Targeted Vitamin D Treatment of Schizophrenia-Associated Hyperprolinemia
Last updated on April 2022Recruitment
- Recruitment Status
- Withdrawn
- Estimated Enrollment
- 80
Inclusion Criteria
- 25(OH)D insufficiency (<30ng/ml).
- Fasting hyperprolinemia (defined as 2 standard deviations (SDs) above the gender-adjusted mean measured for historical controls: 203.3 micromolar (uM) for females and 327.6 uM for males).
- Confirmed diagnosis of schizophreniform disorder, schizophrenia or schizoaffective disorder.
- 25(OH)D insufficiency (<30ng/ml).
- Fasting hyperprolinemia (defined as 2 standard deviations (SDs) above the gender-adjusted mean measured for historical controls: 203.3 micromolar (uM) for females and 327.6 uM for males).
- Confirmed diagnosis of schizophreniform disorder, schizophrenia or schizoaffective disorder.
Exclusion Criteria
- Initiation of Valproate treatment.
- Continued use of dietary supplementation, such as fish oil supplementation or vitamin D supplements (>400 IU/day).
- Abnormal serum/ urine metabolic lab values suggesting hypercalcemia (serum Calcium >10.4mg/dL), hypercalciuria (urine calcium/urine creatinine >0.20 mg/mg), or hyperthyroidism (parathyroid hormone (PTH) > 65pg/ml).
- Initiation of Valproate treatment.
- Continued use of dietary supplementation, such as fish oil supplementation or vitamin D supplements (>400 IU/day).
- Abnormal serum/ urine metabolic lab values suggesting hypercalcemia (serum Calcium >10.4mg/dL), hypercalciuria (urine calcium/urine creatinine >0.20 mg/mg), or hyperthyroidism (parathyroid hormone (PTH) > 65pg/ml).
Summary
- Conditions
- Schizoaffective Disorder
- Schizophrenia
- Type
- Interventional
- Phase
- Phase 2
- Design
- Allocation: Randomized
- Intervention Model: Parallel Assignment
- Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
- Primary Purpose: Treatment
Participation Requirements
- Age
- Between 18 years and 65 years
- Gender
- Both males and females
Description
25-hydroxyvitamin D (vitD) insufficiency is associated with cognitive decline and has long-been considered important in schizophrenia susceptibility. VitD supplementation has been suggested for those at-risk, and recent studies have demonstrated that vitD insufficiency extends into both adolescent a...
25-hydroxyvitamin D (vitD) insufficiency is associated with cognitive decline and has long-been considered important in schizophrenia susceptibility. VitD supplementation has been suggested for those at-risk, and recent studies have demonstrated that vitD insufficiency extends into both adolescent and adult schizophrenia. The mechanism by which vitD deficits confers risk is unknown. However, vitD is a transcriptional regulator, and the investigators recently found that vitD significantly up-regulates PRODH gene expression. This is important because the highest known genetic risk of schizophrenia is conferred by hemizygous microdeletion of chromosome 22q11, to which PRODH maps. Furthermore, PRODH encodes proline oxidase, which catalyzes proline catabolism. Proline is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been associated with learning and memory deficits and neurotransmitter dysregulation in animal models, and in humans, with decreased intelligence quotient (IQ), cognitive impairment, and schizoaffective disorder. The investigators recently found that >25% of schizophrenia patients were hyperprolinemic and hypothesized a causal relationship between vitD, proline elevation, and schizophrenia, such that vitD insufficiency causes decreased PRODH expression and hyperprolinemia. Measuring fasting plasma 25hydroxyvitD and proline in 64 patients and 90 controls, the investigators found that vitD insufficiency (<30ng/ml) was significantly associated with schizophrenia (OR:2.1, p=0.044), vitD levels were negatively correlated with proline (p=0.01), and vitD insufficient subjects had three times greater odds of hyperprolinemia (p=0.046). Moreover, they demonstrated that hyperprolinemia explains >37% of the association between vitD insufficiency and schizophrenia, signifying that vitD insufficiency increases schizophrenia risk, at least in part by elevating proline. These findings advocate that targeting schizophrenia-associated hyperprolinemia by alleviating vitD insufficiency, may improve symptoms including neurocognitive deficits. The Specific Aims of this study are: Aim 1) To Evaluate a clinical response to vitamin D3 (vitD3) treatment, targeting patients with both vitD insufficiency and hyperprolinemia. Aim 2) To Evaluate the relationship between fasting plasma proline change, PRODH expression, and symptoms, for development of an efficacy biomarker. The aims will be accomplished via a ten week, double-blind, placebo controlled trial, in which schizophrenia or schizoaffective disorder subjects who are both vitD insufficient and hyperprolinemic, will be randomized to vitD3 (4,000 international units (IU)/day n=40) or placebo (n=40) as an adjunct to their antipsychotics.
Inclusion Criteria
- 25(OH)D insufficiency (<30ng/ml).
- Fasting hyperprolinemia (defined as 2 standard deviations (SDs) above the gender-adjusted mean measured for historical controls: 203.3 micromolar (uM) for females and 327.6 uM for males).
- Confirmed diagnosis of schizophreniform disorder, schizophrenia or schizoaffective disorder.
- 25(OH)D insufficiency (<30ng/ml).
- Fasting hyperprolinemia (defined as 2 standard deviations (SDs) above the gender-adjusted mean measured for historical controls: 203.3 micromolar (uM) for females and 327.6 uM for males).
- Confirmed diagnosis of schizophreniform disorder, schizophrenia or schizoaffective disorder.
Exclusion Criteria
- Initiation of Valproate treatment.
- Continued use of dietary supplementation, such as fish oil supplementation or vitamin D supplements (>400 IU/day).
- Abnormal serum/ urine metabolic lab values suggesting hypercalcemia (serum Calcium >10.4mg/dL), hypercalciuria (urine calcium/urine creatinine >0.20 mg/mg), or hyperthyroidism (parathyroid hormone (PTH) > 65pg/ml).
- Initiation of Valproate treatment.
- Continued use of dietary supplementation, such as fish oil supplementation or vitamin D supplements (>400 IU/day).
- Abnormal serum/ urine metabolic lab values suggesting hypercalcemia (serum Calcium >10.4mg/dL), hypercalciuria (urine calcium/urine creatinine >0.20 mg/mg), or hyperthyroidism (parathyroid hormone (PTH) > 65pg/ml).
Tracking Information
- NCT #
- NCT02197286
- Collaborators
- Stanley Medical Research Institute
- Columbia University
- Investigators
- Principal Investigator: James D Clelland NYU Langone Health
- James D Clelland NYU Langone Health