Thrombocytopenia Secondary to the Use of Quetiapine

Introduction

T hrombocytopenia is defined as a platelet count of less than 150,000/nL per and is within the lowest 2.5th lower percentiles (Fauci et al. 2008). Thrombocytopenia has long been studied and is caused by one of three mechanisms—decreased bone marrow production, increased splenic sequestration, or accelerated destruction of platelets. One of the most common causes of thrombocytopenia is drug induced, and many common drugs can cause thrombocytopenia (Table 1). Most drugs induce thrombocytopenia by eliciting an immune response in which the platelet is an innocent bystander. Despite the fact that drug induction of thrombocytopenia is the most common cause, current laboratory tests can identify the causative agent in only 10% of patients with clinical evidence of thrombocytopenia (Fauci et al. 2008). The best proof of a drug-induced etiology is a prompt rise in the platelet count when the suspected drug is discontinued. Patients with drug-induced platelet destruction may also have a secondary increase in megakaryocytes number without other marrow abnormalities (Fauci et al. 2008).

We present a case of an adolescent female who developed thrombocytopenia possibly related to the use of quetiapine. Over a period of 10 months, Ms. T. was admitted to our inpatient psychiatric hospital a total of four times.

Case Report

Ms. T. is a 16-year-old Caucasian female who initially presented to our psychiatric hospital on September 4, 2007, after she made a suicide attempt by taking an intentional overdose of 37 ibuprofen 200-mg tablets. She had reported an increasingly depressed mood for several months prior, along with decreased energy, anhedonia, poor concentration, poor appetite, feelings of guilt, and hopelessness. Ms. T. was diagnosed with major depressive disorder (MDD), single, severe and was started on sertraline 50 mg daily. Psychological testing was also done at the time, confirming a diagnosis of MDD. After a 5-day stay, her mood stabilized and she was discharged on sertraline 50 mg/day with a plan for both outpatient psychiatric follow up and individual therapy (Table 2).

Two weeks later, Ms. T. was brought to our emergency room by her parents on September 25, 2007, after she reported to her parents an aborted suicide attempt by hanging. She told her parents she had taken battery jumper cables down to the basement late in the evening and thought about hanging herself from the ceiling. She also wrote suicide notes to her parents but told her parents that she changed her mind. At the time of admission, her thought processes were noted to be circumstantial with some evidence of thought blocking. She was readmitted and her dose of sertraline was increased to 100 mg daily. Buspirone 5 mg twice daily was added to treat her anxiety, and she was also started on quetiapine 25 mg at bedtime to address insomnia (Table 2). A complete blood count (CBC) done during her hospitalization revealed a platelet count within normal limits at 233,000/μL. Ms. T.'s mood symptoms stabilized after a 6-day hospital stay and she was discharged home with her parents to follow up closely in our partial day hospital program.

Ms. T. was followed as an outpatient and did relatively well on this medication regimen until she gradually developed the onset of manic symptoms, which started approximately 9 months later. She was brought by her parents to the emergency room on June 13, 2008, because she had become paranoid, suspicious, and disorganized and was agitated, hypersexual, and preoccupied with sexual themes. She also reported auditory hallucinations at the time and appeared confused and disoriented. She met Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) (American Psychiatric Association 2000) criteria for bipolar disorder type 1, most recent episode manic, severe, with psychotic features. Therefore, she was admitted to our psychiatric hospital for the third time. Sertraline and buspirone were discontinued and she was started on valproic acid 500 mg twice daily. Quetiapine was titrated to 50 mg every morning and at noon, and 100 mg at bedtime (Table 2). She responded well to this medication regimen and was discharged 12 days later on June 25, 2008. At the time of discharge, Ms. T.'s platelet count was 183,000/μL and her valproic acid level was 99.

Ms. T. subsequently entered the partial-day hospital program again and showed improvement in her first week following her discharge. However, she significantly deteriorated after the first week posthospitalization. She was visibly manic and focused on a wide variety of sexual and religious themes again when she was seen in the partial-day program on July 7, 2008. She had pressured speech and accused the attending psychiatrist of “doing something under the table.” She insisted that the attending psychiatrist and residents keep their hands on the table so she could “see them.” She also reported she had been racing her car over the weekend with friends at speeds of up to 70 miles per hour in a 40 mile per hour speed zone. She was therefore readmitted for the fourth time on July 7. On admission, her CBC revealed a decreased platelet count of 149,000/μL and a valproic acid level of 118. Therefore, valproic acid was discontinued at the time of admission. Because she was manic and continued to report poor sleep, her dose of quetiapine was increased to 100 mg three times daily.

On July 10^th (3 days after her fourth hospitalization), Ms. T.'s total dose of quetiapine was titrated to 400 mg daily to address her manic symptoms. A CBC was drawn that morning (prior to the increase in her quetiapine dose) which showed further decrease in her platelet count to 118,000/μL. The treatment team initially blamed valproic acid for this low platelet count and ordered another CBC. On July 12^th, (5 days after discontinuation of valproic acid), Ms. T.'s CBC showed a platelet count of 99,000/μL. Given that Ms. T. was still manic and disorganized, her dose of quetiapine was increased to 600 mg daily. On July 14^th, the patient's CBC results revealed a significantly decreased platelet count of 61,000/μL, but her valproic acid level was less than 10, confirming that this was not a causative factor. The treatment team also observed that with each increase in Ms. T.'s dose of quetiapine, her platelets were noted to have dropped (Table 2). At this point, the treatment team discontinued quetiapine and started following her CBC on a nearly daily basis. Lithium was started at 150 mg twice daily.

