Schizophrenia, Psychotic Disorders, Substance Abuse, Alcohol Abuse
Conditions
Keywords
Risperidone, Schizophrenia, Substance Use Disorder, Alcohol Use Disorder, Treatment, Schizoaffective Disorder
Brief summary
The purpose of this study is to compare the efficacy of oral risperidone (Risperdal) to risperidone long-acting (Consta) in reducing alcohol use in persons diagnosed with schizophrenia or schizoaffective disorder.
Detailed description
Comorbid alcohol/substance use disorder (SUD) in people with schizophrenia is a major concern, both in view of the high frequency of SUD among patients with schizophrenia and the difficulty in managing such patients. Though antipsychotic medications are effective in reducing symptoms and impairment in persons with schizophrenia, the typical antipsychotic agents are of limited value in controlling alcohol/substance use in these patients. Extrapyramidal, dysphoric side effects of conventional neuroleptics may actually promote the use of substances in an attempt to counteract these effects. In addition, medication non-compliance is common among patients with schizophrenia. Novel antipsychotics have altered treatment expectations and outcomes for patients with severe forms of schizophrenia. A growing number of studies have assessed the effects of oral risperidone in persons with dual disorders. Potential mechanisms of action by which risperidone and other atypical antipsychotics could decrease substance use include being less likely to cause extrapyramidal side effects than typical agents, improving negative symptoms and ameliorating a dysfunction of the brain reward system. Risperidone long-acting injectable medication addresses issues of noncompliance, while avoiding peak blood levels of oral preparations, thereby minimizing EPS and improving negative symptoms of schizophrenia. Risperidone may also facilitate dopamine neurotransmission in the prefrontal cortex and correct a hypothesized dysfunction of the brain reward system. This study is an open, randomized, controlled study to compare intramuscular long-acting risperidone to oral risperidone with blinded ratings to determine whether the long-acting form of risperidone has greater efficacy in reducing substance use. Patients with schizophrenia or schizoaffective disorder, age 18 to 65, who are taking any single oral antipsychotic medication except clozapine or risperidone long-acting may be enrolled.
Interventions
DRUGRisperidone Long Acting
Dose 25.00, 37.50 or 50.00 mg q two weeks
DRUGoral risperidone
0.50-6.00 mg oral risperidone daily
Sponsors
Janssen, LP
Dartmouth-Hitchcock Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Ages 18-65 * Schizophrenia or schizoaffective disorder * Meets the Structured Clinical Interview for DSM-IV (SCID) criteria for an alcohol use disorder * Alcohol use on at least 5 days during the 4 weeks prior to randomization * Patient is medically stable to start either form of risperidone.
Exclusion criteria
* Current treatment with clozapine. * Current treatment with injectable risperidone long-acting. * Currently pregnant, planning to become pregnant, or unwilling to use an acceptable form of birth control. * Change in medications (dose of current medication, discontinuation of medication, or new medication) in past 30 days. * History of or current breast cancer. * History of intolerance of or allergy to risperidone or risperidone long-acting. * Currently residing in a residential program designed to treat substance use disorders. * Current treatment with long-acting, injectable antipsychotic medication will require a review by the medication adjustment group before entering the client into the study. * Past treatment with risperidone long-acting will require a review by the medication adjustment group before entering the client into the study. * Treatment at baseline with a second antipsychotic medication will require a review by the medication adjustment group before entering the client into the study. * Treatment at baseline with a psychotropic agent proposed to curtail substance use will require a review by the medication adjustment group before entering the client into the study. * Patients who, in the opinion of the investigator, are judged unsuitable to participate in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change Over Time in Frequency of Heavy Drinking Days (Used to Evaluate Treatment Efficacy) | 6 months | Frequency of heavy drinking days is obtained each week retrospectively as the number of heavy drinking days during the prior week (assessed by the Timeline Followback Scale). A heavy drinking day is defined as 4 or more drinks per day for a female and 5 or more drinks per day for a male. Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Over Time of Frequency of Drinking Days (Used to Evaluate Treatment Efficacy) | 6 months | Frequency of drinking days is obtained each week retrospectively as the number of drinking days during the prior week (assessed using the Timeline Followback). Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number. |
| Average Over Time of Severity of Illness and Global Improvement (Used to Evaluate Treatment Efficacy) | 6 months | A rater assesses the severity of illness and global impression using a scale from 1 to 7 (Clinical Global Impression), where higher values represent a worse outcome. Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number. |
| Average Over Time of Positive and Negative Symptoms (Used to Evaluate Treatment Efficacy) | 6 months | A rater assesses positive and negative symptoms of schizophrenia using a 30-item scale (Positive and Negative Symptom Score) Scores range from 30 to 210, where higher values represent a worse outcome. Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number. |
