Innov Clin Neurosci. 2025;22(1–3):11–13.

Dear Editor:

Emerging data on sex differences in the efficacy and tolerability of antipsychotics in patients with schizophrenia are not taken into account in current guidelines, which can lead to inappropriate sex-specific treatment. Recent studies have generally agreed that there is little difference between male and female sexes when it comes to the effectiveness of antipsychotics, but that side effects are more prevalent in female patients.^1,2 

An analysis of data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial, a large comparative trial of antipsychotic medications not funded by pharmaceutical companies, also demonstrated that there were evident sex differences in the prevalence of side effects. With regard to hormone-related or subjective side effects, such as constipation, dry mouth, galactorrhea, and urinary incontinence/nocturia, these occurred more frequently in female patients.¹ Conversely, no sex-based differences were observed in the assessment of efficacy using the Clinical Global Impression-Severity Scale (CGI-S) and Calgary Depression Scale for Schizophrenia (CDSS).¹ It is crucial to recognize that subjective side effects can significantly impact patient quality of life. It is imperative to consider sex-specific differences in drug metabolism as a potential explanation for the heightened susceptibility of female patients to side effects.³ However, genetic polymorphisms such as cytochromes P450 and p-glycoproteins have a greater impact on pharmacokinetics than sex differences in drug metabolism.⁴ Moreover, no notable discrepancies were observed between the sexes with regard to the prevalence of antipsychotic concentration–dependent side effects, including extrapyramidal symptoms and weight gain.^1,2 

It can be posited that the proclivity of female patients with schizophrenia to report constipation might be attributable to sex-specific differences in the brain networks. The defecation reflex is initiated when nociceptive stimuli in the colonic extension are transmitted to the brain by primary afferent neurons via the ascending pain conducting pathway. When the brain experiences nociceptive colonic extension, it stimulates the periaqueductal gray (PAG) via the dopaminergic neurons to relieve pain perception, activating the descending pain inhibitory pathway that originates PAG and releases neurotransmitters, including serotonin, noradrenaline, dopamine, and gamma-aminobutyric acid (GABA) into the spinal cord. The defecation reflex occurs when the descending pain inhibitory pathway, originating in the PAG, stimulates the defecation center in the sacral spinal cord.⁵ Antipsychotics block dopamine neurons, which carries the risk of reducing PAG activation and reducing the defecation reflex.⁵ In animal models, there is a clear distinction between male and female sexes in the expression of neurotransmitters on descending pain inhibitory pathway.⁵

In male patients, dopamine and serotonin are released, which activate the sacral defecation center and together promote colonic motility. In female patients, dopamine is not released, but serotonin and GABA are released, with serotonin acting to promote defecation and GABA to inhibit it, resulting in a lower defecation reflex than in male patients.⁵ Due to the existence of sex-specific differences in the brain network of the descending pain inhibitory pathway, the reduction of PAG activation through the use of antipsychotic medications has been observed to result in a decreased likelihood of a defecation reflex in female patients.

Female patients with schizophrenia are more likely to experience discomfort from antipsychotics and have a higher prevalence of comorbid chronic unexplained pain conditions, such as fibromyalgia.⁶ Chronic pain of unknown cause comorbid with schizophrenia has no pain stimulus present. This might also be related to the observed sex differences in brain networks. Pain has recently been classified into three categories: nociceptive pain, neuropathic pain, and nociplastic pain. Nociplastic pain represents a third category of pain that is mechanistically distinct from nociceptive pain, which is caused by ongoing inflammation or damage to tissue, and neuropathic pain, which is caused by nerve damage.⁷ Chronic pain of unknown cause comorbid with schizophrenia is a form of nociplastic pain. The mechanisms that underlie this type of pain are not entirely understood, but it is hypothesized that alterations in brain networks, augmented sensory processing, and persistent modifications in pain modulation play a pivotal role.⁷ 

In animal models of nociplastic pain induction in which lower-intensity stimulation was applied at a later stage following injury, the chronicity of mechanical hypersensitivity was observed only in female subjects.⁸ Although the brain network of nociplastic pain is not fully understood, corticotropin-releasing factor (CRF)-producing neurons in the bed nucleus of the stria terminalis (BNST), which connects with dopaminergic neurons and plays a central and critical role in the integration of information on hedonic-valence, mood, arousal states, and processing of emotional information, show a female-biased sexual dimorphism that increases with estrogen.⁹ It is notable that the increased prevalence of antipsychotic-induced distress in female patients relative to male patients might be attributed to the existence of sex-specific neural networks.

In conclusion, the recent studies on sex differences in the side effects of antipsychotic medications in the real world indicate that female patients need to be aware of the risks of potential side effects, such as constipation and dysphoria. These findings are corroborated by evidence of sex differences in brain networks associated with dopaminergic neurons, such as the descending pain inhibitory pathway and BNST. Further research is required to elucidate the sex-specific differences in brain networks, with the objective of incorporating these findings into the development of guidelines for the treatment of schizophrenia with antipsychotics.

With regards,

Takahiko Nagamine, MD, PhD

Dr. Nagamine is with Department of Psychiatric Internal Medicine, Sunlight Brain Research Center in Hofu, Yamaguchi, Japan, and Department of Psychosomatic Dentistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University in Tokyo, Japan.

Funding/financial disclosures. The author has no conflicts of interest relevant to the content of this letter. No funding was received for the preparation of this letter.

References 

1. Galbally M, Wynter K, Siskind D, et al. Sex differences between female and male individuals in antipsychotic efficacy and adverse effects in the treatment of schizophrenia. CNS Drugs. 2024;38(7):559–570.
2. Ercis M, Sanchez-Ruiz JA, Webb LM, et al. Sex differences in effectiveness and adverse effects of mood stabilizers and antipsychotics: a systematic review. J Affect Disord. 2024;352:171–192. 
3. Hoekstra S, Bartz-Johannessen C, Sinkeviciute I, et al. Sex differences in antipsychotic efficacy and side effects in schizophrenia spectrum disorder: results from the BeSt InTro study. NPJ Schizophr. 2021;7(1):39. 
4. Wong YC, Centanni M, de Lange ECM. Physiologically based modeling approach to predict dopamine d2 receptor occupancy of antipsychotics in brain: translation from rat to human. J Clin Pharmacol. 2019;59(5):731–747. 
5. Horii K, Ehara Y, Shiina T, et al. Sexually dimorphic response of colorectal motility to noxious stimuli in the colorectum in rats. J Physiol. 2021;599(5):1421–1437. 
6. Li X, Zhou W, Yi Z. A glimpse of gender differences in schizophrenia. Gen Psychiatr. 2022;35(4):e100823. 
7. Fitzcharles MA, Cohen SP, Clauw DJ, et al. Nociplastic pain: towards an understanding of prevalent pain conditions. Lancet. 2021;397(10289):2098–2110. 
8. Hankerd K, McDonough KE, Wang J, et al. Postinjury stimulation triggers a transition to nociplastic pain in mice. Pain. 2022;163(3):461–473. 
9. Uchida K, Otsuka H, Morishita M, et al. Female-biased sexual dimorphism of corticotropin-releasing factor neurons in the bed nucleus of the stria terminalis. Biol Sex Differ. 2019;10(1):6. Erratum in: Biol Sex Differ. 2019;10(1):10.