Lithium is recommended as the first-line treatment for both acute mania and maintenance phase in bipolar disorder (Yatham et al., 2018). Recent evidence has also suggested the value of lithium in reducing suicidal rate in patients with bipolar or major depression disorder (Smith and Cipriani, 2017). Despite its significant clinical benefits, lithium has gradually become less widely utilized due to its narrow therapeutic index and requirement for frequent blood tests. Some common ADRs of lithium are tremor, polyuria, hypothyroidism, weight gain, and increased thirst. Other more severe ADRs such as bradycardia, sinus node dysfunction, and seizure might happen at a lower rate.

Sex differences were identified in lithium-related thyroid dysfunction, tremor, weight gain, and oedema. Özerdem et al. (2014) assessed sex differences in lithium associated thyroid dysfunction through a retrospective, naturalistic study. One hundred four men and 136 women taking lithium for bipolar disorder with thyroid-stimulating hormone (TSH) level available were included in the study. Using 0.3–3 µIU/mL as the normal range of TSH, the researchers found that significantly fewer female patients (55.9%) were within the normal range compared to male patients (71.2%) (p = 0.016). Notably, the difference in the proportion of normal TSH between male and female patients was not significant in the non-lithium treated group, which suggested that the observed sex differences in thyroid dysfunction is related to lithium treatment rather than the disease state. The vulnerability to thyroid dysfunction in lithium-treated women has also been observed by Chantal Henry in another retrospective study (Henry, 2002). By interviewing 22 male and 38 female patients about lithium ADRs, the researcher found that more female patients than male patients reported new diagnosis of hypothyroidism during the first year of lithium treatment (37% vs. 9%, p < 0.05). Weight gain was also shown to affect more female than male patients (47% vs. 18%, p < 0.05) in the same study whereas tremor was more pronounced in male than female patients (54% vs. 26%, p < 0.05). There is a more recent retrospective study investigating reasons for lithium discontinuation performed by Öhlund et al. (2018). The results showed that female patients were more likely to discontinue lithium due to weight gain (p < 0.01) and oedema (p < 0.01) compared to male patients. To conclude, current evidence suggested that lithium-associated thyroid dysfunction, weight gain, and oedema affect more female patients, while lithium-associated tremor affect more male patients in the treatment of bipolar disorder.

Amisulpride is an atypical antipsychotic with selective blockade of dopamine 2 and dopamine 3 receptors. It has been reported by multiple studies to be an effective and well-tolerated treatment for schizophrenia (Puech et al., 1998; Leucht et al., 2013). More recently, the clinical significance of amisulpride has been evaluated in combination therapies with other antipsychotics such as olanzapine in treatment-resistant schizophrenia (Schmidt-Kraepelin et al., 2022; Woo et al., 2022). On the safety prospective, amisulpride is associated with increased prolactin level, weight gain, hypotension, sexual dysfunction, and prolonged QT interval.

As one of the well-established adverse events of amisulpride, increased prolactin level was reported to be sex-biased by multiple studies (Düring et al., 2019; Hoekstra et al., 2021). In the BeSt InTro study, 93 men and 51 women with schizophrenia diagnosis were randomized to different antipsychotics including amisulpride (Johnsen et al., 2020). When comparing amisulpride induced ADRs between sexes, the researchers found that women had significantly higher mean prolactin level (1,869 mIU/L) then men (920 mIU/L) under amisulpride treatment (p < 0.001) (Hoekstra et al., 2021). Further evaluations showed that the serum level of amisulpride was higher in women than in men after adjusting for the daily dose (p = 0.019), which might explain the observed female-biased ADR. As a potential consequence of elevated prolactin level (Halbreich et al., 2003), sexual disturbance was also evaluated in this study. Using Udvalg for Kliniske Undersøgelser side effect score (UKU score) as the measurement for sexual disturbance, the researchers found that women had more sexual disturbance compared to men with marginal significance (p = 0.051). Notably, similar findings were observed in a separate study conducted by Düring et al., 2019. By following 35 men and 21 women with schizophrenia taking amisulpride monotherapy, the researchers found that prolactin level was higher in women (p < 0.01) compared to men after 6 weeks of amisulpride treatment. Women also reported higher sexual dysfunction load than men did (p < 0.01). In conclusion, amisulpride related prolactin elevation and sexual dysfunction are more common in women than in men in treating schizophrenia, even though the average daily dose is similar between two sexes.

