Summary

• Patients with a both a substance abuse and a mental disorder are often difficult to treat and demonstrate more hostility, suicidality and poorer medication compliance than non-substance abusers.¹
• Results from a 6-month, proof-of-concept study found a statistical trend (P=0.054) toward significance in the difference between changes in heavy drinking days (≥5 drinks/day) for the RISPERDAL CONSTA group vs. oral risperidone.²
• Results from a 12-week, open-label, naturalistic study evaluating RISPERDAL CONSTA in patients with cocaine dependence and a psychotic disorder diagnosis showed a statistically significant improvement in impulsiveness, psychopathology, craving and health emergencies.³
• Results from a 6-month, randomized, rater-blinded, open-label trial comparing RISPERDAL CONSTA to zuclopenthixol-depot in patients with schizophrenia and substance use disorder concluded that RISPERDAL CONSTA was more effective in improving substance abuse and alleviating symptoms of schizophrenia.⁴

CLINICAL STUDIES

Green et al (2015)² conducted a proof-of-concept, randomized, 6-month study (n=95; mean age 42 years) to evaluate the differences in heavy alcohol use (≥5 drinks per day) in patients treated with RISPERDAL CONSTA versus oral risperidone at 4 U.S. study centers. Patients were recruited from community mental centers and Veterans Affairs clinics where patients presented for treatment and evaluation. Patients were diagnosed with schizophrenia or schizoaffective disorder and current alcohol use disorder. Investigators evaluating patients for overall response to treatment and adverse events were unblinded while raters assessing patients for alcohol and other substance abuse, psychiatric symptoms and treatment utilization were blinded. During the 2nd visit patients viewed an alcohol education videotape and were encouraged to seek support through local self-help groups and to continue psychosocial treatment at their clinic.

Treatment was initiated with RISPERDAL CONSTA 25 mg every 2 weeks and titrated up to a target dose of 37.5 mg. Those randomized to receive oral risperidone were titrated over a 2-week period to a target dose of 4 mg/day. The dose could be increased (to a maximum dose of RISPERDAL CONSTA 50 mg or oral risperidone 6 mg) or decreased depending on tolerability and psychiatric symptom response. Both the number of days of heavy alcohol use and intensity of drinking (number of drinks per day) were measured. Analyses included data from weeks 5 (RISPERDAL CONSTA steady state achieved) through 23 (to avoid end of study effects on drinking behavior).

68 patients remained in the study for 6 months and 36 patients discontinued their study medication; 8 patients switched to another antipsychotic but remained in the study. Heavy drinking in the oral risperidone group worsened over time (t₆₇=2.31; P=0.024) with a statistical trend toward significance in the difference between changes in heavy drinking days in the oral and RISPERDAL CONSTA groups (t_63.5=-1.96; P=0.054). The estimated change in the RISPERDAL CONSTA group was -0.11 heavy drinking days/week (t₈₂=0.12; P>0.9) compared to an increase of 0.68 days/week in the oral risperidone group during the same period (t₆₇=2.31; P=0.024). The two groups differed in the mean number of drinking days per week (t₈₈=-2.14; P=0.035); however, between-group differences were not significant over time. There were no significant differences in total Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), and Clinical Global Impressions (CGI) scale or neurological side effects scales (Simpson Angus, AIMS, and BARS). There were no differences in the frequency of adverse effects between groups. The most common adverse events included pain (11.6%), upper respiratory tract infections (5.3%), drooling (5.3%), nausea or stomach discomfort (6.3%), diarrhea (6.3%), vomiting (5.3%), and other digestive or hepatic problems (8.4%).

Haro et al (2011)³ conducted a naturalistic and multicenter study (n=57; mean age 33.7 years) which included four addictive behavior units and one prison in Spain. The study evaluated patients with cocaine addiction and other psychotic diagnoses who received RISPERDAL CONSTA in addition to conventional treatment. Thirty-nine percent of the patients had at least one personality disorder with the most frequent being borderline (25%), followed by antisocial (12.5%), histrionic (8.9%) and paranoid (8.9%). Patients began their treatment with RISPERDAL CONSTA during a 1-year period and underwent a follow-up period of 12 weeks. A multi-drug urine screen analysis was conducted every 14 days to detect cocaine, opiates, cannabis, and amphetamines. Patients were evaluated using several psychometric tests including the International Personality Disorder Examination, the Ramón and Cajal Impulses Control Scale, a test to assess impulsiveness consisting of 20 items scored at four levels of frequency (0-3; never to always) with scores ranging from 0 to 60. A symptom check list (SCL-90-R) to evaluate subjective discomfort and certain psychiatric symptoms and a visual analog scale to quantify the intensity of consumption desire or craving were also employed. The number of hospital admissions and any emergency care within the previous 2 weeks and during the 12-week follow-up period was also recorded.

