Psychosomatics 40:414-421, October 1999
© 1999 The Academy of Psychosomatic Medine
Hematologic Side Effects of Psychotropics
Olu Oyesanmi, M.D.,
Elisabeth J.S. Kunkel, M.D.,
Daniel A. Monti, M.D., and
Howard L. Field, M.D.
Received October 9, 1998; revised January 4, 1999; accepted February 17, 1999. From the Department of Psychiatry and Human Behavior, Jefferson Medical College, Philadelphia, Pennsylvania. Address correspondence and reprint requests to Dr. Kunkel, Jefferson Medical College, 1020 Sansom Street, Thompson Bldg., Suite 1652, Philadelphia, PA 19107–5004.
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ABSTRACT
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Psychiatrists are often unaware of the potential hematologic complications of the psychotropics they prescribe. Although this review is not a hematologic text reference, relevant hematologic syndromes are described so that the consultation-liaison psychiatrist will be familiar with the usual signs, symptoms, and treatments of these syndromes. This article reviews the hematologic side effects of the commonly prescribed psychotropics, including antipsychotics, antidepressants, benzodiazepines, lithium, mood stabilizers (including some of the anticonvulsants), and the acetylcholinesterase inhibitors. Clinical signs and symptoms that should alert the physician to obtain a complete blood count are described.
Key Words: Side Effects, Hematologic • Psychotropics • Pharmacology
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INTRODUCTION
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Drug-induced hematologic problems are rare, but potentially life-threatening, side effects of psychotropics. The incidence of significant hematologic side effects is 1 to 2 cases/year per 100,000 subjects. Caucasian women and the middle-aged are at highest risk for hematologic side effects. Mortality rates from hematologic sequelae of psychotropics range from 8% to 17%.1 In order of descending frequency, serious hematologic side effects of psychotropic drugs include neutropenia, agranulocytosis, eosinophilia, thrombocytopenia, purpura, and anemia.2 Other side effects include leukocytosis, thrombocytosis, and altered platelet function.3 Although a precise pathophysiologic understanding of the hematologic side effects is lacking, different mechanisms have been postulated (e.g., bone marrow suppression, immune-related cell destruction, direct marrow toxicity).4,5
When hematologic problems arise in a patient taking psychotropic agents, it is important to consider possible contributing factors, such as anemia secondary to poor nutrition,6 medical illnesses,7 and other medications such as the nonsteroidal anti-inflammatory drugs that may increase the risk of hematologic problems in patients with low platelet counts. Liver disease itself can result in hematologic abnormalities, as the liver is the primary site of coagulation protein synthesis;5 some psychotropic medications also can cause hematologic problems due to hepatic dysfunction. Certain clinical signs should alert the physician to obtain a complete blood count (CBC). A CBC may be indicated to rule out infection, malignancy, hematologic problems, etc. (see Table 1).
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TABLE 1. Some important clinical signs/symptoms that may indicate the need to obtain a complete blood cell count as part of the patient's clinical evaluation
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Hematologic side effects occur more often at the start of treatment. Agranulocytosis usually appears about 21–28 days after starting treatment and may last up to about 3 months.8 Except for aplastic anemia, most hematologic side effects usually disappear after stopping the drug, without any adverse sequelae.5 In cases of serious hematologic side effects or preexisting hematologic problems, collaboration with the patient's primary care physician is probably warranted.
We briefly review several hematologic syndromes to help the consultation-liaison psychiatrist understand the problems such patients face. We then address the specific complications of several psychotropic classes of medications; this review should help guide psychotropic management of such patients, thereby minimizing the risk of exacerbating the patient's drug-induced or primary hematologic problem.
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HEMATOLOGIC SYNDROMES
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The clinical presentations of several serious hematologic syndromes are reviewed in the following sections. Agranulocytosis and aplastic anemia are discussed first, as they are associated with the highest mortality. Other syndromes are discussed in order of descending frequency. The treatment of choice for all these conditions is to immediately stop the causative agent.
Agranulocytosis occurs when the bone marrow stops production of granular leukocytes, leaving the body vulnerable to bacterial infection. Although the term "agranulocytosis" literally means a complete absence of the granular leukocytes (see Table 2), the term is often used to indicate a state of severe neutropenia.9 The CBC count has a characteristically low white blood cell (WBC <500 cells/mm3) count almost entirely composed of lymphocytes and monocytes. The hematocrit and platelet counts are normal.5 Clinical symptoms include headache, fever, sore throat, oral mucosa infection, fatigue, pharyngeal ulcers, urinary frequency, and bleeding gums.