Clozapine and olanzapine are both atypical antipsychotics with similar molecular structures. Clozapine is known as one of the most effective antipsychotics and it is the gold standard for treatment resistant schizophrenia. However, studies have shown that the use of clozapine in schizophrenia is suboptimal (Warnez and Alessi-Severini, 2014), which might involve several reasons including a range of serious adverse events of this medication. For instance, clozapine is associated with myocarditis, cardiomyopathy, and neutropenia, all of which can be life-threatening. Recently, the use of olanzapine in treatment resistant schizophrenia has been widely discussed, as several studies have shown that olanzapine is non-inferior to clozapine in terms of safety and efficacy in hard-to-treat schizophrenia (Tollefson et al., 2001; Bitter et al., 2004; Naber et al., 2005). In terms of common adverse events, both clozapine and olanzapine are recognized as being high risk for weight gain, hyperglycemia, and dyslipidemia (Rummel-Kluge et al., 2010; Kraal et al., 2017).

Even though clozapine and olanzapine have similar profiles in metabolic ADRs, the impact of sex on some of those ADRs were observed to be different between the two medications. In the BeSt InTro study (Hoekstra et al., 2021), sex differences in BMI increase was evaluated in patients randomized to olanzapine group. BMI increase was found to be more pronounced in men (1.48 kg/m²) than in women (0.24 kg/m²) (p < 0.001). Interestingly, the direction of sex difference in treatment-related weight gain was shown to be opposite in patients taking clozapine. In a retrospective study conducted by Lau et al., 2016, 67 men and 50 women attending the outpatient clozapine clinic were recruited and their weight change from 3 months to 12 months after clozapine initiation was calculated. The percentage weight change (weight change divided by the 3-month weight) was found to be significantly higher in women (+5.5%) than in men (+1.3%) (p = 0.01). To analyze sex differences in more serious ADRs of clozapine, Hollingworth et al. reviewed all reported clozapine related neutropenia, myocarditis, and cardiomyopathy cases in Australia monitoring database from 1993 to 2014 (Hollingworth et al., 2018). Sex differences were observed with neutropenia happening more in women (OR 1.45, CI 1.28–1.67), while cardiomyopathy (OR 2.53, CI 1.9–3.37) and myocarditis (OR 1.58, CI 1.34–1.87) happened more in men. These findings suggest sex as an important factor in clozapine and olanzapine related weight gain as well as in more serious adverse events of clozapine.

Aripiprazole is an atypical antipsychotic with numerous FDA approved indications including schizophrenia, bipolar I disorder, autistic disorder, Tourette’s syndrome, and major depressive disorder. Because of its unique receptor binding profile, aripiprazole has different mechanism of actions from other antipsychotics and is sometimes referred as a third-generation antipsychotic (Freudenreich and Freudenreich, 2020). In addition to its confirmed efficacy in various disease areas, aripiprazole has also been shown to induce less adverse events compared with other antipsychotics (Leucht et al., 2013). Some common ADRs of aripiprazole are weight gain, nausea, vomiting, tremor, and fatigue. More serious ADRs such as prolonged QT interval, myocardial infarction, and neutropenia have been observed at a lower rate.

Among aripiprazole-related ADRs, weight gain and some cardiovascular ADRs were shown to impact men and women differently. In a study evaluating sex differences in pharmacokinetics and ADRs of aripiprazole, 89 men and 68 women from multiple aripiprazole bioequivalence clinical trials were recruited (Belmonte et al., 2016). PK parameters were calculated, and physical assessments were performed several times before and after a single dose of 10 mg aripiprazole. The study found that AUC and C_max of aripiprazole were significantly higher in women (p < 0.05), which indicated a higher aripiprazole exposure in women even under the same dose. In concordance with the observed difference in PK parameters, the blood pressure lowering effects of aripiprazole were found to be more pronounced in women at all measured times (p < 0.01). At 8 h after the dose, the mean systolic blood pressure in women was 105 mmHg versus 116 mmHg in men (p < 0.001). In addition, women were found to have higher heart rate and larger QTc interval compared to men at multiple measured times (p < 0.001). As a well-established ADR of aripiprazole, weight gain has also been shown to impact women and men differently. In the BeSt InTro study (Hoekstra et al., 2021), men were observed to have higher BMI increase compared to women after 52 weeks of aripiprazole use (0.64 kg/m² vs. −0.04 kg/m², p = 0.016). In conclusion, sex differences have been observed in multiple aripiprazole related ADRs including weight gain, blood pressure reduction, increased heart rate and QTc. Since some of the conclusions were based on a single dose of aripiprazole, further investigation is warranted to explore the sex difference in long-term aripiprazole use.

