second generation antipsychotics like olanzapine first came into use in the 1990s and have widespread use due to presumed higher efficacy , less extrapyramidal side effects and fewer adverse drug interactions . although known to produce side effects such as weight gain and metabolic syndrome , a lesser studied phenomenon associated with olanzapine therapy is granulocytopenia . several mechanisms have been proposed as being responsible for the neutropenia generated by these drugs . one mechanism suggests that these drugs may modulate levels of granulocyte colony stimulating factor ( g - csf ) . it is expressed at enhanced levels during increased granulocyte counts . in clozapine and olanzapine - induced granulocytopenia , although the exact mechanism of interaction between these typical antipsychotics and g - csf is not clear , the relationship warrants further study . a second proposed mechanism for clozapine - induced neutropenia is the formation of nitrenium cations catalyzed by flavin - containing monoxenage-3 ( fmo3 ) system of leukocytes . although classified as a thienobenzodiazepine , olanzapine has a similar chemical structure and pharmacological profile to clozapine , thus , it is likely that its mechanism of action in inducing neutropenia is similar to that of clozapine . this case study provides an example and discussion of a patient with schizophrenia experiencing neutropenia suspected to be caused by olanzapine . the purpose of this report is to evaluate the relationship between olanzapine , drug - induced neutropenia , and other contributing factors and to inform clinicians of such possible side effects when considering use of olanzapine . a 27-year - old healthy caucasian male with a history of schizophrenia was hospitalized for severe exacerbation of psychosis . he was hospitalized for 87 days and during this time he was treated with olanzapine , fluoxetine , ziprasidone , valproate , lurasidone , and fluphenazine . thirty - two weeks prior to admission , the patient had 2 ed visits over the course of two weeks while on olanzapine 15 - 20 mg daily with white blood cell ( wbc ) 5.910/l downtrend to 5.010/l and absolute neutrophil counts ( anc ) 4.910/l to 2.310/l ( wbc reference range 4.0 - 10.510/l ; anc reference range 2.0 - 8.110/l ) . on admission , he was started on olanzapine 15 mg with a wbc of 3.510/l and his anc was 1.410/l , within the category of mild neutropenia ( anc > 1000 and < 1500 cells/l ) . the patient did well for the following weeks while hospitalized , with an addition of fluoxetine 10 mg daily as an adjunct for treatment of depression on hospital day 28 and increased to 20 mg on hospital day 37 . forty - one days into his hospitalization , the patient s wbc count remained low . two months into his hospitalization , patient began responding to internal stimulus , endorsed auditory hallucinations , and became hyper - religious in thought process . at hospital day 60 , the patient s wbc and anc remained low ( figure 1 ) . clozapine was initially discussed as a potential treatment option but as the patient s anc was below initiating parameters ( wbc 3.510/l and anc 2.010/l are acceptable for initiating clozapine ) , a trial of clozapine was excluded . ziprasidone , was noted to have been effective for treatment of psychosis in the patient s mother who also has schizophrenia and thus he was started on ziprasidone 40 mg ( bis in die ) bid on hospital day 60 with the intent to cross - taper olanzapine . however , patient reported feeling restless on ziprasidone and no longer wished to continue the cross - taper . sixty - two days into hospitalization , the patient s wbc and anc declined ( figure 1 ) . on hospital day 64 , the patient was also started on valproate er 1500 mg nightly for mood stabilization . his valproic acid serum level was measured to be at a therapeutic level of 81 mg / l on day 67 ( therapeutic range from 50 to 100 mg / l ) . at hospital day 73 , follow - up wbc remained low and his anc trended down ( figure 1 ) . patient was also noted to have decreasing sleep and appeared euphoric , hyper - religious and grandiose . these symptoms were thought to be fluoxetine - induced and it was titrated off on hospital day 75 . at this time , he was also started on lurasidone 40 mg with the intent to titrate off olanzapine due to 15 kg weight gain since admission . lurasidone was titrated to 80 mg and olanzapine was decreased from 40 mg to 30 mg . however , patient s psychotic symptoms worsened , therefore lurasidone was discontinued and the patient was started on fluphenazine 5 mg bid on hospital day 82 . four days later fluphenazine was increased to 10 mg bid for persistent psychotic symptoms . at