Sex Differences in and Pharmacotherapy of Schizophrenia

Abstract

Schizophrenia is a common disorder with a prevalence rate of approximately 1%; its symptoms primarily of consist of positive and negative symptoms as well as cognitive decline. Moreover, sex differences are present in schizophrenia. The age of onset differs between men and women, but other sex differences occur in the symptoms, severity, number of treatments, and suicide rates. Important sex differences in the treatment of schizophrenia include the use of antipsychotic pharmacokinetics, side effects such as metabolic abnormalities, cardiovascular disease, QT prolongation, and gonadal dysfunction, and safety during pregnancy and lactation. Sex differences in antipsychotic side effects have not been fully investigated, but some have been reported to be worse in women. This article outlines sex differences in pharmacokinetics, side effects such as metabolic abnormalities, cardiovascular disease, QT prolongation, gonadal dysfunction, and pregnancy and lactation, as well as the precautions for each antipsychotic.

1. Introduction

Schizophrenia is a common disorder with a prevalence of approximately 1% and mainly consists of positive symptoms (such as delusions and hallucinations), negative symptoms (such as decreased motivation and flat affect), and cognitive decline. Clinical observations have shown sex differences in some psychiatric disorders, including schizophrenia, but the etiology of sex differences in schizophrenia is only partially understood.

Men and women with schizophrenia have been suggested to experience differential disease progression, including age of onset, symptoms, severity, and number of treatments [1]. Men have an earlier age of onset than women, with the average age of onset ranging from 18 to 25 years for men and 25 to 35 years for women [2]; a second peak occurs in women after the age of 40 [3]. In terms of symptoms, men tend to have more negative symptoms and more severe clinical features, especially social withdrawal and substance abuse (of alcohol, nicotine, marijuana, stimulants, etc.). On the other hand, women are more likely to exhibit mood disorders and depressive symptoms as well as affective symptoms. In general, women have a better prognosis than men, with less frequent hospitalization, lower suicide rates, and better relationships with family and friends. Whether these differences are due to sex differences in response to antipsychotic treatment is not well understood, and there are currently no consistent treatment guidelines according to sex. Additionally, sex differences in antipsychotic side effects have not been fully investigated, although some side effects have been reported to be particularly problematic for women.

This article outlines the sex differences in pharmacokinetics, side effects (metabolic abnormalities, cardiovascular disease, QT prolongation, and gonadal dysfunction), and pregnancy and lactation, as well as the precautions for each antipsychotic.

2. Pharmacokinetics in women

Women reportedly experience side effects from more drugs than men, but it is not clear whether this is due to sex differences in drug pharmacokinetics and pharmacodynamics. Changes in pharmacokinetics are thought to play a major role in the efficacy and safety of drug therapy in women. Hormonal influences on physiological function may result in differences in drug absorption, protein binding, distribution volume, and metabolism in women. Sex differences have also been observed in phase I (cytochrome P450) and phase II (especially glucuronide conjugation) responses. In addition, women have a higher percentage of body fat than men, which results in a longer half-life and accumulation of lipophilic antipsychotics. This suggests that longer dosing periods are needed, especially during pregnancy [4]. Furthermore, differences in drug distribution between males and females have been attributed to differences in body size. Differences in hepatic enzyme activity are also believed to play a major role in determining sex differences in pharmacokinetics; CYP3A4, CYP2D6, and CYP1A2 are the most important enzymes in the hepatic metabolism of antipsychotic drugs [5]. Data on potential sex differences in cytochrome (CYP) activity indicate that in women, CYP3A4 and CYP2D6 activity is higher in women, especially during pregnancy and premenopause. On the other hand, CYP1A2, CYP2C19, CYP2E1, and phase II glucuronyltransferases are less active in women. These differences in enzyme activity may result in greater sex differences in plasma concentrations, leading to different clinical outcomes in men and women [6]. In some studies, plasma concentrations of clozapine and olanzapine are higher in women, possibly due to lower CYP1A2 activity [7]. The individual-level factors with the greatest influence on olanzapine pharmacokinetics are sex and smoking status [8]. For example, a young male patient with a history of smoking requires an olanzapine dose three to four times higher to reach the same plasma concentration as an elderly female patient with no smoking history [7]. However, no sex differences in plasma concentrations of risperidone, ziprasidone, quetiapine, or aripiprazole have been found. Furthermore, the renal clearance of drugs that are not actively secreted and reabsorbed is dependent on the glomerular filtration rate, which is directly proportional to body weight and is therefore higher, on average, in men than in women. Most sex differences in renal excretion rates are thought to be due to simple weight differences [9]. In summary, an awareness of the pharmacokinetics of sex differences may provide clues for appropriate drug selection and drug dosage decisions.