Risperidone is a second-generation antipsychotic with serotonin 5-hydroxytryptamine receptor 2 (5-HT₂) blocking activities at low doses and dopamine D₂ receptor blocking activities at higher doses (Megens et al., 1994). Risperidone is proven to mitigate both positive and negative symptoms of schizophrenia, with less concern about dyskinesia which is a prevalent ADR of most antipsychotics (Labelle et al., 2001). Some common ADRs of risperidone are rash, weight gain, hyperprolactinemia, parkinsonism, and fatigue.

Sex differences in risperidone-associated rash, weight gain, parkinsonism, and dystonia have been evaluated. In a randomized study, 100 men and 90 women taking daily risperidone were followed up for 1 year to assess drug-related ADRs (Pu et al., 2020). At the end of the follow-up period, more female patients reported rash related to risperidone than male patients (p = 0.03). In another post hoc analysis on an open-label study, ADRs in 232 men and 98 women taking risperidone were analyzed for differences between sexes (Labelle et al., 2001). Weight gain was found to happen more in men compared to women with marginal significance (p = 0.085). No sex difference was identified for parkinsonism (p = 0.889) or dystonia (p = 0.512). To conclude, risperidone-related rash is more prevalent in women, whereas no significant sex difference was found in weight gain, parkinsonism, or dystonia related to risperidone treatment in schizophrenia.

Amiodarone is a class III antiarrhythmic drug which is highly effective and widely used in both supraventricular and ventricular arrhythmias (Connolly, 1999). However, amiodarone is also well-known for its potential ADRs on different organs such as thyroid, heart, lung, liver, and eyes. A previous study showed that the prevalence of amiodarone-related ADRs is 15% in the first year, and may increase to 50% in long term use, which would ultimately lead to medication discontinuation in 20%–50% of the patients (van Erven and Schalij, 2010). Some common ADRs of amiodarone are thyroid dysfunction, photosensitivity, and visual disturbance. Amiodarone can also cause more serious adverse events such as bradyarrhythmia, sinus arrest, and hepatotoxicity.

In a prospective cohort study (Essebag et al., 2007), Essebag et al. enrolled 583 men and 390 women with new onset atrial fibrillation (AF) and followed the participants for up to 30 months for amiodarone related ADRs. The researchers found that amiodarone use was associated with increased risk of pacemaker insertion only in women but not in men (HR: 4.69, 95% CI: 1.99–11.05, vs. HR: 1.05, 95% CI: 0.42–2.58, p = 0.02). This significant difference remained after adjusting for daily dose, weight, and the use of other antiarrhythmic medications. In another retrospective study (Roten et al., 2009), Roten et al. reviewed amiodarone associated ADRs in 192 men and 72 women who were referred to clinic for AF management. Their analysis showed that women overall experienced more amiodarone-related ADRs than men (56% vs. 36%, p = 0.046), and there were significant sex differences in the occurrence of phototoxicity under amiodarone treatment (21% in women vs. 8% in men, p = 0.047). The results above suggest that closer monitoring is needed in female population taking amiodarone since they are more likely to experience ADRs such as bradyarrhythmia requiring pacemaker insertion and phototoxicity.