Treatment was initiated with RISPERDAL CONSTA 25 mg every 2 weeks and could be adjusted during the first 8 weeks. After week 10, 50% of the patients remained on 25 mg, 25% on 37.5 mg and 25% on 50 mg. There were 19 dropouts at study end with 38 patients completing the study. The SCL-90 showed a significant improvement (P<0.001) when comparing the first and final visits in all scales and in Global Symptomatology Index (GSI). Impulsiveness scores dropped significantly (P<0.001) from week 6 (31.59) to week 12 (27.78). A decrease in craving was demonstrated between the first and last visit with intensity decreasing more than frequency. The number of emergency requests was also reduced during the study period (P<0.001).

Rubio et al (2006)⁴ published the results of a 6-month, randomized, rater-blinded, open-label trial of RISPERDAL CONSTA and zuclopenthixol-depot, a conventional antipsychotic not marketed in the United States. Adult patients with a diagnosis of schizophrenia and DSM-IV classified substance use disorder, for substances other than caffeine and nicotine, were included. Patients were selected for study inclusion while hospitalized due to a worsening of psychosis. Once stabilized, patients received either RISPERDAL CONSTA or zuclopenthixol-depot and remained as inpatients for an additional 7 to 15 days before being referred to an outpatient center for treatment. The starting dose and administration frequency for RISPERDAL CONSTA or zuclopenthixol-depot were not disclosed in the publication. Oral risperidone (2 mg to 6 mg) and zuclopenthixol (10 mg to 50 mg) were also used in conjunction with the injectable medications. All patients were treated with oral haloperidol (80%) or chlorpromazine (20%) prior to study enrollment.

The objective of this trial was to compare the efficacy of RISPERDAL CONSTA to zuclopenthixol-depot in improving substance abuse in patients with a dual diagnosis. This was measured by the number of positive urine tests and elapsed time before the first positive urine test. Schizophrenia symptoms were evaluated with the PANSS and the CGI scale.

In total 115 patients entered the trial (n=57, RISPERDAL CONSTA; n=58, zuclopenthixol-depot). Patient demographics and baseline clinical characteristics were similar among both groups. The average age of the patients was 37.9 years in the RISPERDAL CONSTA group and 33.5 years in the zuclopenthixol-depot group. At endpoint, the mean dose of the RISPERDAL CONSTA group was 47.2 mg every 15 days along with 3.4 mg daily oral risperidone. The zuclopenthixol-depot group received a mean dose of 200 mg every 21 days and 15 mg daily oral zuclopenthixol at endpoint. Three RISPERDAL CONSTA patients (5.3%) and 6 zuclopenthixol-depot patients (10.3%) discontinued the trial. Ten patients from the RISPERDAL CONSTA group (17.5%) and 11 patients from the zuclopenthixol-depot group (19.0%) were admitted to a psychiatric hospital during the trial due to psychopathological symptom exacerbation.

The mean number of positive urine tests per patient was significantly higher in the zuclopenthixol-depot group than in the RISPERDAL CONSTA group (P=0.005). All patients consumed substances during the trial, although the first positive urine test occurred during Week 9 in the RISPERDAL CONSTA group and Week 7 in the zuclopenthixol group (P<0.09). Significant differences were found between the RISPERDAL CONSTA group and zuclopenthixol-depot group for the PANSS total (P=0.02), PANSS negative subscale (P=0.008), and PANSS general subscale (P=0.05) at endpoint, with the RISPERDAL CONSTA group having greater improvements. The PANSS positive subscale did not significantly differ between groups at endpoint (P=0.59). Also at endpoint, a higher percentage of patients in the RISPERDAL CONSTA group (89%) than the zuclopenthixol-depot group (50%) had a PANSS score 20% lower than baseline (P<0.0001). CGI scores were not reported in the publication.

Limited safety information was reported in the publication. The RISPERDAL CONSTA group had a significant reduction on the Extrapyramidal Symptom Rating Scale (ESRS), used to evaluate movement disorders, and the Udvalg for Kliniske Undersøgelser (UKU) side effect rating scale when compared to the zuclopenthixol-depot group (P<0.04). Antiparkinsonian medications were also used more frequently in the zuclopenthixol-depot group (P<0.01).

other relevant literature

Additional relevant articles identified during a literature search have been referenced.^5,6

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 30 July 2024.