and SUs, patients with narrow schizophrenia diagnoses performed significantly poorer overall.