Program Evaluation to Aid Choice of Aripiprazole or Risperidone for Hospitalized Adolescents with Cannabis Use Disorder and Psychosis

Abstract

Introduction:

Co-occurring cannabis use and psychosis is an increasing problem. No single behavioral or pharmacologic treatment has emerged as clearly superior. To address the gap, this nonrandomized, quality improvement project compares outcomes for adolescents with co-occurring cannabis use disorder and psychosis prescribed risperidone or aripiprazole.

Materials and Methods:

This project is a retrospective chart review of 110 adolescents (ages 13–21 years) hospitalized for psychosis and co-occurring cannabis use disorder. The primary outcomes are length of stay and length of stay index.

Results:

Adolescents prescribed risperidone compared with aripiprazole had a significantly greater length of stay (9.7 days vs. 5.8 days, p = 0.002) and length of stay index (1.4 vs. 0.79, p = 0.004).

Conclusions:

Adolescents hospitalized for co-occurring psychosis and cannabis use disorder had a significantly longer length of stay and length of stay index. These data are consistent with a more rapid reduction in acute psychotic symptoms for aripiprazole compared with risperidone in the context of co-occurring cannabis use disorder.

Introduction

Co-occurring cannabis use and psychosis is an increasing problem. A national survey in Denmark shows that the incidence of cannabis-induced psychosis increased from 2.8 per 100,000 person years to 6.9 per 100,000 person years in 2014 (Hjorthoj et al., 2021). The incidence of schizophrenia with cannabis use disorder increased from 0.6 per 100,000 person years in 2006 to 2.4 per 100,000 person years in 2014 (Hjorthoj et al., 2021). These numbers represent a doubling to quadrupling of these disorders over the last decade and are consistent with findings from other countries. For example, emergency department presentations for cannabis-induced psychosis doubled in Canada from 2015 to 2019 (Callaghan et al., 2022). This timing corresponds to the legalization of cannabis in Canada and the availability of commercialized cannabis products. Colorado experienced similar increases in cannabis-related emergency department visits and hospitalizations before and after cannabis commercialization (Roberts, 2019). Many of these studies cite increased use of more potent cannabis as a likely cause of their findings (Callaghan et al., 2022; Hjorthoj et al., 2021; Roberts, 2019).

These findings occur in the context of multiple studies showing an association between psychosis and cannabis use, especially among youth and young adults (Fiorentini et al., 2021). Psychosis can occur acutely, subacutely, or chronically after cannabis intoxication (Fiorentini et al., 2021; Starzer et al., 2018). In fact, 47% of people who experience cannabis-induced psychosis develop chronic bipolar disorder or schizophrenia (Starzer et al., 2018). Therefore, psychosis is increasingly recognized as a problem associated with cannabis use.

The diagnosis of cannabis-induced psychosis is challenging since it is difficult to know if a psychotic episode is related or unrelated to cannabis use (Fiorentini et al., 2021). Nevertheless, research shows that cannabis-induced psychosis has some distinct features. It is associated with less family history of psychosis, fewer positive and negative psychotic symptoms, more depressive symptoms, more anxiety, more visual hallucinations, more pressured speech, and more insight as compared with primary psychosis (Fiorentini et al., 2021; Padhi et al., 2021; Rentero Martín et al., 2020). Furthermore, compared with patients with cannabis-induced psychosis, those with schizophrenia are more likely to have various cognitive deficits, atypical brain morphology, and atypical findings on electroencephalogram (Fiorentini et al., 2021; Ghosh et al., 2022; Shah et al., 2021). In summary, cannabis use is clearly associated with psychosis, and cannabis-induced psychosis is likely distinct from primary psychosis. As a distinct process, cannabis-induced psychosis may also have a different response to standard treatments.

There is need for more research on the treatment of cannabis-induced psychosis. Evaluations of behavioral interventions such as motivational interviewing, case management, cognitive behavioral therapy (CBT) and contingency management for cannabis and psychosis in patients with first episode psychosis have had mixed findings (Alcover et al., 2019; Baker et al., 2006; Barrowclough et al., 2014; Bonsack et al., 2011; Cather et al., 2018; Edwards et al., 2006; Hjorthoj et al., 2013; Madigan et al., 2013; Rains et al., 2019; Smeerdijk et al., 2015), with the exception of at least one trial of CBT that showed benefit in reducing cannabis use and symptoms of psychosis (González-Ortega et al., 2022). In summary, no behavioral intervention has clearly emerged as superior in reducing cannabis use or symptoms of psychosis among patients with cannabis-induced psychosis or first episode psychosis with cannabis use. Therefore, there is a need for research to create more effective behavioral interventions for patients with early psychosis and cannabis use.

