Cariprazine in First-Episode Psychosis with Comorbid Cannabis Use: A Case Series of Eight Patients from Two Greek Early Intervention Units

1. Introduction

Early intervention in the psychosis paradigm has been expanding in recent years, demonstrating improved symptom management, reduced hospitalization rates, and better social integration in early-onset psychosis, particularly First-Episode Psychosis (FEP) [1]. It involves antipsychotic medication combined with psychosocial interventions delivered by a multidisciplinary team; patients receiving early intervention report better quality of life, higher functioning, and improved treatment compliance [2].

The comorbidity of substance use disorder (SUD) with psychosis, referred to as dual disorder (DD), significantly increases morbidity and mortality compared with psychosis alone, with cannabis being the most frequently used substance [3]. In genetically vulnerable individuals, cannabis may precipitate FEP by disrupting dopaminergic and endocannabinoid signaling. Its use is linked to an earlier age of psychosis onset and poorer clinical outcomes, with an estimated prevalence of cannabis use of 33.7% in FEP patients [3,4]. Regular use confers a 3–5-fold increase in the risk of developing a psychotic disorder in a dose-dependent fashion [3]. Continued use following FEP worsens prognosis and increases relapse risk [4,5].

Cariprazine is a third-generation atypical antipsychotic acting as a partial agonist at D3 and D2 dopamine receptors with preferential D3 affinity, as well as affinity for serotonin 5-HT1A and 5-HT2A receptors [6]. A systematic review and meta-analysis has demonstrated its transdiagnostic efficacy across positive, negative, manic, depressive, and cognitive symptom domains [7]. A six-month observational study in patients with established schizophrenia and cannabis use disorder reported improvements in both psychotic and addiction-related measures, tentatively attributed to its D3-preferential binding profile [8].

This case series reports preliminary naturalistic observations on cariprazine treatment in patients experiencing FEP with comorbid cannabis use, in view of the clinical relevance of this dual disorder presentation and the absence of structured individual-level data from this population.

2. Materials and Methods

This was a retrospective naturalistic case series of consecutive patients diagnosed with FEP and concomitant cannabis use who were treated with cariprazine for six months between 2023 and 2025. The sample comprised eight patients receiving care at the Early Intervention Units for Psychosis in Athens and Thessaloniki (PNOES Ath and PNOES SKG) of EPAPSY (Association for Regional Development and Mental Health). The inclusion criteria were: (a) clinical diagnosis of FEP, (b) documented current cannabis use at the time of presentation, and (c) clinical initiation of cariprazine as part of routine care. The decision to prescribe cariprazine was based solely on the clinical assessment by the treating psychiatrist and was not part of any predefined research protocol. No structured psychosocial intervention was standardized across participants, although all patients received standard psychosocial support as part of the Early Intervention Unit’s multidisciplinary care. Table 1 presents the sociodemographic, clinical, and outcome data for each participant.

The sample included four men and four women, with a mean age of 26.75 years. The diagnoses (ICD-10) included schizophrenia (F20, n = 4), schizoaffective disorder (F25, n = 1), bipolar disorder (F31, n = 1), brief psychotic disorder (F23, n = 1), and unspecified functional psychosis (F39, n = 1). The mean Duration of Untreated Psychosis (DUP) was 18.5 weeks. All participants received cariprazine at doses ranging from 1.5 to 4.5 mg/day; one participant additionally received adjunctive olanzapine 20 mg from the third month onward.

Antipsychotic symptom outcomes were measured using the Positive and Negative Syndrome Scale (PANSS) at baseline and six months, reported using the Five-Factor model encompassing positive symptoms, negative symptoms, disorganization, anxiety/depression, and hostility. Cannabis use frequency and patterns were assessed using items 15.4 and 15.9 of the Greek-validated Cannabis Experience Questionnaire (CEQ) at baseline and six months [9]. Given the small sample size, only descriptive statistics were computed; no inferential statistical tests were applied and no causal inferences could be drawn.

This retrospective observational case series was conducted in accordance with the Declaration of Helsinki. The Human Investigation Committee (IRB) of EPAPSY approved this study. Written informed consent was obtained from all participants. During the preparation of this manuscript, the authors used Claude (Anthropic, 2025) to assist with language editing and text condensation; all outputs were reviewed and edited by the authors, who take full responsibility for the content.

