by Robert J. Philipps, PharmD; Tammie Lee Demler, PharmD, BS(Pharm), MBA; and Claudia Lee, MD, BS(Pharm)
Dr. Philipps is from the University at Buffalo, School of Pharmacy and Pharmaceutical Sciences, and Drs. Demler and Lee are from the Buffalo Psychiatric Center, Buffalo, New York.

Innov Clin Neurosci. 2012;9(9):14–17

Funding: No funding was received for the development of this article.

Financial Disclosures: All authors report no financial interests or any other potential conflicts of interest.

Key words: Proton pump inhibitors, omeprazole, clozapine, blood dyscrasia, agranulocytosis, drug-induced, radiotherapy, neutropenia

Abstract: Proton pump inhibitors are among the world’s most widely used therapeutic classes. Much of their use is attributed to their documented efficacy and apparent safety. For the most part, proton pump inhibitors are well tolerated with very few serious adverse events reported in the literature. Only a few previously identified case reports of severe neutropenia or agranulocytosis attributed to proton pump inhibitors use have been identified in the literature. However, agranulocytosis, neutropenia, and/or leukopenia are labeled as possible adverse events from post-marketing surveillance in the summary of product information for various proton pump inhibitors. In this report, we describe a case of probable omeprazole-induced blood dyscrasia in a clozapine-treated patient.


Proton pump inhibitors (PPIs) are among the world’s most widely used therapeutic classes.[1] For 2010 in the United States, omeprazole accounted for over 53 million prescriptions dispensed, ranking as the sixth most dispensed prescription that year.[2] PPIs are commonly used to treat a variety of disorders and carry a number of United States Food and Drug Administration (FDA) approved indications, including, but not limited to, dyspepsia, gastroesophageal reflux disease (GERD), and peptic ulcer disease. Much of their use is attributed to their documented efficacy and apparent safety. For the most part, PPIs are well tolerated, with very few rare serious adverse events reported in the literature. Only a few previously identified case reports of severe neutropenia or agranulocytosis have been identified.[3–7] However, agranulocytosis, neutropenia, and/or leukopenia are labeled as possible adverse effects from post-marketing surveillance in the summary of product information for various PPIs.8–12 We report a case of a probable omeprazole-induced blood dyscrasia in a clozapine-treated patient.

Case Report

In July of 2007, a 45-year-old woman was hospitalized in a state-run, long-term care, psychiatric facility for severe psychotic mania and treatment-refractory schizoaffective disorder. Despite multiple treatments with various typical and atypical antipsychotics and various mood stabilizers, antidepressants, and anxiolytics in the past, her psychiatric illness remained unstable and refractory. She was soon initiated on clozapine with cautious titration and close monitoring of her white blood cell (WBC) counts and absolute neutrophil counts (ANC). Her symptoms slowly started to improve over the course of many weeks to several months while her WBC counts and ANC remained relatively stable, within the normal ranges (WBC?3500/mm3, ANC?2000/mm3).

In April of 2009, a malignant melanoma was discovered on the heel of the patient’s right foot. Soon after, she was transferred to a local oncology center for surgical excision of the melanoma and also received a subsequent lymphadenectomy of her right inguinal lymph nodes. The patient responded well to the surgical interventions, and she was scheduled for a full course of follow-up radiation therapy to her right inguinal area thereafter. The high risk of side effects from chemotherapy outweighed the benefit for the patient and was, therefore, not recommended. A series of recurrent cellulitis infections in the popliteal area of her right leg requiring intravenous antibiotics between May and September of that year kept causing the radiation treatment to be postponed until complete resolution of the ulcer. In October of 2009, the patient’s radiation therapy was started, constituting 25 treatments over the course of five weeks (from October 12 to November 13). The patient responded well to the radiotherapy and was maintained successfully on clozapine throughout the course of treatment.

In August of 2009, just prior to the radiation therapy, the patient started experiencing symptoms consistent with GERD and was treated with 20mg of omeprazole by mouth once daily with some relief. Her WBC count and ANC remained relatively stable for several months, but the patient started trending down in April of 2010. On May 19, 2010 the patient’s WBC count was 3400/mm3 with an ANC of 799/mm3 (Figures 1 and 2). Her severe granulocytopenia (ANC<1000/mm3) warranted the discontinuation of the clozapine. Other medications that the patient was on at the time included: levothyroxine 25mcg/day, olanzapine 7.5mg/day, oxcarbazepine 600mg/day, and sertraline 50mg/day. After discontinuing the clozapine, the patient rapidly decompensated and started requiring more supervision from the hospital staff. Despite her psychiatrist trying alternative treatments with olanzapine, quetiapine, oxcarbazepine, valproate, sertraline, citalopram, and clonazepam in various combinations, she remained severely psychotic. Over this time course, the patient was irritable, intrusive, paranoid, hyperalert, and highly reactive to social stimuli with oppressive insomnia. Even more troubling, was that her WBC count and ANC consistently remained in a state of moderate leukopenia (WBC<3000/mm3) and/or state of moderate granulocytopenia (ANC<1500/mm3). Thus, a rechallenge with clozapine was deemed too high a risk and unsafe for the patient. A review of her WBC counts and ANC history versus medication use led her observing physician to believe that omeprazole was one of the factors associated with the suppression of her blood counts. With its discontinuation on August 6, 2010 (ANC=1900/mm3), her WBC and ANC counts rose back into an acceptable range by August 9, 2010 (ANC=3500/mm3) for a clozapine rechallenge. With slow titration and close monitoring, the patient was able to be reinitiated on clozapine without further problems of blood dyscrasia (Figure 3).