3. Sex differences in the risk of antipsychotic-induced metabolic abnormalities and cardiovascular disease

Women have often been excluded from large cardiovascular clinical trials in the past, but in recent years, a vast amount of accumulated data has led to the optimization of cardiovascular health in female patients by addressing sex-specific health issues [10]. Cardiovascular disease (CVD) is the leading cause of death in patients with schizophrenia, resulting in lifespans up to 30 years shorter in patients with schizophrenia compared to the general population [11]. Antipsychotic use increases the risk of certain metabolic abnormalities and may increase the risk of CVD [12]. In particular, second-generation antipsychotics cause obesity (especially abdominal obesity) due to weight gain, dyslipidemia (hypercholesterolemia, hypertriglyceridemia, hypo-high-density lipoproteinemia [hypo-HDLemia], and hyper-low-density lipoproteinemia [hyperLDLemia]), and glucose homeostasis disorders (hyperglycemia, insulin resistance, and type 2 diabetes). Up to 50% of patients receiving second-generation antipsychotics meet the criteria for metabolic syndrome, significantly increasing CVD morbidity and mortality [13]. The results of Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), a large clinical trial of antipsychotics, showed a higher prevalence and risk of metabolic syndrome in women than in men [14]. In particular, a higher incidence of metabolic syndrome was reported in patients receiving clozapine and olanzapine [15], suggesting that the risk of metabolic syndrome and CVD is very high in women receiving these drugs. On the other hand, there are also reports of elevated total cholesterol and LDL in women taking clozapine and olanzapine, whereas men have the highest risk of low HDL [16]. The above findings should be kept in mind when prescribing antipsychotic medications, and the risks and benefits should be considered. It is also important to conduct preventive screening, such as blood tests, at least once a year for men and every 6 months for women, with the goal of reducing the risk of metabolic abnormalities.

4. Sex differences in the effect of antipsychotics on the corrected QT (QTc) interval

The QT interval is defined as the interval between the beginning of the Q wave and the end of the T wave on the electrocardiogram (ECG) and is a measure of the duration of the action potential of ventricular muscle or the time from the start of depolarization to the end of repolarization. Studies in humans have shown that a prolonged QT interval increases the risk of developing torsades de pointes, a hyperplastic ventricular disease leading to ventricular fibrillation and sudden death [17]. According to a meta-analysis, women accounted for 70% of the 332 cases of torsade de pointes, but the proportion of cardiovascular drugs used in these cases was only 44%. A higher than expected incidence of torsades de pointes in women was consistently observed for all cardiovascular drugs analyzed [18]. In clinical and experimental studies, being female is associated with a longer baseline QTc interval and greater responsiveness to drugs that block cardiac voltage-dependent potassium channels, both of which increase arrhythmia induction [19]. Antipsychotics are associated with prolongation of the QT interval, which can lead to ventricular arrhythmias and sudden death [20]. First-generation antipsychotics are associated with a higher risk of QTc interval prolongation than second-generation antipsychotics [21]; however, one retrospective cohort study reported a twofold increased risk of sudden cardiac death from taking quetiapine, olanzapine, and risperidone, which was attributed to prolongation of the QT interval [22]. Aripiprazole is better tolerated than other antipsychotics with respect to its side effects, including QT prolongation, but its exact effects on the QT interval remain unknown [23]. A study conducted in Japan reported that olanzapine and quetiapine treatment had a greater impact on the QTc interval than risperidone and aripiprazole and that these effects were particularly pronounced in female subjects [24]. As noted above, healthy women have longer QT intervals than healthy men [25], and female sex is known to be a risk factor for QTc interval prolongation [25]. Sex hormones are a major factor affecting the length of the QT interval, and estrogen has been suggested to prolong the QT interval due to bradycardia. Moreover, studies have reported a negative correlation between body mass index (BMI) and the QTc interval in women taking antipsychotics [24], which is thought to be due to decreased plasma concentrations of antipsychotics associated with increased drug distribution. In light of the above, if an individual exhibits risk factors for QT interval prolongation, such as being female or having a low BMI, it is necessary to take sex differences into account when considering the effect of each antipsychotic on the QTc interval to select an appropriate drug.