Similarly, there is need for more research evaluating specific pharmacologic interventions for cannabis use and psychosis. Randomized controlled trials of haloperidol versus olanzapine (Berk et al., 1999; Green et al., 2004) and risperidone versus olanzapine (Sevy et al., 2011; Van Nimwegen-Campailla et al., 2010) show no difference between treatment groups with respect to cannabis use or psychosis. A trial of clozapine versus ziprasidone showed equal reductions in cannabis use and a greater reduction in positive symptoms with clozapine (Schnell et al., 2014). We are not aware of randomized controlled trials involving other antipsychotic medications although case reports of aripiprazole and lurasidone show promise (Ricci et al., 2022; Rolland et al., 2013). There is need for research to compare other pharmacologic agents such as aripiprazole, which has a unique receptor-binding profile, including partial agonism at the dopamine-2 receptor (Siafis et al., 2017).

This quality improvement project seeks to address this knowledge gap with naturalistic, observational, nonrandomized data of adolescents hospitalized for psychosis with a co-occurring cannabis use disorder. Specifically, it has the aim of comparing aripiprazole and risperidone. Aripiprazole was chosen as a comparator because of its unique receptor-binding profile. Risperidone was chosen as the other comparison group because it is the most prescribed antipsychotic medication for children and adolescents globally (Hálfdánarson et al., 2017; Rettew et al., 2015). The primary dependent variables are hospital length of stay and length of stay index, which the project uses as functional and pragmatic measures of treatment response. The hypothesis is that there may be a differential response because of the distinct receptor-binding profile of the two medications (Siafis et al., 2017).

Materials and Methods

Study design

This quality improvement project is a retrospective chart review of adolescents admitted to a psychiatric hospital at an urban, safety-net institution. The project took place from April 1, 2016, to February 27, 2023. The Revised Standards for Quality Improvement Reporting Excellence (SQUIRE 2.0) were used to carry out the project and report its outcomes (Ogrinc et al., 2016). Patients were not randomized to a treatment group but were prescribed aripiprazole or risperidone based on the clinical judgment of the physician.

Procedures

This retrospective chart review was reviewed by the Quality Improvement Committee of Denver Health (QIRC), which is authorized by the Colorado Multiple Institutional Review Board at the University of Colorado, Denver (COMIRB), and was determined exempt from review. Consecutive admissions to an acute psychiatric inpatient unit of adolescents for cannabis use and a psychotic disorder were extracted from the electronic health record. To create a dichotomous independent variable, the discharge medication was divided into aripiprazole or risperidone. The dependent variables were hospital length of stay measured in days and length of stay index, as described below. All patients participated in a standard schedule of milieu therapy consisting of 4 hours of school daily, group and family therapy with a psychologist, individual psychotherapy as indicated, occupational therapy, nursing assessments every shift, and medication management supervised by a child psychiatrist.

Patients

Inclusion criteria were: (1) adolescent 13–21 years of age; (2) psychiatrically admitted with a diagnosis of cannabis use disorder and a psychotic disorder (schizophrenia, schizophreniform disorder, brief psychotic disorder, unspecified psychotic disorder); and (3) prescribed either aripiprazole or risperidone upon discharge. The International Classification of Diseases 10th edition (ICD-10) codes used for cannabis-related disorders were any of the F12 codes, and the ICD-10 codes used for psychosis were any of the F20 through F29 codes (World Health Organization, 1993). Adolescents who were not prescribed an antipsychotic medication or were prescribed another medication upon discharge were not included in the analysis. There were no adolescents who were prescribed both risperidone and aripiprazole.

Measures

Baseline clinical and demographic variables were collected by clinical interview. Clinical diagnoses were made using Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), criteria (American Psychiatric Association, 2013). The independent variable, medication prescribed at discharge, and the dependent variables, length of stay and length of stay index, were extracted from the electronic health record.

