The trajectory of two negative symptom dimensions in first-episode psychosis and the role of cannabis use: A 10-year follow-up study

The study examines whether cannabis use is associated with the course of two negative symptom dimensions—diminished expression (blunted affect and alogia) and apathy (avolition, asociality, anhedonia)—over 10 years following a first episode of psychosis (FEP). Negative symptoms are prevalent in psychosis and predict disability, yet their etiology includes both primary (intrinsic) and secondary (e.g., depression, medication side effects) sources. Prior work using unidimensional negative symptom measures often found no differences by cannabis use, potentially masking dimension-specific effects. Two-dimensional conceptualizations of negative symptoms have gained support, and short-term findings in FEP suggested cannabis use relates to diminished expression. There is limited long-term evidence on trajectories of these dimensions and on how cannabis exposure timing (baseline versus persistent use) influences them. The study aims to characterize 10-year trajectories of diminished expression and apathy in FEP, test associations with baseline and persistent cannabis use while accounting for potential secondary sources, and clarify temporal directionality of associations.

Cannabis use is common in psychosis and linked to earlier onset, higher positive symptoms, rehospitalizations, and disability, and may increase risk of cannabis-induced psychosis and later schizophrenia. Meta-analyses using unidimensional negative symptom measures reported no differences between cannabis users and non-users; however, two-factor models distinguishing diminished expression and apathy are supported by factor analytic work on PANSS and newer scales (BNSS, CAINS). Longitudinal studies using unidimensional negative symptom constructs report overall improvements with subgroups of persistent symptoms, and suggest substance use may relate to less improvement. Two-dimensional studies report group-level improvements and heterogeneous trajectories. Short-term work in FEP found cannabis use associated specifically with diminished expression, and apathy trajectories predicted by DUP and depressive symptoms. The literature highlights gaps regarding the long-term impact of cannabis on dimension-specific negative symptoms and the importance of accounting for secondary sources such as depression and antipsychotic side effects.

Design and cohort: Prospective longitudinal cohort within the Thematically Organized Psychosis (TOP) Study. Participants aged 18–65 were recruited at first treatment contact and classified as first-episode non-affective psychosis (FEP) if adequate psychosis treatment (hospitalization or antipsychotic medication in prescribed doses ≥12 weeks or symptom remission) began ≤12 months before inclusion. Assessments occurred at baseline, 1 year, and 10 years. Sample: N=351 at baseline (49.9% schizophrenia n=175; 8.5% schizophreniform n=30; 9.1% schizoaffective n=32; 32.5% psychosis NOS n=114). Follow-up completers: 155 at 1 year; 139 at 10 years. Clinical assessments: Diagnoses via SCID-I (DSM-IV) with calibrated raters and consensus procedures. PANSS used for positive and negative symptoms; negative symptoms operationalized into two dimensions: diminished expression (PANSS items N1, N3, N6, G7) and apathy/experiential (N2, N4, G16) per validated factor analyses and guidelines. Positive symptoms per Wallwork factor model. Depressive symptoms: Calgary Depression Scale for Schizophrenia (CDSS). Antipsychotic side effects: UKU scale (relevant items scored ≥2: emotional indifference; dystonia; rigidity; hypokinesia/akinesia). Premorbid adjustment: PAS (social and academic domains; childhood/early adolescence; participants with onset <15 years had no PAS score). DUP: weeks from first psychotic episode (PANSS ≥4 on P1/P3/P5/P6/G9) to adequate treatment. Substance use: Cannabis categorized as non-use, sporadic, monthly, weekly, daily, based on last 2 weeks, last 6 months, and last 2 years (baseline and 10-year) and last 2 weeks/6 months (1-year). Other illicit drugs (amphetamine, cocaine, opioids, hallucinogens): use ≥1×/month in last 6 months vs non-use. Nicotine: average cigarettes/day. Alcohol: average units/week. Antipsychotic treatment: regular use (oral or LAI) vs sporadic/non-use. Statistical analysis: IBM SPSS 27. Group comparisons of completers vs non-completers by t-test, Mann–Whitney U, and chi-square. Spearman correlations between negative symptom dimensions and clinical/sociodemographic variables at each timepoint. Linear mixed models (LMMs) modeled longitudinal trajectories of diminished expression and apathy across three time points. Fixed effects: time (linear) and time^2 (quadratic) where significant; random effects: intercept (significant) and slope (tested; retained only if improving fit) with autoregressive heterogeneous covariance. Model selection by −2 Log Likelihood and BIC. Candidate predictors (based on theory and significant bivariate associations) included PAS social (academic PAS excluded due to intercorrelation), diagnosis (schizophrenia vs other), positive symptoms, depressive symptoms, antipsychotic side effects (UKU), antipsychotic regular use, DUP (log), alcohol (log), nicotine (log), other illicit drugs, and gender (for apathy). Interaction with time tested and retained if significant. Cannabis use entered last using three dichotomous dummy variables reflecting increasing frequencies: (1) ≥monthly vs ≤sporadic, (2) ≥weekly vs ≤monthly, (3) daily vs ≤weekly; the lowest frequency with significance was retained. Two models: baseline exposure only, and persistent exposure (time-varying cannabis use across all assessments). Additionally, a piecewise latent trajectory specification was evaluated: slope 1 (baseline→1 year) and slope 2 (1→10 years), and adopted where superior fit.