5. Antipsychotic-induced gonadal dysfunction

Gonadal dysfunction is common in patients with schizophrenia and leads to decreased quality of life and drug adherence [26]. Many studies have reported that psychiatric disorders are not the cause of gonadal dysfunction; instead, the cause is suspected to be the administration of antipsychotic medications [27]. In contrast, reports have indicated that mental illness itself is a risk factor [28]. Of the individuals treated with antipsychotic drugs, it is estimated that more than 50% of men and 30% of women experience gonadal dysfunction [29]. The most common side effects include erectile dysfunction, ejaculation problems, orgasm disorders, and decreased sexual interest in men; in women, the most common side effects are amenorrhea, dysmenorrhea, orgasm disorders, and decreased sexual interest. The most common side effects reported by men and women are erectile dysfunction in men and decreased sexual interest in women [30]. Patient distress due to these side effects is also reported to be greater in men [31]. There is no apparent relationship between the duration of treatment and gonadal dysfunction [32]. However, a higher incidence of sexual dysfunction is associated with the use of typical antipsychotics compared to atypical antipsychotics [33]. These side effects may be caused by anticholinergic effects, alpha1 adrenergic receptor inhibition, or hyperprolactinemia [34]. A study that evaluated sexual dysfunction in 101 patients receiving typical antipsychotics reported a relationship between prolactin levels and sexual dysfunction in both men and women [33]. In contrast to other atypical antipsychotics, risperidone causes a sustained increase in prolactin levels [35]. While there are reports of no significant differences in gonadal dysfunction among antipsychotics [36] significant differences have been shown between olanzapine and risperidone [30]. One study reported that olanzapine modification improved hyperprolactinemia and reduced sexual dysfunction in female schizophrenic patients treated with risperidone [37]. Additionally, relatively low rates of gonadal dysfunction are reported with quetiapine [30]. Thus, the prevalence of gonadal dysfunction in schizophrenic patients is high, the resulting decrease in drug adherence is a concern, and drug modification should be considered if necessary.

6. Antipsychotics during pregnancy and lactation

The risks of treatment with antipsychotics during pregnancy or lactation must be evaluated separately for the mother and child, comparing the risk of untreated maternal disease with the risk of toxic effects on the mother and child. One study reported that alterations in drug metabolism occur during pregnancy, with decreased CYP1A2 activity and increased CYP2D6 and CYP3A activity. Drug adjustment during pregnancy depends on the drug and the enzyme responsible for metabolism. Atypical antipsychotics have not demonstrated a clear advantage in safety during pregnancy or lactation compared to typical antipsychotics [38]. Olanzapine, risperidone, quetiapine, and clozapine do not increase the risk of fetal teratogenicity, but the use of aripiprazole, amisulpride, and ziprasidone is undesirable. However, several case reports have documented the development of gestational diabetes in women treated with clozapine or olanzapine during pregnancy. Clozapine is not recommended for use during pregnancy because it can cause floppy infant syndrome, neonatal seizures [39], gestational diabetes associated with shoulder dystocia in newborns [40], and agranulocytosis in newborns. During breastfeeding, infant drug exposure is generally less than 10% of the mother’s dose. Plasma concentrations of olanzapine and risperidone in infants are also very low and may be below the detection limit [41], and quetiapine has been reported to be ingested at very low doses of 0.09% of the weight-adjusted maternal dose [42]. In contrast, clozapine tends to accumulate in infant serum, and concentrations in breast milk are relatively high and should be avoided [43].

7. Conclusion

This review has outlined sex differences in pharmacotherapy for schizophrenia. In addition to the sex differences described here, many studies are currently investigating others. In clinical practice, however, treatment based on sex differences has not yet become widespread, and both men and women are treated almost identically. Psychiatric disorders, in particular, are likely to be chronic and require long-term intervention. Therefore, it can be inferred that the importance of sex-specific medical care tailored to the characteristics of each patient will increase in the future.

Conflict of interest

The all authors have no relationships with companies or organizations that would result in conflicts of interest that should be disclosed.