Of the various drug-induced blood dyscrasias, agranulocytosis is known for its high mortality. Before the use of antibiotics, the mortality rate from agranulocytosis was about 80%, with death resulting from septicemia or pneumonia.10 Currently, infection is managed with intravenous antibiotics. Transfusion of granulocyte-stimulating factors (GSFs) should be reserved for patients who fail to respond after a 72-hour trial of appropriate antibiotics. Usually after the causative drug has been discontinued, the WBC count normalizes and the infection resolves. Due to the rapid onset of agranulocytosis, one cannot solely rely on decreasing WBC counts to herald this problem; hence, the prescribing physician also should watch for clinical symptoms of infection, such as sore throat, dry cough, fever, etc.5 Because of the severity of this complication, patients with agranulocytosis need to be admitted to a hospital for aggressive antibiotic treatment. The challenge for the clinician is to distinguish ordinary viral pharyngitis from early agranulocytosis. Particular caution is warranted in patients taking clozapine, carbamazepine, or conventional antipsychotic agents.
Aplastic anemia, or pancytopenia, is a clinically serious medication side effect that can cause infection and result in death.11 The criteria for diagnosis are as follows: neutrophil count <500/ul, platelet count <20,000/ul, corrected reticulocyte count <1%, and anemia with hemoglobin concentration <10g/dl. Lymphocytes and monocytes are not affected. Symptoms include lassitude, purpura, bleeding, infection with fever, pallor, and tachycardia. Bone marrow aspirates typically show empty fatty spaces and few hematopoietic cells. The hypocellularity is secondary to a marked decrease in megarkaryocytes, granulocytes, and erythroid cells. The hematocrit drops less precipitously than other cell lines, because the half-life of red cells is about 120 days. Interventions beyond discontinuation of the causative drug are sometimes required, such as blood transfusion; corticosteroids; granulocyte-stimulating factor (GSF); lithium carbonate (to induce leukocytosis, see next section); bone marrow transplant (in young patients); and antibiotics, when there is documented infection. Prophylactic use of antibiotics in afebrile neutropenic patients has little benefit, and antibiotics are not routinely used. Rather, antibiotic treatment favors the development of resistant strains of bacteria.12
Neutropenia is defined as a consistently low neutrophil count <1,500/mm3.9 Neutropenia can be due to reduced production, as seen with the use of carbamazepine, or increased peripheral destruction, as seen with the phenothiazines. Neutrophils comprise 45%–74% of the total leukocyte count (see Table 3). Their main physiologic function is phagocytosis of foreign bodies and defense against bacteria infection. Clinical symptoms of severe neutropenia include rash, aches, fever, and sore throat. The CBC may show an increase in bands (immature neutrophils). Infections are unusual, with WBC counts between 1,000–1,500/mm3, and are more common between 500 and 1,000/mm3. Severe infections are seen with counts below 500/mm3. Treatment is to stop the psychotropic medication.
Eosinophilia is diagnosed when the eosinophils exceed between 350 and 500 cells/mm.3,9 Eosinophils normally constitute up to 7% of total circulating leukocytes. Eosinophils are important in the phagocytosis of foreign bodies. Eosinophils also are involved in allergic reactions and may be involved in coagulation. Eosinophils infiltrate the involved tissues and are thought to cause tissue damage by local deposit of toxic eosinophil proteins (e.g., eosinophil cationic protein and eosinophil major basic protein). Patients can present with dry cough, chest pain, dyspnea, diarrhea, weight loss, pneumonitis, neck ache, stiffness, and central nervous system symptoms. The treatment of eosinophilia is to discontinue the drug.
Thrombocytopenia occurs when platelet counts drop below 130,000/mm3, usually resulting in abnormal bleeding. Bleeding time is generally prolonged. The greatest risk of severe bleeding occurs at platelet levels below 10,000/mm3. However, at platelet counts <20,000/mm3, there is increased risk of spontaneous bleeding.13 The most feared complication of thrombocytopenia, intracranial bleeding, occurs at platelet counts <2,000/mm.3,14 The treatment of choice is stopping of the suspected agent.4 Platelet transfusions are indicated for very severe thrombocytopenia, or if evidence of bleeding exists.