- Sample and follow-up: 351 FEP participants at baseline; 155 at 1 year (44.2%); 139 at 10 years (39.6%). Baseline means: PANSS diminished expression 8.4 (SD 4.1), apathy 7.6 (SD 3.2), positive symptoms 10.6 (SD 4.0), CDSS 6.4 (SD 4.8). Any cannabis use: 41.3% at baseline, 26.8% at 1 year, 18.1% at 10 years. - Native growth models: Both diminished expression and apathy decreased over time. • Diminished expression: significant negative linear effect of time (estimate −0.159, p<0.001); quadratic term non-significant; significant random intercept; random slope not significant. • Apathy: significant negative linear effect of time (estimate −1.523, p<0.001) and positive quadratic effect (estimate 0.135, p<0.001) indicating decelerating improvement; significant random intercept; random slope not significant. - Piecewise two-slope models with predictors outperformed continuous models for both dimensions. - Predictors common to both dimensions: Worse premorbid social functioning (PAS social) and schizophrenia diagnosis predicted higher symptom levels with enduring effects; antipsychotic side effects (UKU) also predicted higher symptom levels. For diminished expression, the effect of PAS social decreased over time (interaction with 1–10 year slope negative). - Apathy-specific predictors: Male gender and higher depressive symptoms predicted higher apathy; positive symptoms had a direct enduring positive association. - Diminished expression-specific time interactions: Positive symptoms significant only in interaction with time (1–10 years). - Baseline cannabis use effects (Table 3.3.1, diminished expression model): • Time slope 0–1 year: −1.137 (SE 0.557), p=0.015; 1–10 years: −0.091 (SE 0.097), p=0.347. • PAS social: 0.529 (p=0.003); PAS social × time 1–10 y: −0.078 (p=0.002). • Schizophrenia diagnosis: 1.287 (p=0.004). • UKU symptoms: 2.305 (p<0.001). • Regular antipsychotic use: 1.478 (p<0.001). • Positive symptoms main effect: n.s.; Positive symptoms × time 1–10 y: 0.026 (p=0.004). • Monthly-or-more cannabis at baseline: 2.899 (SE 0.995), p=0.004; interaction with time 0–1 y: 1.901, p=0.052 (trend); interaction with time 1–10 y: −0.234, p=0.038 (effect decreases over years 1–10). • Apathy model showed no significant effect of baseline cannabis use. - Apathy piecewise model (Table 3.3.2): • Time slope 0–1 year: −1.380 (p<0.001); 1–10 years: 0.603 (p=0.138, n.s.). • Gender (female reference): −0.927 (p=0.004) indicating higher apathy among males. • PAS social: 0.346 (p=0.005); PAS social × time 1–10 y: −0.394 (p=0.052, trend). • Schizophrenia diagnosis: 1.080 (p<0.001). • UKU symptoms: 1.371 (p<0.001). • Depressive symptoms: 0.245 (p<0.001) with additional interaction increasing early decline (Depression × time 0–1 y: 0.147, p=0.007). • Positive symptoms: 0.160 (p<0.001). - Persistent cannabis use effects (Table 3.4.1): Adding persistent weekly cannabis use significantly predicted higher diminished expression (estimate 1.281, SE 0.573, p=0.026) and improved model fit beyond baseline use alone. Persistent cannabis use did not significantly predict apathy or improve its model. - Overall pattern: Both dimensions improved most between baseline and 1 year. Cannabis exposure (baseline and especially persistent weekly use) was associated with a higher and more persistent burden of diminished expression over 10 years, but not apathy.

Findings demonstrate that in FEP, both diminished expression and apathy tend to improve over 10 years, with the most pronounced gains in the first year, supporting the critical period hypothesis for early intervention. However, cannabis use shows a dimension-specific association: higher frequency use at baseline and persistent weekly use over time are linked to greater severity of diminished expression, with attenuated early improvement compared to non-users, while apathy trajectories are unaffected by cannabis exposure. This specificity suggests distinct neurobiological underpinnings of the two negative symptom dimensions and potential sensitivity of expressive deficits to cannabis-related mechanisms (e.g., motoric/expressive or cognitive facets). The models accounted for key secondary sources of negative symptoms, strengthening the inference that cannabis exposure itself contributes to diminished expression beyond confounders like depression and antipsychotic side effects. Clinically, reducing cannabis use before and after psychosis onset may mitigate expressive negative symptoms and improve early-course outcomes.

The study advances understanding of long-term negative symptom trajectories in FEP by separating diminished expression and apathy. Both dimensions decline over 10 years, with the greatest improvement in year 1. Cannabis use exhibits a selective, adverse association with diminished expression: baseline monthly-or-more use and, more strongly, persistent weekly use predict higher severity over time, while apathy is unaffected. These results support a likely causal role of cannabis exposure in expressive negative symptoms and identify modifiable targets—screening and interventions to reduce or cease cannabis use integrated within early psychosis care. Future research should use dimension-specific measures (e.g., BNSS, CAINS), examine cannabis exposure with biomarker/objective measures and cannabinoid composition, and employ denser longitudinal sampling between years 1 and 10 to refine temporal dynamics.

- High attrition across follow-up may bias results despite mixed-models with maximum likelihood and lack of baseline differences in key variables between completers and non-completers. - Sparse measurement between 1 and 10 years limits resolution of intermediate trajectory changes. - Negative symptoms assessed with PANSS rather than newer, more sensitive instruments (BNSS, CAINS); baseline predated widespread use of these tools. - Cannabis use relied on self-report without data on cannabinoid composition or potency; cannot assess specific roles of THC/CBD or changing potency over time.