On July 15^th, 24 hours after quetiapine had been discontinued, the patient's CBC showed an increased platelet count of 122,000/μL. Another CBC done on July 16^th revealed a platelet count of 149,000/μL. At that point Ms. T.'s dose of lithium was titrated to a total of 300 mg twice daily and she responded well to this. The patient's CBC was rechecked again 3 days later, revealing a platelet count within normal limits at 183,000/μL. After a 1-week stay, her manic and psychotic symptoms were resolved and her mood stabilized.

Ms. T. was discharged home with her parents on lithium 300 mg twice daily and lorazepam 1 mg three times daily to address her anxiety. She was followed closely in the partial-day hospital program for nearly 1 month after her discharge. Her dose of lorazepam was gradually tapered and finally discontinued during her stay in the partial-day hospital program. Ms. T. has done well on lithium, and her symptoms have continued to be in remission since her last hospitalization.

Discussion

To the best of our knowledge, this is one of the only known cases of thrombocytopenia associated with quetiapine in the treatment of an adolescent with bipolar disorder. A review of Medline and the existing literature indicates only two case reports that associate thrombocytopenia with quetiapine. Huynh et al. (2005) reported one case of thrombotic thrombocytopenic purpura (TTP) associated with quetiapine in a 25-year-old male. This case report differed from ours, however, in that the patient was prescribed only quetiapine. He developed TTP on two occasions 2 years apart.

Another case report of quetiapine-induced leukopenia and thrombocytopenia in a 45-year-old male was reported by Shankar in 2007. In this case report, the patient had already been prescribed 1,500 mg daily of valproic acid and lorazepam 2 mg twice daily. Quetiapine was started at 25 mg twice daily along with valproic acid and lorazepam. As quetiapine was gradually titrated, the patient's platelet levels and white blood cells continued to drop progressively until quetiapine was discontinued. This case report was different from ours in that the patient remained on valproic acid while taking quetiapine. Furthermore, the patient also developed leukopenia, which our patient did not. This case is similar to ours in that the author noted a dose-dependent drop in the patient's platelet count as the dose of quetiapine was increased.

In another study done by Perrella and colleagues (Perrella et al. 2007), 29 patients with borderline personality disorder were given quetiapine to treat their symptoms. Out of the 23 patients who completed the study, the authors found that 2 of the patients developed transient thrombocytopenia that occurred when their doses of quetiapine were advanced. In both cases, their thrombocytopenia resolved within 5–12 days of discontinuing quetiapine (Perrella et al. 2006). The authors noted that the average dose of quetiapine prescribed in their study was 543 mg, and they felt this higher dosage could have contributed to the patients developing thrombocytopenia.

Leukocytopenia and agranulocytosis can be seen during treatment with all known conventional antipsychotics, with the risk estimated at 0.01–0.14% (Shankar 2007). The highest risk of leukocytopenia and agranulocytosis remains with clozapine with an incidence of approximately 1–3% (Shankar 2007). Because quetiapine and clozapine are related in chemical structure and pharmacological profile, the same mechanism of bone marrow suppression could be hypothesized for quetiapine (Shankar 2007). Another potential mechanism for quetiapine causing thrombocytopenia was proposed by Pessina and colleagues (Pessina et al. 2006). In this study, the direct toxic effects of clozapine, olanzapine, and quetiapine on myeloid progenitors was studied using a previously standardized granulocyte-macrophage colony-forming unit (GM-CFU) assay. This study used chlorpromazine as the reference drug and found that toxicity of clozapine was the highest, followed by olanzapine and quetiapine. The authors noted that atypical antipsychotics may lead to agranulocytosis because of apoptosis caused by cells binding nitrenium molecules, establishing another possible mechanism by which quetiapine may cause thrombocytopenia.

Valproic acid has a long-established and well-known association with thrombocytopenia (PDR 2009). The rates of thrombocytopenia reported in the literature range from 0% to 40%, depending on the population under study. The risk of thrombocytopenia has been noted to be a dose-related effect, with patients at higher doses are at greater risk (Physicians Desk Reference 2009). In a clinical trial of valproic acid as monotherapy in patients with epilepsy, 34 out of 126 patients (27%) receiving approximately 50 mg/kg per day on average had at least one value of platelets less than or equal to 75,000/nL (Abbott Laboratories 2009). Valproic acid has been postulated to cause thrombocytopenia by inhibiting the second phase of platelet aggregation (Conley et al. 2001). In our patient, platelet count remained stable while on valproic acid and only started to drop as her dose of quetiapine was advanced. This occurred several days after valproic acid had already been discontinued.

We feel that several valuable points can be learned from this case. The potential medical consequences of thrombocytopenia can be life threatening, with intracerebral hemorrhage and gastrointestinal hemorrhage being the two most common complications in patients with platelet counts less than 20,000/nL (Fauci et al. 2008). According to practice-based guidelines from the National Guideline Clearinghouse (endorsed by the U.S. Department of Health and Human Services), physicians should start following CBCs at regular intervals of even symptomless patients with platelet counts between 100,000 and 150,000/μL. For patients who develop thrombocytopenia with platelets counts below 100,000μL, a referral to a specialist in internal medicine or hematology is recommended. Basic investigations including a CBC with differential and peripheral smear should also be done. Physicians should carefully review the patient's complete list of medications, and any medications that may potentiate thrombocytopenia should be discontinued. It is important to be careful to not assume that all cases of thrombocytopenia are attributable to valproic acid, especially in cases where this has been discontinued for several days prior.

Conclusions

In summary, psychiatrists should be cognizant of side effects of medications that are not common. Antipsychotics such as quetiapine have been associated with thrombocytopenia, and it is important for the treatment team to also consider the antipsychotic medication when trying to establish an etiology for a patient's thrombocytopenia.