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SIDE EFFECTS OF SPECIFIC TYPES OF PSYCHOTROPIC AGENTS
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After summarizing the features of the relevant hematologic syndromes, it is useful to review the hematologic side effects of the various classes of psychotropics that are commonly prescribed.
Antipsychotics
Of all the hematologic side effects seen with the use of the classic neuroleptics, agranulocytosis is the most common (<0.1%).15 Other side effects include aplastic anemia, leukopenia, lymphomonocytosis (elevation of the nongranular WBCs), and thrombocytopenia (see Table 2 and Table 4). Low-potency neuroleptics have a higher frequency of agranulocytosis than high-potency drugs. Table 2 and Table 4 include all reported hematologic side effects.
Clozapine (ClozarilTM) is a newer, atypical antipsychotic agent that has met with much success in treating patients with refractory psychoses and patients who have had problems with tardive dyskinesia. Careful evaluation before starting treatment with clozapine is necessary because of potentially life-threatening agranulocytosis.16 The Clozaril National Registry reported 12 deaths that were attributed to agranulocytosis from clozapine use.17 While clozapine-associated agranulocytosis has been reported extensively (incidence: 1%–2%), recent publications have identified that eosinophilia also may be of concern. Worldwide, there have been 25 reported cases of eosinophilic cardiomyopathy secondary to clozapine; of these, four patients died and their deaths were attributed to the eosinophilic cardiomyopathy.18 Clinicians should be alerted to the clinical consequences of both agranulocytosis and eosinophilia in patients receiving clozapine.
All patients on clozapine must receive weekly WBC counts. Patients with a past medical history of agranulocytosis or blood dyscrasias due to other drugs can be placed on clozapine, but these patients must be closely monitored, especially during the first 6 months, a period that includes the peak risk period (the first 18 weeks of treatment). Recent data on weekly WBC counts from patients treated with clozapine suggest that with close monitoring, the risk of agranulocytosis is relatively low (0.8% of patients receiving clozapine). A WBC count <2,000/mm3 or an absolute neutrophil count (ANC) <1,000/mm3 are indications for immediate cessation of clozapine. If the WBC falls <1500/mm3, or the ANC is less than or equal to 1,500/mm3, clozapine therapy should never be resumed. Agranulocytosis is an indication for hospitalization. Once admitted, reverse isolation and a full septic workup can proceed. Prophylactic use of antibiotics is often advisable. If infection starts before clozapine is stopped, the mortality risk associated with agranulocytosis is significantly increased.16 Usage of one of the known GSFs may help to restore normal bone marrow production.16,19
Antidepressants
A variety of hematologic side effects are seen with the antidepressants (see Table 5A and Table 5B). Agranulocytosis due to the tricyclic antidepressants (TCAs) is a rare, idiosyncratic condition caused by direct bone marrow toxicity, with a lower frequency than is reported for neuroleptics. Only ten cases of agranulocytosis secondary to the TCAs have been reported in the literature; they all occurred during treatment with imipramine (TofranilTM).20,21 Clinical symptoms of agranulocytosis may be overlooked in patients receiving TCAs, because early symptoms are also manifestations of depression (e.g., fatigue, malaise). With discontinuation of the TCAs, and supportive treatment, patients feel better within 1 week.20 Agranulocytosis has also been reported in patients taking mirtazapine (RemeronTM), with an incidence of 1.1/1,000 patients.22
The selective serotonin reuptake inhibitors (SSRIs) recently have come under scrutiny because of their association with reports of bruising and bleeding.23 SSRIs increase central nervous system 5-HT, and reduce 5-HT in the platelets (leading to a reduction in aggregability of the platelets). Notably, more than 99% of whole-body serotonin is found in the platelets. Normally, platelets release serotonin at vascular tears, which allows torn vessels to seal without thrombosing. Blood vessel tonicity can be affected by the released serotonin through various mechanisms, such as contraction via 5-HT2 receptors, and endothelium-dependent relaxation via 5-HT1 receptors. In intact blood vessels, platelet aggregation leads to vasodilatation, which limits occlusive damage; whereas in the damaged blood vessels, aggregation of platelets causes vasoconstriction, reducing blood loss.24
The 5-HT2 receptor mediates serotonin-induced platelet aggregation; this aggregation can be blocked experimentally by ketanserin (a 5-HT2 selective receptor antagonist).25 The SSRIs inhibit the reuptake of serotonin into the platelet, depleting the platelet serotonin stores, and reducing platelet aggregability. Continued use of SSRIs decreases platelet serotonin stores and predisposes patients with mild underlying platelet disorders to SSRI-induced bruising or bleeding. Such patients have impaired platelet aggregation, prolonged bleeding time (BT), increased prothrombin time (PT), and increased partial thromboplastin. Concomitant use of nonsteroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen) may aggravate the bleeding tendency.
