M202. SEX-RELATED DIFFERENCES IN CLOZAPINE SIDE EFFECTS IN PATIENTS WITH TREATMENT-RESISTANT SCHIZOPHRENIA
Authors: Martini Francesca , Bosia Marta , Buonocore Mariachiara , Spangaro Marco , Bechi Margherita , Federica Cocchi , Carmelo Guglielmino , Laura Bianchi , Cavallaro Roberto 
Published: May 2020

Abstract

Background
Treatment resistant schizophrenia (TRS) affects up to 30% of patients with psychosis and is a major cause of disability. Although clozapine is the only indicated drug for TRS, it is largely underused, partially due to its life-threatening adverse effects (AEs) as agranulocytosis and myocarditis. However, clozapine treatment is also burdened by other AEs as constipation, hypersalivation, postural hypotension, tachycardia, metabolic abnormalities and weight gain. In recent years many efforts have been made to outline clinical and neurobiological characteristics of TRS. Although sex is one of the most relevant factors accountable for the clinical variability of schizophrenia, literature on sex differences in clozapine’s tolerability is still limited. Studies showed that women experience more often than men weight gain, hyperglycemia and constipation. Conversely, hypertension and dyslipidemia seem more frequent in men. Based on these premises, our study aimed to investigate sex differences in prevalence of clozapine’s chronic AEs in TRS patients.

Methods
We performed an observational cross-sectional study with TRS on 147 patients, 93 males and 54 females with at least two-year clozapine treatment. We assessed metabolic status and AEs by interviews, collection of clinical data (BMI, waist circumference, blood pressure and heart rate) and blood tests including lipid profile, fasting glucose and HbA1c.
Chi-square analysis was used to investigate the association between sex and clozapine AEs (tachycardia, postural hypotension, constipation, hypersalivation and metabolic syndrome). Multiple logistic regression analyses were performed to further analyze the relationship between sex and AEs considering the role of possible confounding factors as plasmatic concentration, oral dosage, number of daily administration, age and duration of therapy.

Results
We found a higher prevalence of tachycardia in males (p=0.034, χ2=4.49) and of orthostatic hypotension (p=0.01, χ2=6.70) and constipation (p=0.01, χ2=6.45) in females. Logistic regressions showed that male sex was the only significant predictor of tachycardia (p=0.01), while female sex predicted hypotension (p=0.04) and constipation (p=0.03). Although no differences emerged for hypersalivation and metabolic syndrome (MetS), Chi-square showed significant differences in prevalence for two MetS criteria: hypertriglyceridemia (56.94% in men, 29.79% in women, p=0.003, χ2=8.43) and central obesity (83.33% in men, 97.44% in women, p=0.03, χ2=4.69).

Discussion
Consistent with previous literature, our study showed sex differences in prevalence of chronic clozapine’s AEs. Although perceived as minor AEs, hypotension, constipation and tachycardia could affect patient’s quality of life, cause treatment discontinuation or increase mortality. In particular, postural hypotension and tachycardia have been associated with an increased risk of all-cause death and cardiovascular events in the general population.
Clozapine-related constipation can develop into full-blown ileus in up to 2.1% of cases, a higher, more durable and more dangerous risk than agranulocytosis. Finally, hypertriglyceridemia and central obesity are well known cardiovascular risk factors.
Our study suggests clinicians should carefully monitor for clozapine’s AEs also considering sex, in order to early detect them, promptly treat them and prevent severe complications.
Literature suggest some of the sex differences reported in schizophrenia may be due to the protective role of estrogens. Further studies, with a particular attention to hormonal status, could contribute to better understand the pathophysiology of sex differences in TRS and define a personalized therapeutic approach.