Biomarker and Safety Study of Clozapine in Patients With Benign Ethnic Neutropenia (BEN)
| Status: | Recruiting |
|---|---|
| Conditions: | Schizophrenia, Hematology |
| Therapuetic Areas: | Hematology, Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 64 |
| Updated: | 2/3/2019 |
| Start Date: | July 2015 |
| End Date: | April 2020 |
| Contact: | Ann Kearns, BS |
| Email: | akearns@mprc.umaryland.edu |
| Phone: | 410-402-6854 |
Clozapine (CLZ) is the most effective antipsychotic for treatment-refractory schizophrenia
(SZ). Despite the overwhelming evidence of superior efficacy, CLZ is infrequently prescribed
in the US, at a considerably lower rate than the estimated prevalence of treatment-resistant
SZ, especially for African-Americans (AA). Recent evidence suggests that low Absolute
Neutrophil Counts (ANC), either at baseline or during treatment are a significant barrier to
CLZ use in AA patients in the US, where guidelines mandate CLZ discontinuation if ANC drops
below 1500 cells/mm3. The investigators group has found that discontinuation of CLZ in AA
patients is over twice that in European-American (EA) patients (N~400; 42% vs.19%, P=0.041)
and initiation rates are 50% lower. In a Statewide study (N=1875), the investigators reported
that discontinuation was more frequently due to neutropenia in the AA sample, though no AA
had developed agranulocytosis (8 cases in EA). Benign Ethnic Neutropenia (BEN) in people of
African ancestry, including AAs, identifies a group (50% of AA) with low ANCs but no
increased risk of agranulocytosis or infection. Low baseline or in-treatment fluctuations
requiring CLZ discontinuation under current prescribing guidelines are common in CLZ-treated
persons with BEN. In the investigators recent pilot study of N=12 AA patients with BEN,
treatment was safely and successfully continued with CLZ despite low baseline ANC (outside
current guidelines). Recent evidence implicates a polymorphism in the Duffy Antigen Receptor
Chemokine (DARC) gene in the pathophysiology of BEN. In homozygotes (FY-/-) for the DARC null
allele, mean within-subject neutrophil counts are reduced, resulting in sporadic ANC <1500
cells/mm3 in 10-15% of people with the allele. In population studies, the FY-/- genotype is
found in 0.01% of EAs, 99.3% of sub-Saharan Africans (SSA), and 68% of AAs. Further, a
missense DARC mutation has been reported to interact with the DARC FY-/- in determining low
WBC in AAs. Normal patterns of week-to-week fluctuation in ANC levels in individuals of
African ancestry with BEN and the DARC null genotype are not known, and no published research
has examined variation in ANC in African ancestry CLZ-treated SZ patients with BEN and the
DARC null genotype (FY-/-). Such data are also lacking on individuals with BEN without the
DARC null genotype. Conducting such research will generate genetic marker and safety data
that could be used to expand access to CLZ for AA patients who otherwise are eligible to
receive this superior treatment option.
(SZ). Despite the overwhelming evidence of superior efficacy, CLZ is infrequently prescribed
in the US, at a considerably lower rate than the estimated prevalence of treatment-resistant
SZ, especially for African-Americans (AA). Recent evidence suggests that low Absolute
Neutrophil Counts (ANC), either at baseline or during treatment are a significant barrier to
CLZ use in AA patients in the US, where guidelines mandate CLZ discontinuation if ANC drops
below 1500 cells/mm3. The investigators group has found that discontinuation of CLZ in AA
patients is over twice that in European-American (EA) patients (N~400; 42% vs.19%, P=0.041)
and initiation rates are 50% lower. In a Statewide study (N=1875), the investigators reported
that discontinuation was more frequently due to neutropenia in the AA sample, though no AA
had developed agranulocytosis (8 cases in EA). Benign Ethnic Neutropenia (BEN) in people of
African ancestry, including AAs, identifies a group (50% of AA) with low ANCs but no
increased risk of agranulocytosis or infection. Low baseline or in-treatment fluctuations
requiring CLZ discontinuation under current prescribing guidelines are common in CLZ-treated
persons with BEN. In the investigators recent pilot study of N=12 AA patients with BEN,
treatment was safely and successfully continued with CLZ despite low baseline ANC (outside
current guidelines). Recent evidence implicates a polymorphism in the Duffy Antigen Receptor
Chemokine (DARC) gene in the pathophysiology of BEN. In homozygotes (FY-/-) for the DARC null
allele, mean within-subject neutrophil counts are reduced, resulting in sporadic ANC <1500
cells/mm3 in 10-15% of people with the allele. In population studies, the FY-/- genotype is
found in 0.01% of EAs, 99.3% of sub-Saharan Africans (SSA), and 68% of AAs. Further, a
missense DARC mutation has been reported to interact with the DARC FY-/- in determining low
WBC in AAs. Normal patterns of week-to-week fluctuation in ANC levels in individuals of
African ancestry with BEN and the DARC null genotype are not known, and no published research
has examined variation in ANC in African ancestry CLZ-treated SZ patients with BEN and the
DARC null genotype (FY-/-). Such data are also lacking on individuals with BEN without the
DARC null genotype. Conducting such research will generate genetic marker and safety data
that could be used to expand access to CLZ for AA patients who otherwise are eligible to
receive this superior treatment option.
Inclusion Criteria
- Eligible and recommended for clozapine treatment (e.g. treatment resistant
schizophrenia, schizoaffective disorder, bipolar disorder, other psychotic disorder,
delusional disorder, hostility, other documented rationale)
- Male or Female
- African Ancestry (African, African-American or African-Caribbean). This population
will make up the majority of the study. However, there are cases of BEN in individuals
of Middle Eastern, Caucasian, and other ethnicity. The investigators will accept these
patients as they may have unknown African ancestry and genotyping will be important.
- Age: 18 to 64 years.
- History of a low absolute neutrophil count (ANC<2500 cells/mm3 in past 24 months)
- Documented ability to sign informed consent. This is a score of ≥10/12 on ESC.
- Effective birth control if of child bearing potential
Exclusion Criteria
- DSM-IV diagnosis of Mental Retardation
- Pregnancy or lactation
- History of myeloproliferative disorder
- Uncontrolled seizure disorder
- History of paralytic ileus
- History of clozapine-induced ANC < 700 mm3
- Systemic Lupus Erythematosus, Multiple Sclerosis, Hashimoto's Thyroiditis, Sjogren's
Syndrome, Grave's Disease*
- Medical condition whose pathology or treatment would likely alter the presentation or
treatment of schizophrenia or significantly increase the risks associated with the
proposed protocol.
- Medical condition affecting patient's ability to mount an immune response
- Current bacterial or viral infection*
- Sickle cell anemia
- Positive for bacteria in urine culture*
- Temperature > 37.5 º Celsius, 99.5 º Fahrenheit*
- Current treated or untreated cancer*
- Documented nutritional deficiencies (such as Beriberi, Pellagra, Rickets, Scurvy,
Keshan Disease)*
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