Skop and Brown26 described 15 cases of SSRI-related bleeding in association with fluoxetine (ProzacTM), fluvoxamine (LuvoxTM), and paroxetine (PaxilTM) administration. Symptoms included ecchymosis, menorrhagia, petechiae, bleeding internal hemorrhoids, epistaxis, ulceration with hemorrhage, and melena. Fluoxetine was the most common offending agent (personal communication, Skop B and Brown T, 1998). In another study, it was demonstrated that fluoxetine prevents serotonin-induced amplification of platelet aggregation.27 Fluvoxamine administered for 12 weeks at 100–150 mg/d reduced platelet serotonin to 11% of pretreatment concentrations.28 Patients with thrombocytopenia, suspected platelet dysfunction, or a history of unexplained bruising or bleeding should be monitored carefully when placed on fluoxetine or the other SSRIs.
Concerns about drug interactions between warfarin and the SSRIs has arisen because of the possible effects the SSRIs can have on warfarin metabolism. Cytochrome P450 is important in the metabolism of many psychotropics. Fluvoxamine inhibits the cytochrome P4501A2 system, and fluoxetine inhibits the cytochrome P4502C9 system.29 As both these systems help metabolize warfarin, theoretically, warfarin levels and prothrombin time could be increased to dangerous levels with simultaneous administration of these drugs and warfarin.29 While SSRI-induced bleeding is usually seen as problematic, this side effect was capitalized on by the makers of citalopram, an SSRI that was recently patented for the prevention of stroke.30 Laboratory animal studies by the manufacturer of citalopram showed that it is effective in preventing platelet aggregation. These studies led to Food and Drug Administration approval of citalopram for its use in lowering the risk of thrombotic complications from stroke.
If an SSRI is to be used in a patient following myocardial infarction, checking the PT and BT before surgical procedures is recommended. Before elective surgery, Beliles and Stoudemire recommend that fluoxetine should be discontinued in patients with documented elevation of bleeding time.31 It is not clear if this recommendation is warranted for the other SSRIs as well. For emergency surgical procedures, the clotting time can be adjusted by administering fresh frozen plasma or clotting factors.31,32
Benzodiazepines
Agranulocytosis due to benzodiazepines has been reported rarely.2 A direct causal relationship has not been established. Thrombocytopenia has been described with clonazepam (KlonopinTM)22 and diazepam (ValiumTM)22,33 (see Table 6). Diazepam and chlordiazepoxide (LibriumTM) also can reduce platelet aggregation. There is no definitive relationship between the daily dose or total cumulative dose and the occurrence of hematologic side effects.4 Clonazepam can also cause anemia, eosinophilia, and leukopenia.
Lithium
Following therapeutic doses of lithium, fairly reproducible hematopoietic effects have been documented. Lithium-induced stimulation of leukocytosis involves a true proliferative response; it is not just a shift of cell populations from the marginating to the circulatory pool of cells. Lithium may also induce thrombocytosis; the mechanism for this is unclear.34 In patients on lithium carbonate therapy for cluster headache, Medina et al. documented increases, both in the number of platelets and in serotonin and histamine levels.35 Hayes and Hargreaves reported inhibition of blood coagulation and fibrinogen precipitation with the use of lithium.36
Lithium-induced hematologic side effects are sometimes used to manage hematologic toxicities associated with other agents and disorders. For example, lithium-induced neutrophilia has been used alongside cytotoxic agents while treating malignancies such as lymphomas, acute myelogeneous leukemia, aplastic anemia, and Felty's syndrome (chronic rheumatoid arthritis, splenomegaly, neutropenia, and, on occasion, anemia and thrombocytopenia).