Length of stay index is a normalized variable with respect to expected length of stay, which is based on clinical complexity in a reference sample (Rylander et al., 2021). For example, expected length of stay for complex presentations with multiple co-occurring diagnoses is longer than for presentations with a single diagnosis. Furthermore, the expected length of stay for severe mental illnesses such as schizophrenia or bipolar disorder is generally longer than for an adjustment disorder or an unspecified mood disorder. Length of stay index is calculated by dividing actual length of stay by expected length of stay. An index less than one marks a length of stay less than the reference sample, and values greater than one are longer than the reference sample. This calculation is generally considered to be a quality metric of efficiency and flow. In this quality improvement project, length of stay index is used as a proxy measure of treatment response.

Analyses

Analyses and data cleaning were done in RStudio using tidyverse (Wickham et al., 2019). After assessing for normal distribution of data, a two-tailed Welch's t-test was used to evaluate the difference in length of stay, length of stay index, and expected length of stay. Welch's t-test was used because of a large difference in group sizes between the risperidone (n = 79) and aripiprazole (n = 31), as well as large differences in group variance. A p-value of <0.05 was used to reject null hypotheses. Comparison of length of stay and length of stay index was also conducted without two outliers (>3 standard deviations), who were both in the risperidone group, in case the extended length of stay was due to nonmedical reasons such as lack of housing or legal issues related to custody. Descriptive statistics were used to characterize the baseline demographics of the sample. Multiple comparisons were controlled by Bonferroni correction.

Results

In general, the sample (n = 110) included adolescents with diverse ethnicity and race. Consistent with the safety-net mission of the hospital, many of the patients had Medicaid. Table 1 below describes the sample in detail.

Table 1.

Baseline Demographic Variables (n = 110)

Variable	Total sample (n = 110)	Risperidone (n = 79)	Aripiprazole (n = 31)
Age in years, mean ± SD	17.82 ± 2.1	17.95 ± 2.12	17.48 ± 2.05
Sex, % (n)
Female	31.8 (35)	29.1 (23)	38.7 (12)
Male	68.2 (75)	70.9 (56)	61.3 (19)
Ethnicity, % (n)
Hispanic	31.8 (35)	32.9 (26)	29.0 (9)
Not Hispanic	62.7 (69)	63.3 (50)	61.3 (19)
Other, decline to answer	5.5 (6)	3.8 (3)	9.7 (3)
Race, % (n)
African American	22.7 (25)	24.1 (19)	19.4 (6)
Caucasian	55.5 (61)	53.2 (42)	61.3 (19)
Other	14.5 (16)	16.5 (13)	9.7 (3)
Asian and Pacific Islander	0.9 (1)	1.3 (1)	0 (0)
Decline/missing	6.4 (7)	5.1 (4)	9.7 (3)
Payer source, % (n)
Commercial insurance	33.6 (37)	30.4 (24)	41.9 (13)
Medicaid	58.2 (64)	60.8 (48)	51.6 (16)
Other	8.2 (9)	8.9 (7)	6.5 (2)

SD, standard deviation.

The total daily dose of oral risperidone on discharge ranged from 0.5 to 6 mg, with 2 and 1 mg daily being the most common doses (n = 19 and n = 16, respectively). Four patients were discharged on risperidone long-acting injection. The total daily dose of aripiprazole on discharge ranged from 2.0 to 30 mg daily, with 5 and 15 mg being the most common doses (n = 8 for both). No patients were on a long-acting injectable of aripiprazole on discharge. The mean expected length of stay did not differ between the risperidone and aripiprazole groups. However, the risperidone group had a significantly longer length of stay and length of stay index compared with the aripiprazole group. Length of stay and length of stay index were compared with and without two outliers (>3 standard deviations), both of which were in the risperidone group. These results are shown in Table 2 below.

Table 2.

Comparison of Length of Stay

Variable	Risperidone (n = 79)	Aripiprazole (n = 31)	p
Expected length of stay, mean (SD)	7.6 days (2.4)	8.3 days (3.3)	0.29
Length of stay, mean (SD)	9.7 days (10.0)	5.8 days (3.0)	0.002
Length of stay without outliers, mean (SD)	8.4 days (5.5) (n = 77)	5.8 days (3.0)	0.002
Length of stay index, mean (SD)	1.4 (1.7)	0.79 (0.53)	0.004
Length of stay index without outliers, mean (SD)	1.2 (0.79) (n = 77)	0.79 (0.53)	0.004

SD, standard deviation.

