Male-Specific Metabolic Considerations Concerning the Prescription of Second-Generation Antipsychotics to Adolescents

Introduction

The World Federation of Societies of Biological Psychiatry (WFSBP)'s Task Force on Men's Mental Health (TFMMH) aims to raise awareness among clinicians and researchers about the impact of common mental health care practices to specific male populations, including male adolescents. Although longitudinal studies demonstrate that both males and females gain comparable weight when prescribed second-generation antipsychotics (SGAs) (Bazo-Alvarez et al. 2019), comparable weight gain does not translate to comparable biological and psychosocial impact. The unique impact of this adverse effect upon males warrants consideration. Endocrinological, immunological, and psychosocial implications of metabolic SGA adverse drug effects in male adolescents warrant consideration to advance thoughtful and optimal care for the male adolescent prescribed an SGA.

Endocrinological Implications

Androgens affect synthesis, metabolism, receptor concentration, and trafficking of neurotransmitter systems (Schiller et al. 2016), neuroprotection and neurogenesis (Mahmoud et al. 2016), and central nervous system functional connectivity (Barendse et al. 2018). Whereas aripiprazole and clozapine are prolactin sparing, all other SGAs, and particularly paliperidone and risperidone, increase prolactin levels (Leucht et al. 2013; Peuskens et al. 2014), disrupting the healthy functioning of the hypothalamic–pituitary–gonadal axis and androgen levels. Although these effects may alter male adolescent development, the weight gain associated with all SGAs may in particular exacerbate detrimental endocrinological implications.

Obesity affects male androgen levels throughout adolescence (Vandewalle et al. 2015). Total testosterone levels decline, whereas increased adipose tissue promotes aromatization of testosterone creating increased levels of estradiol. In addition, obese pre- and early-pubertal adolescents experience increased adrenal activity and elevated androstenedione and dehydroepiandrosterone levels, further impacting sex hormones. Sex-specific hormonal alterations may further alter metabolic programming throughout the life style, exacerbating weight gain and obesity (Morford and Mauvais-Jarvis 2016).

Inflammatory and Immunological Implications

Although SGAs are generally thought to be anti-inflammatory (Stapel et al. 2018), their prescription is associated with an accumulation of adipose tissue, which itself is associated with an inflammatory state (Walther et al. 2017). The levels of testosterone, which consistently suppresses immune function, decline, whereas the levels of estrogens, which has no clear effect on immunosuppression, rise (Foo et al. 2017).

Sex-specific analysis of the effects of SGAs on the immune system need to be considered. In male rodents, chronic olanzapine administration induces macrophage infiltration of white adipose tissue and increases proinflammatory parameters, including tumor necrosis factor-α and interleukin-1β levels (Victoriano et al. 2010). Although an alternate study found olanzapine induced an increase in interleukin-1β and interleukin-8 secretion only in female rats, this study found that both male and female rats showed increased adiposity and macrophage infiltration into adipose tissue (Davey et al. 2012). Further studies in this important area are needed.

Adult schizophrenic men treated with SGAs exhibit reduced levels of adiponectin, an insulin-sensitizing and anti-inflammatory peptide, which potentially causes increased inflammation, insulin resistance, and altering glucose and lipid metabolism (Sapra et al. 2016). Meta-analytic investigation shows sex-nonspecific findings that clozapine and olanzapine, but not quetiapine or risperidone, are associated with reduced adiponectin levels, whereas this is not observed for quetiapine or risperidone treatment (Bartoli et al. 2015). Yet, due to small sample sizes and insufficient power to detect sex differences, scarce attention has been paid to potential sex differences of SGA-related alterations in inflammatory processes. Further investigation, including in adolescent and young adult populations, is needed.

Psychosocial Implications

Obese adolescents of both sexes demonstrate increased psychosocial stress sensitivity and reduced resilience (Ruiz et al. 2019). Male adolescents may have gender-specific troubles related to obesity (Sweeting 2008). Obesity is generally better tolerated in adolescent males relative to females, although this protection may be related to the muscular male body ideal among adolescents (Peixotolabre 2002). SGA-induced androgen deficiencies may reduce muscle mass and deprive obese male adolescents of these gendered protections. Feminization and special considerations such as SGA-induced gynecomastia, already known to significant detrimental psychosocial effects on male adolescents (Guss and Divasta 2017), may further exacerbate these problems.

These psychopharmacological considerations may impact male-specific weight-related harassment in school settings (Lampard et al. 2014). SGA-induced obesity-related reduced exercise tolerance and deconditioning may deprive male adolescents of the healthy self-esteem deriving from physical activity (Liu et al. 2015) and athletic accomplishments. Further studies regarding the experiences of male adolescents in relation to the school environment and peers, as well as among family relations and male paternal identifications, are needed.

Conclusions

Based on the findings presented, it is evident that a sex-specific analysis of the effects of SGAs on the predisposition to metabolic disorders is of greater importance than previously assumed. The rapid increase of androgens in puberty in boys in connection with SGA treatment bears biological and psychological risk for increased vulnerability to metabolic abnormalities in this patient group.

Clinical Significance

Providers should consider male-specific metabolic implications of second generation antipsychotic prescription when developing treatment planning for optimal care of male youth.