To date, the patient has continued to experience beneficial results in her psychiatric illness. Her clozapine treatment eventually led to complete resolution of her psychosis, affective lability, paranoia, and insomnia. On August 8, 2011, she was granted discharge from the psychiatric hospital to a family care home. At present, she still continues to improve on her psychiatric illness and is doing well.


Agranulocytosis is defined as a drop in ANC?500/mm3 and can be fatal in the presence of an infection. Clozapine carries a black box warning for agranulocytosis and should be reserved for use in the treatment of severely ill patients with schizophrenia who are refractory to other antipsychotic agents.[13] The mortality rate from drug-induced agranulocytosis is approximately 5 to 10 percent, but decreases with early identification and treatment.[14,15] Various drugs are associated with an increased risk of agranulocytosis; examples include chemotherapy agents, analgesics, antipsychotics, antiepileptics, and anti-infective agents.[15] Of the antipsychotics, clozapine displays the highest propensity to induce agranulocytosis, with incidence rates of roughly 0.8 percent, predominantly occurring in the first year of treatment.[14,16] Once a patient experiences an episode of agranulocytosis while on clozapine, it must be discontinued, contraindicating future use. After the initial 18 months of treatment, the risk is substantially less, however, and many patients are able to benefit greatly from clozapine’s use.[16] As in the case of this patient, clozapine can substantially improve a patient’s quality of life, especially for those individuals with treatment-resistant schizophrenia and schizoaffective disorder.

In this patient, her episode of severe granulocytopenia was considered drug-related due to the lack of any other compelling or predisposing factors during that time. Whether the incident was due to her clozapine alone, any of the other medications she was taking (omeprazole, levothyroxine, olanzapine, oxcarbazepine, or sertraline), and/or a result of her radiotherapy remained in question. At first, the omeprazole was not appreciably considered, especially since all of her other medications have a more significant track record for causing blood dyscrasias. In fact, the majority of the available literature on drug-induced neutropenia and agranulocytosis makes very little to no mention at all of omeprazole-induced leukopenia/agranulocytosis.[14,18–21] Additionally, radiation therapy has been known to induce neutropenia in some cases[22,23] and could have been another potential cause of the severe granulocytopenia. However, after 11 weeks of tweaking, adjusting, and trying various other medications to treat the patient’s severe mental illness without discernible improvement in her ANC, omeprazole was suspected. The patient’s ANC rose from 1900/mm3 to 3500/mm3 after three days of stopping omeprazole, confirming her physician’s concern for the PPI. In this case, the manifestation of the patient’s blood dyscrasia took about nine months from the initiation of omeprazole therapy. In another previously published case of omeprazole-induced agranulocytosis, the patient reportedly had been taking the PPI for roughly four years before the incident.[3] The other four published cases report their occurrences of omeprazole-induced blood dyscrasia at nine days, three weeks, six weeks, and 17 weeks from initiation of the PPI.[4–7] Whiskey and Taylor in 2007 suggested that neutropenia can arise because of various other factors unrelated to clozapine therapy; and in such cases, clozapine may be restarted if the non-clozapine cause of neutropenia is identified and resolved24—as was the case with this patient.

Most cases of severe leukopenia (WBC<2000/mm3), severe granulocytopenia (ANC<1000/mm3), or agranulocytosis (ANC?500/mm3) seen in clinical practice are observed as adverse events from drugs.14 The annual incidence of drug-induced agranulocytosis, excluding cytotoxic agents, has been estimated to be approximately seven cases per million people.[17] Two mechanisms are commonly regarded to explain the pathogenesis of drug-induced neutropenia.[18] The first is postulated as an immune-mediated reaction based on the body’s detection of drug-dependent antibodies against circulating neutrophils. The second is attributed to a toxic mechanism, which refers to a drug’s direct (or its metabolite’s) toxicity toward hematopoietic cells either in circulation or in the bone marrow. The issue is further complicated due to the fact that not all individuals treated with drugs known to potentially cause blood dyscrasias actually end up developing neutropenia or agranulocytosis. This indicates that genetic determinants also play a significant role in these types of idiosyncratic reactions, making it difficult to point out a single causative reason for drug-induced neutropenias.[15] Our review of the literature only revealed five other cases of omeprazole-induced neutropenias or agranulocytosis.[3–7] One of these reports suggested that there is possible cross-reactivity among the PPIs for individuals susceptible to omeprazole-induced neutropenia.[4] Given our patient’s history of severe mental illness only being responsive to clozapine, the risk of a recurrent blood dyscrasia from a PPI was considered too high. Thus, her GERD was effectively treated with ranitidine following discontinuating of the PPI without altering her WBC counts and ANC. Additionally, our patient benefited greatly from her routine WBC count and ANC monitoring while on clozapine, allowing us to identify the drop in ANC promptly. With omeprazole’s widespread use in the community, this may not be the case for most individuals. Omeprazole’s popularity is attributed to its well-known effectiveness for dyspepsia, GERD, and peptic ulcer disease with few serious adverse reactions. Although omeprazole-induced neutropenias are probably very rare, clinicians should be aware of this dangerous possibility. References
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