Use of clozapine alongside chemotherapy in a treatment-resistant bipolar disorder patient with ovarian carcinoma: A case report and brief review.

Regular monitoring of blood counts ensures the safety of clozapine use; however, certain clinical situations may pose a dilemma for management such as use of clozapine in the presence of myelosuppressive chemotherapy. Further, there is very limited literature to guide such decisions. We report a case of a clozapine-stabilized, treatment-resistant bipolar disorder patient with ovarian carcinoma requiring chemotherapy. The clinical challenges are discussed in light of a brief review of the available reports.

INTRODUCTION

Clozapine has demonstrated superior efficacy in the management of treatment-resistant schizophrenia and bipolar disorder.[1] Regular monitoring of blood counts ensures the safety of clozapine use; however, certain situations may pose a dilemma.[23] One such difficult scenario is decision about clozapine use with myelosuppressive chemotherapy. No controlled studies are feasible in this context for obvious reasons and it is not a common encounter in psychiatric settings, with just a few cases reported worldwide.

We report a case of a clozapine-stabilized, treatment-resistant bipolar disorder patient with ovarian carcinoma requiring chemotherapy. The clinical challenges are discussed in light of a brief review of the available reports.

CASE REPORT

Ms. A, 38-year-old, unmarried female, educated till 9th standard, is a known case of obsessive-compulsive disorder[4] since 8 years of age, and bipolar affective disorder[4] since 22 years of age. She has been on regular treatment, with highly inadequate control of illness, multiple hospitalizations, and modified electroconvulsive therapies (MECTs) since adolescence. Following a failure to respond to several psychotropic medications/combinations thereof, the patient was finally initiated on clozapine (200–300 mg/day) in addition to lithium (900 mg/day; adequate serum levels) in the year 2002, with a remarkable decrease in the frequency and duration of episodes. Improvement continued with a further addition of lamotrigine since 2007 (to control intermittent mild depressive episodes). On these medications, course was stabilized. There was no need of any further hospitalization between 2002 and 2014. She continued to have brief hypomanic episodes twice or thrice a year. In addition, the patient had hypertension, hypothyroidism (possibly, lithium-induced), and obesity (body mass index: 33.8). The medical illnesses were under control on regular treatment.

In July 2014, the patient was diagnosed to have ovarian carcinoma (papillary adenocarcinoma Stage IIIC). In the same month, she underwent operative surgery (total abdominal hysterectomy with bilateral salpingo-oophorectomy and debulking), with a plan to initiate chemotherapy with carboplatin. A review of psychiatric management was warranted since carboplatin is known to be associated with a significant drop in blood counts in the course of treatment. Due to high likelihood of developing cytopenia with chemotherapy and difficulty in identifying the culprit drug, after several discussions, it was planned that clozapine may be tapered off gradually (at least during chemotherapy). Lithium and lamotrigine were continued as before.

Chemotherapy cycles were started at a dose of 200 mg in 5% dextrose on a weekly basis (one full cycle of chemotherapy involved three sessions of weekly carboplatin followed by 3 weeks gap, i.e., 6 weeks in total). Before each chemotherapy, complete blood counts and renal function test were checked.

Around 2 weeks after the cessation of clozapine, the patient started to have manic symptoms with irritable mood, increase in goal-directed activity, demandingness, reduced sleep, and occasional aggression. Lithium levels were within therapeutic range (0.87–1.1 mEq/L) and thyroid function tests were within normal limits. Haloperidol was added and increased to 20 mg/day with only a mild improvement in her symptoms. The patient was discharged after three full cycles of chemotherapy, with a plan to continue the rest three cycles from her hometown. The manic symptoms increased in ensuing weeks, posing difficulty in managing her at home.

The patient received the 4th chemotherapy in her hometown, which was associated with a drop in blood counts within 3 weeks (Hemoglobin: 7 g/dL, total lymphocyte count: 1800 cells/µL, neutrophils: 600 cells/µL, platelet: 38,000/µL, and dipping further to 18,000/µL), after which they again presented. After consulting a hematologist and a medical oncologist, it was considered to be postchemotherapy drop, with advice to manage it conservatively (and a plan to initiate granulocyte colony-stimulating factor [G-CSF] in case of further decline/complications). The patient was readmitted for monitoring. Repeat counts over the next week came out to be trending upward.

