Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine

Tsuda, Yoshiyuki; Saruwatari, Junji; Yasui‐Furukori, Norio

doi:10.1136/bmjopen-2013-004216

“…3 The relationship between smoking and plasma clozapine levels has been the subject of numerous reports. 5 As expected, we did find differences in dose-adjusted plasma clozapine levels in our sample, with the group who smoked having significantly lower levels. Unfortunately, we did not have the required data to provide further insight into the relationship between plasma clozapine levels and incidence of anemia.…”

Section: Drs Lee and Remington Replysupporting

confidence: 84%

Anemia Among Schizophrenic Patients

Lozano

¹

,

Franco²,

Marin³

et al. 2016

J. Clin. Psychiatry

0

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To the Editor: Lee et al 1 studied the impact of clozapine on the erythroid lineage in a sample of schizophrenic patients and found a high incidence of anemia in the first 2 years following clozapine initiation, with smoking and baseline hemoglobin level shown to be significant protective factors. They concluded that there was a need for further studies of the relationships between schizophrenia, clozapine, and anemia. Following their observations and conclusions, we would like to note the following 2 main points:First, regarding the known dose-related clozapine toxicity, the presence of a mean plasma clozapine level above the upper limit of the therapeutic range (360-690 ng/mL) 2 among anemic patients should be highlighted. In fact, the group of anemic patients 1 presented a mean value of 771.7 ± 287.1 ng/mL (n = 7), which suggests a potentially toxic outcome, compared with a lower mean value of 575.0 ± 262.8 ng/mL (n = 19) in non-anemic patients, although the difference was not significant because of a lack of sufficient statistical power. In this regard, we know that cytochrome P450 reductase (CYP) 1A2 is the most important route of clozapine metabolism, 2 the metabolic activity of which is mediated by smoking, as it is one of most important CYP1A2 inducers. Smoking, which has been shown to have different incidences among anemic and non-anemic patients (22% vs 65%, Z = 3.6; 95% CI, 0.1967-0.6653; P < .001) according to Lee and colleagues' study, 1 is crucial for the presence of toxicity associated with high plasma clozapine levels; further, there is a proven dose-response relation between plasma concentration and the risk of adverse events. 3,4 Thus, if Lee et al 1 had submitted data on plasma clozapine level and compared smokers with nonsmokers, we would have additional information about the influence of smoking on the plasma levels of clozapine and their toxicity.Second, regarding clozapine-related anemia that presents following treatment initiation within the first 2 years, the effect of clozapine on high-sensitivity C-reactive protein (hs-CRP), an acute-phase reactant and marker of inflammation, as a possible confounder for the typing of anemia and, therefore, the attribution of its pathogenesis, should be highlighted. For example, anemia of inflammation is most commonly described as normocyticnormochromic, but it can become microcytic-hypochromic (a typical pattern of iron-deficiency anemia) or resolved in accordance with the development of the inflammatory disorder. 5 In fact, we know that clozapine, especially at the beginning, leads to increased hs-CRP unrelated to age, race, or smoking status. 6-8 Moreover, hs-CRP level is inversely related to hemoglobin level, which could result in transient anemia through hs-CRP elevation. 9,10 In this regard, observations based on post hoc comparative data analysis (2010 vs 2013), from our own previous study, 11 showed a decrease in the mean value of hs-CRP (t = 2.1786; 95% CI, 0.183-4.217; P < .05) and anemia prevalence over time (Table 1). Thus, if Lee et al 1 ...

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“…6,7 When a person stops smoking, there is a time delay while the excess induced CYP1A2 enzyme is eliminated. This enzyme has a half-life of approximately 40 hours and, hence, the effect of the reduced enzymes will become apparent starting at about three to five days post-smoking cessation.…”

Section: Abrupt Smoking Cessationmentioning

confidence: 99%

Nuggets of Knowledge: The dangers of smoking cessation... and medicines

Bryant¹

2015

J Prim Health Care

0

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“…For example, anemia of inflammation is most commonly described as normocyticnormochromic, but it can become microcytic-hypochromic (a typical pattern of iron-deficiency anemia) or resolved in accordance with the development of the inflammatory disorder. 5 In fact, we know that clozapine, especially at the beginning, leads to increased hs-CRP unrelated to age, race, or smoking status. 6-8 Moreover, hs-CRP level is inversely related to hemoglobin level, which could result in transient anemia through hs-CRP elevation.…”

mentioning

confidence: 99%

Drs Lee and Remington Reply

Lee¹,

Remington²

2016

J. Clin. Psychiatry

0

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To the Editor: Lee et al 1 studied the impact of clozapine on the erythroid lineage in a sample of schizophrenic patients and found a high incidence of anemia in the first 2 years following clozapine initiation, with smoking and baseline hemoglobin level shown to be significant protective factors. They concluded that there was a need for further studies of the relationships between schizophrenia, clozapine, and anemia. Following their observations and conclusions, we would like to note the following 2 main points:First, regarding the known dose-related clozapine toxicity, the presence of a mean plasma clozapine level above the upper limit of the therapeutic range (360-690 ng/mL) 2 among anemic patients should be highlighted. In fact, the group of anemic patients 1 presented a mean value of 771.7 ± 287.1 ng/mL (n = 7), which suggests a potentially toxic outcome, compared with a lower mean value of 575.0 ± 262.8 ng/mL (n = 19) in non-anemic patients, although the difference was not significant because of a lack of sufficient statistical power. In this regard, we know that cytochrome P450 reductase (CYP) 1A2 is the most important route of clozapine metabolism, 2 the metabolic activity of which is mediated by smoking, as it is one of most important CYP1A2 inducers. Smoking, which has been shown to have different incidences among anemic and non-anemic patients (22% vs 65%, Z = 3.6; 95% CI, 0.1967-0.6653; P < .001) according to Lee and colleagues' study, 1 is crucial for the presence of toxicity associated with high plasma clozapine levels; further, there is a proven dose-response relation between plasma concentration and the risk of adverse events. 3,4 Thus, if Lee et al 1 had submitted data on plasma clozapine level and compared smokers with nonsmokers, we would have additional information about the influence of smoking on the plasma levels of clozapine and their toxicity.Second, regarding clozapine-related anemia that presents following treatment initiation within the first 2 years, the effect of clozapine on high-sensitivity C-reactive protein (hs-CRP), an acute-phase reactant and marker of inflammation, as a possible confounder for the typing of anemia and, therefore, the attribution of its pathogenesis, should be highlighted. For example, anemia of inflammation is most commonly described as normocyticnormochromic, but it can become microcytic-hypochromic (a typical pattern of iron-deficiency anemia) or resolved in accordance with the development of the inflammatory disorder. 5 In fact, we know that clozapine, especially at the beginning, leads to increased hs-CRP unrelated to age, race, or smoking status. 6-8 Moreover, hs-CRP level is inversely related to hemoglobin level, which could result in transient anemia through hs-CRP elevation. 9,10 In this regard, observations based on post hoc comparative data analysis (2010 vs 2013), from our own previous study, 11 showed a decrease in the mean value of hs-CRP (t = 2.1786; 95% CI, 0.183-4.217; P < .05) and anemia prevalence over time (Table 1). Thus, if Lee et al 1 ...

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Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine

Cited by 91 publications

References 51 publications

Anemia Among Schizophrenic Patients

Anemia Among Schizophrenic Patients

Nuggets of Knowledge: The dangers of smoking cessation... and medicines

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