Sotalol is a class III antiarrhythmic agent which is approved for treatment of AF and ventricular arrhythmia. Its efficacy in reducing death and preventing recurrence of arrhythmia has been proven to be superior to other antiarrhythmic drugs (Mason, 1993). However, along with its high efficacy, sotalol can induce some lethal ADRs such as Torsades de pointes (TdP), which may lead to sudden cardiac death. To unveil whether sex is a risk factor for sotalol induced TdP, Lehmann et al. assessed the prevalence of TdP development under sotalol treatment in 3,135 adult patients and compared the results between sexes (Lehmann et al., 1996). TdP was observed in 44 of 2,336 men (1.9%) and in 33 of 799 women (4.1%), and the difference was statistically significant (p < 0.001). Further logistic regression also suggested female sex as a significant risk factor in TdP development (p < 0.0001), even after adjusting for sotalol dose. Since TdP is such a lethal ADR, the results above emphasize the need for closer monitoring of cardiac function in female patients taking sotalol.

Despite the recent advancement in the treatment options for hyperlipidemia and in the prevention of coronary artery disease, statins remain the first line therapy due to their high efficacy, low cost, and relatively safe profile. The pharmacological effects of statins have been proven in lowering the low density lipoprotein cholesterol (LDL-C) by 20%–50%, as well as lowering triglyceride by 10%–20% (Taylor et al., 2013). In terms of safety, statins are well tolerated by the vast majority of patients, but they can still cause some ADRs such as myalgias, urinary tract infection, and increased liver enzymes, which can all lead to treatment interruption or discontinuation. Sex differences in the ADRs of two commonly used statins, simvastatin and atorvastatin, have been evaluated in a prospective cohort study (Smiderle et al., 2014). A total of 164 men and 331 women on simvastatin or atorvastatin treatment participated in the study, and they were evaluated every 3 months for statin related ADRs. The researchers observed higher occurrence of myalgia in women than in men (25.9% vs. 20.3%, p = 0.002), while more creatinine phosphokinase (CPK) increase and/or elevated liver enzymes were observed in men than in women (11.1% vs. 7.6%, p = 0.017) under simvastatin or atorvastatin treatment. These results request more attention on the role of sex in statin associated ADRs, and further studies are warranted to explore the potential mechanism of the observed sex differences.

Angiotensin converting enzyme (ACE) inhibitors are effective antihypertensives working through inhibition of renin-angiotensin system. ACE inhibitors are recommended by multiple guidelines as first-line treatment for hypertension (Williams and Mancia, 2018), and their use has been expanded to other disease areas such as acute myocardial infarction, heart failure, and kidney diseases. While most patients tolerate ACE inhibitors well, some patients can still experience hypotension, dizziness, dry cough, and other more serious ADRs such as angioedema and renal impairment during the treatment.

Evidence of sex differences in ACE inhibitor induced ADRs was found in lisinopril, enalapril, and captopril. Interestingly, most of the sex difference analysis has been focused on ACE inhibitor induced bronchospasm and cough. In a retrospective study (Wood, 1995), the prevalence of new onset bronchospasm and cough was assessed in 1,013 patients taking captopril, lisinopril, or enalapril. Women were found to experience more bronchospasm (58% vs. 42%) and cough (59% vs. 41%) reactions compared to men; however, the difference was not statistically significant. Notably, patients under the three different treatments were not separated when the prevalence was reported, which means that the rate of bronchospasm and cough in each individual medication group was unknown. In another randomized, double-blind clinical trial investigating sex differences in efficacy and safety of antihypertensives, 3,535 hypertensive patients (1,209 men and 2,326 women) were recruited and followed during 8 weeks of treatment (Fan et al., 2008). In patients randomized to captopril group, the prevalence of cough was found to be significantly higher in women than in men (14.3% vs. 8.4%, p = 0.005). This female-biased ACE inhibitor induced cough was also observed in lisinopril by Os et al. in a randomized, double-blind clinical trial (Os et al., 1994). In this study, 206 men and 206 women were randomized to lisinopril group, and cough was found to happen three times more often in women than in men (12.6% vs. 4.4%, p = 0.0027). Overall, although some non-significant findings exist, more evidence suggests an increased risk of ACE inhibitor induced cough in women.

Both amlodipine and nifedipine are dihydropyridine calcium channel blockers (CCBs) which are widely used for treating hypertension, stable and variant angina. Although structurally similar, amlodipine differs from nifedipine and other dihydropyridine CCBs by its long half-life, enabling once daily dosing (Haria and WagstaffAmlodipine, 1995). In terms of ADRs, both amlodipine and nifedipine are observed to cause hypotension, palpations, edema, and flushing with slightly different occurrence rate.