More recently, hematologic studies of lithium have highlighted its potential role in reducing the hematopoietic toxicity of azidothymidine (AZT). AZT-induced depletion of cell lines can be reversed with lithium. In addition to AZT's effectiveness in producing immunological improvement (decreasing the incidence of opportunistic infections and reducing AIDS mortality), AZT causes anemia, neutropenia, and overall bone marrow suppression.37
Anticonvusants/Mood Stabilizers
In patients receiving carbamazepine (TegretolTM), agranulocytosis is the complication of greatest concern. Carbamazepine should be avoided in patients with a past medical history of bone marrow depression. A baseline CBC always is advised before starting treatment with carbamazepine. Carbamazepine produces a transient reduction in WBCs in about 10% of patients during the first 4 months of treatment.38 In extremely rare cases, carbamazepine produces potentially fatal agranulocytosis and aplastic anemia.
In most cases, carbamazepine should be discontinued if the WBC count drops below 3,500/mm3. In situations in which the indications for carbamazepine are very strong, or if a concurrent medical problem is contributing to the decreased blood count, then consultation with the patient's primary care physician is needed to assist in determining the appropriate frequency of monitoring WBC counts and cutoffs for drug discontinuation or in obtaining additional input from a hematologist. Administration of lithium and carbamazepine concurrently lowers the risk for carbamazepine-induced neutropenia, because lithium stimulates WBC production. Therefore, the lithium–carbamazepine combination might be an option for patients with concurrent hematological problems, in whom the WBC count is suppressed, and in those who have bipolar disorder unresponsive to lithium alone.39,40
In patients receiving valproate (DepakoteTM), Ozkara et al.41 noted increases in red blood cell mean corpuscular volume and mean corpuscular hemoglobin concentration values. The researchers postulated a generalized effect, resulting from alterations in erythrocyte membrane phospholipids.41 Neutropenia, thrombocytopenia, and macrocytic anemia also have been reported in valproate-treated patients42 (see Table 7).
Lamotrigine (LamictalTM) and gabapentin (NeurontinTM) are anticonvulsants that recently have been used as mood stabilizers in patients with bipolar disorder.43,44 Lamotrigine has been shown to have a weak inhibitory action on dihydrofolate reductase in vitro;45 however, this effect has not proven to be clinically significant. Cocito et al. observed macrocytic anemia in a patient on lamotrigine after 23 months.46 Leukopenia has been reported in about 1% of patients treated with gabapentin.47 Gabapentin should be discontinued when the WBC count decreases to less than 3,000/mm3.48
Acetylcholinesterase Inhibitors
In trial studies, donepezil (AriceptTM) was found to be associated with hematologic side effects such as anemia, thrombocythemia, thrombocytopenia, ecchymosis (4%), and eosinophilia. The mechanism for the side effects of donepezil is not known (personal communication, spokesman for Eisai Inc., 1998). Purpura may occur in 2% of patients on Tacrine (CognexTM). So far, only one case of agranulocytosis has been reported due to Tacrine.22
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DISCUSSION AND CONCLUSIONS
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Agranulocytosis has a high mortality risk, and has been associated with administration of the antipsychotics, the TCAs, mirtazapine, chlordiazepoxide, and carbamazepine. Similarly, aplastic anemia has been seen in patients on conventional antipsychotic agents and carbamazepine. Other hematologic side effects seen with use of psychotropics include neutropenia and leukocytosis, eosinophilia, purpura, anemia, thrombocytopenia and thrombocytosis, and altered platelet function.5,10,22,33,49–52
The authors of this paper review the more serious and more frequent hematologic syndromes and then discuss their association with specific classes of psychotropics. This review serves as a reference for internists and hematologists who consult on psychiatric patients, consultation-liaison psychiatrists, and for general psychiatrists who may encounter such problems in their patients. In most cases, the treatment is to stop the offending psychotropic agent. In syndromes associated with high mortality, the patient's primary care physician should be involved in all decisions, so that he/she can then refer these patients accordingly.
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ACKNOWLEDGMENTS
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The authors thank Dr. Jaime Caro, Division of Hematology, Department of Internal Medicine, Thomas Jefferson University, for his input and medical advice in their preparation of this manuscript, and Dr. Alan Stoudemire for inspiring us to write this article.
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ABSTRACT
INTRODUCTION