As the patient had not shown response to haloperidol for optimum dose and duration, the reintroduction of clozapine was considered in addition to on-going lithium and lamotrigine. At this point, both clozapine versus MECT were considered as possible options, however it was decided first to go in favor of clozapine in view of excellent response to clozapine in the past few years stabilizing the course of illness and a definite requirement of long-term prophylaxis in her case. Risk benefits of clozapine were reassessed and the decision was finalized only after discussion with the patient's family members. Close monitoring and interdepartmental liaison were kept. Clozapine was initiated and built up more gradually, 12.5–25 mg for every 3–4 days. When the weekly chemotherapy dose was due, the dose of clozapine was kept static for additional 2–3 days. A final dose of 275 mg/day was reached with regular monitoring of blood counts. She continued to receive two further chemotherapy cycles over coming weeks. Steady improvement in her mood and behavioral symptoms paralleled the buildup of clozapine dosage. The patient was subsequently discharged in early 2015 with no further drop in blood counts at any other point.

For the past 1 year, the patient continues to be in active follow-up with no recurrence of carcinoma and largely stabilized on previous medications (viz., clozapine, lithium, and lamotrigine).

DISCUSSION

This report contributes to a very limited literature on the concurrent use of clozapine with chemotherapy, which is expected to cause a significant drop in blood counts in the usual course. The initial options involve discontinuing clozapine or replacing it with another antipsychotic drug/s, or concurrent administration of clozapine and chemotherapy with careful monitoring. On one hand, the circuitous path of withdrawing a medication on which a treatment-resistant patient is stabilized may compromise psychiatric stability, yet there is a valid argument that such inconvenience would pale in the face of serious hematological risks. Such difficult decisions could also be better informed if the evidence support becomes more robust and elaborates on the various clinical considerations.

A PubMed-based literature search (1995–2015), followed by cross-references search, using relevant keywords found only 16 case reports worldwide (one from India) reporting clozapine use during chemotherapy. These have been summarized in Table 1.[567891011121314151617181920] In some cases, initially, it was decided to discontinue clozapine, but it had to be reintroduced after a failed trial with another antipsychotic drug/s.[891216] Leukopenia/neutropenia was observed in a large majority (all except three) of these reports, it was attributed to consequent drop of chemotherapy. Usually, it normalized over the next few days on its own. A precaution which has been taken in several reports is the modified white blood cell monitoring protocol, i.e., for every 2 days as opposed to weekly in the presence of leukopenia. It is important to discuss with oncologists whether the clinical presentation is consistent with chemotherapy-induced leukopenia. In some case reports, G-CSF administration was required after the drop in blood counts.[14]

Table 1

Clozapine use during chemotherapy: A review of indexed literature (1995-2015)

Some studies have suggested the concurrent use of G-CSF along with clozapine, when the counts are low. Although the G-CSF guidelines restrict its use as a primary prophylaxis (to patients with ≥20% risk for febrile neutropenia based on patient-, disease- and treatment-related factors),[21] it has been given along with chemotherapy and clozapine in few case reports.[1216] Lithium may also promote leukocytosis[22] and it is suggested to be potentially beneficial in patients with leukopenia. In this patient, lithium was continued for her psychiatric condition, but may have contributed beneficially to blood counts.

Clinicians from western countries have to apply for a “waiver” from manufacturer to use clozapine in such exceptional circumstances. Even then, clozapine has to be stopped in the event of severe reduction in blood counts. Till date, there is no nationwide clozapine registry in India. Nonetheless, clinicians need to clearly document the reasons favoring the continuation of clozapine and consent of family members.

The mechanism of clozapine-induced agranulocytosis remains controversial. The pathophysiological mechanisms may involve genetic susceptibility or immune-mediated toxicity. A possible activation of common apoptotic pathways by clozapine, similar to anticancer drugs, has also been hypothesized, but no concrete evidence points to such a synergistic effect. Clozapine-induced leukopenia usually occurs within the 1st year of initiation, and it is nondose dependent and idiosyncratic, which contrasts with its predictable occurrence at the nadir of chemotherapy. There is a need for further research on the underlying mechanisms causing agraulocytosis.

To resolve the dilemma, we considered three points of utmost importance in guiding the decision/s, namely, (1) a careful risk-benefits assessment, depending on the patient's oncological status and psychiatric condition, (2) detailed discussion with patient/family members and their consent, and (3) availability of strong consultation-liaison services, with support from medical oncology, hematology, and emergency medicine.

At times, there is a need to make calculated decisions and take “acceptable” risks, along with watchful monitoring and high level of preparedness. This case highlights one such instance and adds to very limited reports worldwide with the concurrent use of clozapine and chemotherapy.

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Conflicts of interest

There are no conflicts of interest.