Sex difference studies are available for amlodipine-related neurological ADRs and nifedipine-related cough and edema. Abad Santos et al. conducted a bioequivalent study in 36 healthy volunteers (18 men and 18 women) to study sex differences in amlodipine induced ADRs as their secondary objective (Abad-Santos et al., 2005). All subjects received a single 10 mg dose of each amlodipine formulation with a 14-day washout period. After statistical analysis, the researchers did not find any significant difference between men and women in amlodipine related headache (44% vs. 28%), dizziness (11% vs. 28%), or tiredness (17% vs. 6%). Sex difference in nifedipine-related edema was studied in a prospective study by Fan et al. (Fan et al., 2008). A total of 327 men and 620 women were randomized to nifedipine sustained release (SR) group and were followed up for 8 weeks to evaluate drug related ADRs. Women were found to be more susceptible to ADRs related to nifedipine SR than their men counterpart (15.8% vs. 9.8%, p = 0.017), with intolerable edema being the main type of ADR observed. In another study assessing the role of sex in nifedipine associated cough, 218 men and 198 women were randomized to nifedipine group and were followed up for 10 weeks (Os et al., 1994). No sex difference was identified by this study in nifedipine related cough (men 3% vs. women 2.8%). To conclude, women were found to experience more intolerable edema from nifedipine SR, while no sex difference was found in nifedipine associated cough or amlodipine associated headache, dizziness, or tiredness.

Atenolol is one of the drugs classified as beta-blocker, and it is used to treat several conditions such as hypertension, cardiac dysrhythmia, angina pectoris, etc. Recently, the effectiveness of atenolol has been assessed in other disease areas including anxiety (Armstrong and Kapolowicz, 2020). In terms of its safety profile, most patients tolerate atenolol well. Bradyarrhythmia, hypotension, dizziness, and fatigue are the most common ADRs observed with atenolol treatment. There is one study evaluating sex difference in ADRs related to atenolol in treating hypertension. After following 191 men and 403 women on atenolol therapy for 8 weeks, the researchers found that fatigue and bradycardia were most common ADRs during treatment period, and there was no sex difference in the occurrence rate of those ADRs (men 15.8% vs. women 11.6%, p = 0.497) (Fan et al., 2008).

Opioids are widely used in the management of moderate to severe pain. As one of the potent opioid analgesia, morphine is recommended for pain management in various disease types such as cancer, acute pulmonary edema, and myocardial infarction (Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology ESC, 2012; Wiffen et al., 2016). However, the use of morphine has been cautioned due to a wide range of ADRs including pruritus, nausea, vomiting, dizziness, urinary retention, and more seriously, drug dependence, respiratory depression, and cardiac arrest.

Sex differences have been investigated in multiple morphine induced ADRs such as gastrointestinal ADRs and respiratory depression. In a prospective observational study undertaken by Sadhasivam et al. (Sadhasivam et al., 2015), 219 children undergoing tonsillectomy or adenotonsillectomy (T/TC) surgery were recruited and the efficacy and safety of morphine were compared between boys and girls. No sex difference was observed in respiratory depression (10% in boys vs. 7% in girls, p = 0.81), postoperative nausea and vomiting (6% in boys vs. 9% in girls, p = 0.2), and pruritus (41% in boys vs. 33% in girls, p = 0.54). Likewise, sex differences in morphine related ADRs were also assessed by Fillingim et al. in healthy adult women (n = 61) and men (n = 39) (Fillingim et al., 2005). All subjects in the study were intravenously administered 0.08 mg/kg single dose of morphine, after which the incidence of pruritus, nausea, and emesis were assessed. Similar to the previously described study, no evidence of sex difference was found in pruritus (8% in men vs. 10% in women). However, the prevalence of nausea and emesis were found to be significantly higher in women than in men (nausea 35% vs. 3%, emesis 18% vs. 0, p < 0.005). The results from the two studies above indicates that the role of sex in morphine related nausea and vomiting might be different in different disease states and/or age groups.