Discussion

This project examined a functional outcome related to hospitalization of adolescents with co-occurring psychosis and cannabis use disorder. In this sample, adolescents prescribed risperidone had a longer length of stay and longer length of stay index compared with adolescents prescribed aripiprazole. However, there was no difference in expected length of stay, which is a proxy measure of clinical complexity. Therefore, these findings suggest that adolescents with co-occurring psychosis and cannabis use disorder may have a more rapid response to aripiprazole compared with risperidone.

Limitations of this study are that it was an observational study and was not a randomized controlled trial. Therefore, there may be factors that confound the results. Without a detailed baseline research interview, it is possible that the sample included diagnostic heterogeneity such as adolescents with cannabis-induced psychosis or schizophrenia with co-occurring cannabis use disorder. Even though there was no difference in expected length of stay, it is possible that there is a baseline difference that made the risperidone cases more complicated. Furthermore, this study took place in one facility. Therefore, we do not have data on prior hospitalizations at other facilities and which medications were prescribed at those facilities. The findings from this study may also not generalize to other sites. Finally, this project used proxy measures, length of stay, and length of stay index, of treatment response. While treatment response and length of stay are not exactly synonymous, using a functional, pragmatic measure such as length of stay index may also be considered a strength of the study. Future research using validated measurements of psychotic symptoms and a randomized, controlled design are needed to address these limitations.

Nevertheless, the finding that adolescents with psychosis and cannabis use disorder who were prescribed risperidone had a mean length of stay up to 3.9 days or 67% longer than youth prescribed aripiprazole is likely to be clinically significant. The result is also important because length of hospital stay may be associated with important economic and social consequences for adolescents and their families. Our finding is strengthened by the significant difference in length of stay index, which was 77% greater in the risperidone group compared with the aripiprazole group. Since we did not find a difference in expected length of stay, which is a measure of clinical complexity, it is not likely that this finding is due to a baseline difference in severity of illness. The result is also strengthened by finding a difference even when excluding two outliers, both in the risperidone group, who could have remained in the hospital for social or other reasons. These data suggest that acute psychosis with co-occurring cannabis use disorder may respond more rapidly to aripiprazole compared with risperidone.

These results are important because there is little research comparing antipsychotic medications in this growing population. The controlled trials that exist compare risperidone with olanzapine, haloperidol with olanzapine, or ziprasidone with clozapine (Berk et al., 1999; Green et al., 2004; Schnell et al., 2014; Sevy et al., 2011; Van Nimwegen-Campailla et al., 2010). Of these, most had small sample sizes, and all were conducted in adult populations. This project extends the field by reporting a different comparison and in an adolescent population. It also extends the field by reporting pragmatic outcomes, such as length of stay and length of stay index.

In addition, the findings of this project are interesting because aripiprazole may also have a direct impact on substance use disorders. Animal studies show that aripiprazole compared with placebo modulates the dopaminergic response to alcohol, amphetamine, and cocaine administration in mice (Jerlhag, 2008; Leite et al., 2008). Similarly, human laboratory studies show that aripiprazole in doses ranging from 10 to 20 mg reduces the reinforcing effects of amphetamine, cocaine, and methamphetamine (Lile et al., 2011; Stoops et al., 2006). Finally, small clinical trials generally support the use of aripiprazole for alcohol use disorder and cocaine use disorder (Anton et al., 2008; Beresford et al., 2005; Brown et al., 2005). Therefore, aripiprazole may have an impact not just on psychosis in the context of substance use disorder but also upon substance use directly. Given this research and our current findings, a randomized controlled trial to provide definitive and conclusive results is indicated.

Conclusions

In summary, this project reports a significant difference in hospital length of stay and length of stay index for adolescents with psychosis and cannabis use disorder who were prescribed risperidone or aripiprazole. Specifically, those prescribed risperidone had a longer length of stay and length of stay index compared with those prescribed aripiprazole. There was no difference between groups with respect to expected length of stay, which is a measure of clinical complexity. This finding supports the need for further research.

Clinical Significance

The results of this evaluation suggest that hospitalized adolescents with psychosis and cannabis use disorder may stabilize more rapidly with aripiprazole than risperidone.

Footnotes

Disclosures

No competing financial interests exist.

Authors' Contributions

C.T.: Conceptualization, Methodology, Writing—Original draft, Writing—Review and editing, Supervision, and Funding acquisition. R.L.: Methodology, Formal analysis, Data curation, and Writing—Review and editing. K.F.: Investigation, Writing—Review and editing. C.A.T.: Writing—Review and editing, Visualization. C.W.: Investigation, Writing—Review and editing.

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