| Average Over Time of Global Functioning (Used to Evaluate Treatment Efficacy) | 6 months | A rater assesses social, occupational and psychological functioning on a hypothetical continuum of mental health - illness (using Global Assessment of Functioning); scores range from 100 to 1, where higher values represent a better outcome. Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number. |
| Number of Participants With Medication Adherence | 6 months | Number of participants with medication adherence (defined as taking medication at least 75% of the days in the treatment period). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Risperidone Long Acting Injectable (LAI) Risperidone Long Acting Injectable (LAI), begun with 25 mg dose given intramuscularly(IM)every two weeks. The dose was titrated up to a target dose of 37.5 mg IM, with injections given every two weeks. The maximum dose of LAI risperidone was 50 mg every two weeks. | 49 |
| Oral Risperidone Aka Risperal Oral Risperidone aka Risperdal. Participants who were randomized to take oral risperidone were titrated over two weeks up to a target dose of 4 mg per day. The maximum daily dose of oral risperidone was 6 mg. | 46 |
| Total | 95 |
Baseline characteristics
| Characteristic | Oral Risperidone Aka Risperal | Risperidone Long Acting Injectable (LAI) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 46 Participants | 49 Participants | 95 Participants |
| Age, Continuous | 41.7 years STANDARD_DEVIATION 11.5 | 41.7 years STANDARD_DEVIATION 10.1 | 41.70 years STANDARD_DEVIATION 10.7 |
| Region of Enrollment United States | 46 Participants | 49 Participants | 95 Participants |
| Sex: Female, Male Female | 10 Participants | 12 Participants | 22 Participants |
| Sex: Female, Male Male | 36 Participants | 37 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 49 | 14 / 46 |
| serious Total, serious adverse events | 16 / 49 | 12 / 46 |
Outcome results
Primary
Change Over Time in Frequency of Heavy Drinking Days (Used to Evaluate Treatment Efficacy)
Frequency of heavy drinking days is obtained each week retrospectively as the number of heavy drinking days during the prior week (assessed by the Timeline Followback Scale). A heavy drinking day is defined as 4 or more drinks per day for a female and 5 or more drinks per day for a male. Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Risperidone Long Acting Injectable (LAI) | Change Over Time in Frequency of Heavy Drinking Days (Used to Evaluate Treatment Efficacy) | -.11 heavy drinking days per week |
| Oral Risperidone Aka Risperal | Change Over Time in Frequency of Heavy Drinking Days (Used to Evaluate Treatment Efficacy) | .68 heavy drinking days per week |
p-value: 0.054Mixed Models Analysis
Secondary
Average Over Time of Frequency of Drinking Days (Used to Evaluate Treatment Efficacy)
Frequency of drinking days is obtained each week retrospectively as the number of drinking days during the prior week (assessed using the Timeline Followback). Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Risperidone Long Acting Injectable (LAI) | Average Over Time of Frequency of Drinking Days (Used to Evaluate Treatment Efficacy) | 2.84 drinking days per week |
| Oral Risperidone Aka Risperal | Average Over Time of Frequency of Drinking Days (Used to Evaluate Treatment Efficacy) | 3.46 drinking days per week |
p-value: 0.035Mixed Models Analysis
Secondary
Average Over Time of Global Functioning (Used to Evaluate Treatment Efficacy)
A rater assesses social, occupational and psychological functioning on a hypothetical continuum of mental health - illness (using Global Assessment of Functioning); scores range from 100 to 1, where higher values represent a better outcome. Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Risperidone Long Acting Injectable (LAI) | Average Over Time of Global Functioning (Used to Evaluate Treatment Efficacy) | 50.8 ordinal severity of impairment |
| Oral Risperidone Aka Risperal | Average Over Time of Global Functioning (Used to Evaluate Treatment Efficacy) | 49.9 ordinal severity of impairment |
p-value: 0.44Mixed Models Analysis
Secondary
Average Over Time of Positive and Negative Symptoms (Used to Evaluate Treatment Efficacy)
A rater assesses positive and negative symptoms of schizophrenia using a 30-item scale (Positive and Negative Symptom Score) Scores range from 30 to 210, where higher values represent a worse outcome. Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Risperidone Long Acting Injectable (LAI) | Average Over Time of Positive and Negative Symptoms (Used to Evaluate Treatment Efficacy) | 78.2 ordinal severity of symptoms |
| Oral Risperidone Aka Risperal | Average Over Time of Positive and Negative Symptoms (Used to Evaluate Treatment Efficacy) | 75.5 ordinal severity of symptoms |
p-value: 0.32Mixed Models Analysis
Secondary
Average Over Time of Severity of Illness and Global Improvement (Used to Evaluate Treatment Efficacy)
A rater assesses the severity of illness and global impression using a scale from 1 to 7 (Clinical Global Impression), where higher values represent a worse outcome. Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Risperidone Long Acting Injectable (LAI) | Average Over Time of Severity of Illness and Global Improvement (Used to Evaluate Treatment Efficacy) | 4.02 ordinal unit of severity |
| Oral Risperidone Aka Risperal | Average Over Time of Severity of Illness and Global Improvement (Used to Evaluate Treatment Efficacy) | 3.96 ordinal unit of severity |
p-value: 0.57Mixed Models Analysis
Secondary
Number of Participants With Medication Adherence
Number of participants with medication adherence (defined as taking medication at least 75% of the days in the treatment period).
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Risperidone Long Acting Injectable (LAI) | Number of Participants With Medication Adherence | 43 Participants |
| Oral Risperidone Aka Risperal | Number of Participants With Medication Adherence | 28 Participants |
p-value: 0.003Chi-squared