Antipsychotic Medications: Women and Men Respond Differently

Clinically women with psychotic disorders tend to have better outcomes than men; women are less likely to be hospitalized, carry a lower risk for suicide, and are more likely to retain relationships with friends and family. This may reflect underlying differences in the illness; however, some speculate that better outcomes may be related to a better response to antipsychotic medications in women versus men. But there are other differences between men and women when it comes to treatment with antipsychotic medications.

Dosage of Antipsychotic Medications

In general, psychotic symptoms in women respond to lower doses of antipsychotic medication than in men. Various studies have demonstrated that men require higher doses of medication than women in order to achieve an equivalent reduction in psychotic symptoms. The effectiveness of lower doses of antipsychotic medication in women is most evident for clozapine and olanzapine. This finding likely reflects the ameliorative or potentiating effects of estrogen in women, as it has been observed that women who are postmenopausal typically require higher doses of antipsychotic medication than premenopausal women. 

Impact of the Menstrual Cycle on Symptoms

How women respond to antipsychotic medications may also be influenced by changes in hormone levels that occur during the menstrual cycle. Some studies have demonstrated worsening of psychotic symptoms during the premenstrual phase of the cycle, the period during which levels of estrogen are falling. Although this has not been well-studied, it is possible that women respond to antipsychotics better at times when their estrogen levels are higher, during the first part of the menstrual cycle. Given that symptoms may vary across the menstrual cycle, it may be helpful to have women use daily ratings of their symptoms to determine if variability is associated with their menstrual cycle.

Differing Patterns of Side Effects

Although women’s psychotic symptoms may respond to lower doses of antipsychotic medication than men’s, women are more likely than men to suffer from side effects, which may complicate dose escalation and may ultimately impact adherence to medication. The side effects that occur more commonly in women include weight gain, metabolic symptoms, and sexual dysfunction.

Exactly why women are more vulnerable to side effects is not well understood but most likely reflect gender-based differences in medication pharmacokinetics and pharmacodynamics. Another possible explanation is that women are more likely than men to take antipsychotic medications in combination with other psychotropic medications which may increase side effect burden. 

Women taking antipsychotic medications are also at greater risk than men for cardiac arrhythmias. In the absence of medication, women tend to have slightly longer average QT intervals on the electrocardiogram than men. Antipsychotics such as haloperidol and ziprasidone are commonly associated with QTc prolongation, increasing the risk of potentially dangerous heart rhythm abnormalities. Other factors may also play a role, including age, dosage of medication, and underlying genetic vulnerability.

Although older studies suggest that women are more vulnerable than men to tardive dyskinesia (TD), more recent studies show similar prevalence rates of TD and other extrapyramidal symptoms in men and women.

Some studies suggest that women may be more prone to developing allergic reactions compared to men, possibly due to hormonal influences on immune responses. 

Impact on Menstrual Cycles and Reproduction

Antipsychotic medications exert varying effects on the menstrual cycle and reproductive health in women compared to men. Certain antipsychotics with more potent antagonism of dopamine D2 receptors, including first generation antipsychotics and risperidone, may increase prolactin levels, resulting in menstrual irregularities, amenorrhea, or even hyperprolactinemia-induced galactorrhea. 

While the reproductive system in men appears to be less vulnerable, some studies have reported decreased libido and erectile dysfunction in men receiving antipsychotic treatment, particularly with medications that possess strong anticholinergic properties, such as chlorpromazine and olanzapine. 

Summary

Compared to men, women generally require lower doses of antipsychotic medications to achieve symptom reduction, possibly due to the ameliorative effects of estrogen. Hormonal fluctuations during the menstrual cycle may influence medication response, with some evidence suggesting better outcomes during phases of higher estrogen levels. However, women are more likely to experience side effects such as weight gain and metabolic symptoms, potentially impacting medication adherence. Additionally, antipsychotic use can affect reproductive health differently in men and women, with some medications leading to menstrual irregularities in women and decreased libido in men.

Ruta Nonacs, MD PhD

References

Sáenz-Herrero M, Recio-Barbero M, López-Atanes M, Santorcuato A, Bacigalupe A, Segarra R. Gender differences in the management of acute psychiatric episodes in the emergency department: a cross-sectional analysis of the 2017-2019 triennium. Arch Womens Ment Health. 2023 Dec;26(6):777-783. 

Seeman MV. Men and women respond differently to antipsychotic drugs. Neuropharmacology. 2020 Feb; 163:107631. 

Shan Y, Cheung L, Zhou Y, Huang Y, Huang RS. A systematic review on sex differences in adverse drug reactions related to psychotropic, cardiovascular, and analgesic medications. Front Pharmacol. 2023 May 2;14:1096366.