High Risk MC4R Genotype, Low Risk MC4R Genotype, One Week or Less Antipsychotic Lifetime Exposure
Conditions
Keywords
MC4R genotype, antipsychotic induced weight gain, pediatric population
Brief summary
We will conduct a 12-week, randomized open label study, comparing usual care (UC) antipsychotic treatment (aripiprazole, quetiapine, risperidone) with ziprasidone (ZIP) in children and adolescents aged 13-18 years old. Patients will have 10 days or less lifetime antipsychotic exposure and be in clinical need for antipsychotic treatment for a pediatric psychiatric disorder with FDA indication for antipsychotic use, i.e., bipolar mania, schizophrenia-spectrum disorders, and irritability associated with autistic disorder. In addition, we will also include youth fulfilling research diagnostic criteria for severe mood dysregulation (SMD). Randomization will be stratified by high vs. low genetic risk for antipsychotic-induced weight gain based on MC4R genotype and the primary outcome will be weight change from baseline to endpoint between ZIP and UC antipsychotic treatment in each of the two genotype groups. As detailed below, other metabolic and cardiac safety parameters will also be measured and compared across treatments in each of the genotype groups.
Interventions
DRUGZiprasidone
random assignment to ZIP (20-160mg/d, bid dosing)
DRUGaripiprazole, quetiapine, or risperidone
random assignement to Usual Care antipsychotic UC antipsychotic (aripiprazole 2-30mg/d, quetiapine 25-800mg/d or risperidone 0.1-8mg/d)
Sponsors
Northwell Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
13 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* age 13-18 years * English-speaking * DSM diagnoses that have an FDA indication for SGA use for at least one agent in the respective pediatric or adult age group. Specifically, primary DSM-IV diagnosis of early-onset schizophrenia spectrum disorders; bipolar I disorder mania (and BP-NOS); irritability associated with autism spectrum disorder, as well as severe mood dysregulation (SMD) according to Leibenluft et al. (2011) with an ABC-irritability score of \>/=18 Sexually active girls must agree to use two effective forms of birth control or be abstinent * Participant has a primary caretaker who has known the child well for at least 6 months before study entry Primary caretaker is able to participate in study appointments * Ability of child to participate in all aspects of the protocol per investigator clinical judgment.
Exclusion criteria
* Major neurological or medical illnesses that affect weight (e.g., unstable thyroid disease), require a prohibited systemic medication (e.g., diabetes mellitus \[insulin\], chronic renal failure \[steroids); Fasting glucose \> 125 mg/dL on 2 occasions during screening * Any medication (other than currently prescribed psychotropic medications) that would significantly alter weight * Antidepressants not allowed for at least 2 weeks in BP-I or BP-NOS patients * DSM-IV diagnosis of anorexia or bulimia nervosa * DSM-IV diagnosis of Substance Dependence disorder (other than tobacco dependence) within the past month * Initial urine toxicology screen and follow-up screen indicate ongoing use of illicit substance * Hypersensitivity to ZIP or UC antipsychotics * Pregnant, breast feeding or unwilling to comply with contraceptive requirements * Screening or baseline QTc \> 450 msec * IQ \< 55 * Significant risk for dangerousness to self or to others * Ongoing or previously undisclosed child abuse requiring new department of social service intervention.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Weight Change | baseline to week 12 |
Secondary
| Measure | Time frame |
|---|---|
| Percent Weight Change Compared to Baseline Weight | baseline to week 12 |
| BMI Z-scores | baseline to week 12 |
| BMI Percentile | baseline to week 12 |
Countries
United States
Participant flow
Pre-assignment details
14 subjects were consented to the study and received screening, 7 subjects did not meet the eligibility criteria to the study and were therefore not randomized to the study
Participants by arm
| Arm | Count |
|---|---|
| Ziprasidone (20-160mg/d, bid) for 12 weeks
Ziprasidone: random assignment to ZIP (20-160mg/d, bid dosing)
4 patients were randomized to Ziprasidone | 4 |
| Aripiprazole, Quetiapine, Risperidone Aripiprazole (2-30mg/d), Quetiapine (25-800mg/d) or Risperidone (0.1-8mg/d) for 12 weeks
aripiprazole, quetiapine, or risperidone: random assignement to Usual Care antipsychotic UC antipsychotic (aripiprazole 2-30mg/d, quetiapine 25-800mg/d or risperidone 0.1-8mg/d)
3 patients were randomized to usual care | 3 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | refused medication switch | 1 | 0 |
| Overall Study | stopped taking meds | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Ziprasidone | Aripiprazole, Quetiapine, Risperidone |
|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 4 Participants | 3 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 7 participants | 4 participants | 3 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 4 | 0 / 3 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 |
Outcome results
Primary
Weight Change
Time frame: baseline to week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | Weight Change | baseline | 120.5 lbs | Standard Deviation 8.23 |
| Ziprasidone | Weight Change | week 12 (n=1,2) | 151 lbs | Standard Deviation 0 |
| Aripiprazole, Quetiapine, Risperidone | Weight Change | baseline | 118.5 lbs | Standard Deviation 27.92 |
| Aripiprazole, Quetiapine, Risperidone | Weight Change | week 12 (n=1,2) | 141 lbs | Standard Deviation 7.06 |
Secondary
BMI Percentile
Time frame: baseline to week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | BMI Percentile | baseline | 32 BMI percentile | Standard Deviation 20.31 |
| Ziprasidone | BMI Percentile | week 12 (n=1, n=2) | 59 BMI percentile | Standard Deviation 1 |
| Aripiprazole, Quetiapine, Risperidone | BMI Percentile | baseline | 37.67 BMI percentile | Standard Deviation 36.66 |
| Aripiprazole, Quetiapine, Risperidone | BMI Percentile | week 12 (n=1, n=2) | 62.5 BMI percentile | Standard Deviation 30.41 |
Secondary
BMI Z-scores
Time frame: baseline to week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | BMI Z-scores | baseline | -0.51 BMI z-score | Standard Deviation 0.55 |
| Ziprasidone | BMI Z-scores | week 12 (n=1, n=2) | 0.22 BMI z-score | Standard Deviation 0 |
| Aripiprazole, Quetiapine, Risperidone | BMI Z-scores | baseline | -0.37 BMI z-score | Standard Deviation 1.05 |
| Aripiprazole, Quetiapine, Risperidone | BMI Z-scores | week 12 (n=1, n=2) | 0.38 BMI z-score | Standard Deviation 0.85 |
Secondary
Percent Weight Change Compared to Baseline Weight
Time frame: baseline to week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ziprasidone | Percent Weight Change Compared to Baseline Weight | 11.58 percentage of weight change | Standard Deviation 0 |
| Aripiprazole, Quetiapine, Risperidone | Percent Weight Change Compared to Baseline Weight | 5.66 percentage of weight change | Standard Deviation 4.66 |