discharge , patient was psychiatrically stable and discharged to a residential treatment center with olanzapine 30 mg nightly , valproate er 1500 mg nightly , and fluphenazine 10 mg bid . the patient is a 27 year old caucasian male with no known history of hematologic disease or previous episodes of antipsychotic - induced granulocytopenia or neutropenia . additionally , he did not exhibit symptoms of infection and did not require any special medical treatment or work - up . although there has not been a clear link between fluoxetine and neutropenia , there have been case reports of fluoxetine - induced neutropenia . however , this patient was neutropenic prior to starting fluoxetine and his wbc and anc levels did not appear to change with higher doses of fluoxetine . however , the addition of valproate to the patient s regimen did not reveal a further decrease in wbc and only showed a slight decrease in anc from 1.710/l to 1.610/l . thus , valproate is less likely to be the predominant contributor to the patient s hematologic depression . another potential cause of the patient s neutropenia may have been related to his history of substance use . upon admission , the patient admitted to using methamphetamine five days prior to admission , marijuana twice in the previous month , and injecting heroin three times in the previous month . while there is no clear causal link between illicit substances and neutropenia , there are several case reports as well as a surveillance study reporting neutropenia due to use of cocaine or heroin contaminated with levamisole ( ergamisole ) , a hydrochloride salt with antihelmithic and immunomodulatory property . the patient was not evaluated for levamisole in his urine upon admission , was only mildly neutropenic during his hospitalization and otherwise asymptomatic . as a result , it is unclear whether contamination of illicit substances may have played a role in this patient s neutropenia or the concurrent use of heroin or amphetamine with olanzapine may have potentiated neutropenia . prior to admission and throughout his hospitalization , as the patient was neutropenic early in his admission , it is possible his home medication of olanzapine may have caused hematologic depression prior to admission . it is convincing that while on olanzapine in the hospital , the patient remained slightly hematologically depressed with wbc and anc levels below reference range . therefore , it is likely that the patient s hematologic depression was due to his olanzapine use . although multiple attempts had been tried to titrate off of olanzapine to observe any normalization of his wbc and anc , his wbc and anc levels increased only slightly during his hospitalization but remained below reference range . should his wbc and anc have continued to rise while on olanzapine , this finding would have been consistent with case reports of transient granulocytopenia with spontaneous resolution despite continued olanzapine treatment . two hypothesized risk factors are a previous history of antipsychotic - induced neutropenia/ agranulocytosis ( including clozapine - induced neutropenia / agranulocytosis ) , and a dose - dependent effect of antipsychotic - induced hematologic depression . the mechanism for olanzapine s effect on hematologic function is currently unknown , however due to chemical structural similarities to clozapine , the mechanisms are thought to be similar . this case report represents evidence of neutropenia induced by olanzapine use . although poorly described in literature , olanzapine - induced neutropenia is a potentially serious side effect that should be considered with the use of olanzapine . further studies are needed to investigate the mechanism and risk factors for olanzapine - induced neutropenia . one risk factor to be considered may be concurrent use of heroin or amphetamine contaminated with levamisole with olanzapine . additionally , there are currently no guidelines for examining wbc and anc levels with olanzapine dosing , but this case emphasizes the importance of monitoring cbc at higher dosages of olanzapine .
olanzapine - induced neutropenia is a rare adverse effect that is currently poorly described in literature . 
 although neutropenia is a known adverse effect of clozapine , it has been associated with the use of other antipsychotic medications like olanzapine . 
 this case report describes and reviews a case of olanzapine - induced neutropenia in a schizophrenic patient . 
 although the mechanism of antipsychotic - induced neutropenia is still debated , this report attempts to discuss current theories as well as supply evidence in literature of this rare but potentially dangerous adverse effect .