3. Results

Table 2 presents individual raw scores for the Five-Factor PANSS and CEQ items at baseline and six months. At the group level, lower mean scores were observed at six months across most PANSS subscales. Specifically, lower mean values were observed for Positive Symptoms (12.75 vs. 10.38), Disorganization (11.25 vs. 9.13), and Hostility (9.13 vs. 8.38). Mean Negative Symptom scores showed a smaller difference (16.00 vs. 15.12), suggesting a modest and clinically uncertain change. No difference was observed in the Anxiety/Depression dimension (11.63 at both time points).

All eight participants reported active cannabis use at baseline. The frequency distribution at baseline was: 50% used cannabis more than once a week, 25% a few times a year, 12.5% a few times a month, and 12.5% daily. At the six-month reassessment, two participants (25%) reported no cannabis use, while the overall distribution shifted toward lower frequency: 50% reported using cannabis a few times a month, 12.5% a few times a year, 12.5% more than once a week, and 25% not at all.

4. Discussion

The present report describes preliminary naturalistic observations from an exploratory case series of eight FEP patients with comorbid cannabis use treated with cariprazine for six months within early intervention units.

The key contribution of this case series is not the confirmation of efficacy but rather the provision of individual-level clinical data from a specific and underrepresented population: FEP patients with active cannabis use receiving cariprazine within an early intervention framework. To our knowledge, structured naturalistic data from this population have not been previously reported. These findings complement an observational study examining 58 patients with established schizophrenia and cannabis use disorder over six months, which reported improvements in both psychotic and addiction-related measures [8].

Lower PANSS scores at six months were observed in the positive symptoms, disorganization, and hostility dimensions. The numerically small change in negative symptoms (mean difference 0.88 points) and the absence of change in anxiety/depression may reflect the diagnostic heterogeneity of the sample, the relatively short follow-up period, or the characteristics of the specific patients included. These observations align broadly with the established antipsychotic profile of cariprazine across symptom domains [7].

Longitudinal data from larger cohort studies provide an important reference frame. Clausen et al. found that FEP patients who discontinued cannabis use showed substantially lower psychotic symptom levels at five-year follow-up [5]. Setién-Suero et al. reported that cannabis cessation was associated with significantly better long-term outcomes in the PAFIP cohort [10]. An earlier report from the same group documented sex-related differences in clinical and neuropsychological outcomes associated with cannabis use in FEP [4]. Additionally, the CAFEPS study demonstrated that cannabis use at the time of the first episode adversely influenced psychopathology and short-term outcome in a pediatric-onset FEP sample [11]. These findings collectively underscore the clinical relevance of reducing cannabis use in FEP.

The observed shift in cannabis use frequency—with two participants reporting cessation and an overall reduction at six months—is noted descriptively. This reduction cannot be attributed to cariprazine alone, as all participants received structured multidisciplinary psychosocial support within the early intervention units.

This study has several limitations. First, a naturalistic non-controlled design precludes any causal relationship between cariprazine and observed changes. Second, the small sample size and diagnostic heterogeneity substantially limit interpretability and generalizability. Third, cannabis use was assessed via self-report using the CEQ, introducing potential under-reporting bias. Fourth, no inferential statistical analyses were conducted. Fifth, potential confounding variables—including psychosocial interventions, therapeutic alliance, natural illness course, and concurrent life events—were not controlled systematically. Sixth, the six-month follow-up may be insufficient to detect long-term changes, particularly in negative symptoms. Future research should employ randomized or controlled designs with larger, diagnostically homogeneous samples, objective cannabis use monitoring, and standardized psychosocial intervention protocols.

5. Conclusions

This exploratory naturalistic case series provides preliminary descriptive observations suggesting the possible clinical utility of cariprazine in FEP patients with comorbid cannabis use. Lower PANSS scores across several symptom dimensions and a reduction in cannabis use frequency were observed over six months, although these findings are not interpretable as evidence of efficacy given the study’s methodological constraints. The data are best understood as hypothesis-generating and as a contribution to the limited individual-level clinical literature on this population within an early intervention context. Controlled prospective studies are required to evaluate the therapeutic potential of cariprazine in this population.