Dose-Adjusted Sex Differences in Antipsychotic Serum Concentrations

We retrieved three database studies [45•, 46, 47] and one randomized controlled trial (RCT) [48] providing sex-specific dose-adjusted antipsychotic serum concentrations (Fig. 2 in supplement, Table 1). Castberg and colleagues [46] included 11,968 patients (48% women) using clozapine, olanzapine, risperidone, or quetiapine from a routine therapeutic drug monitoring (TDM) database and found that dose-adjusted serum concentrations for clozapine, olanzapine, and risperidone were significantly higher in women compared to men (28.2%, 26.1%, and 18.7%, respectively, higher in women). For quetiapine, no significant sex differences were found in younger age groups (age < 40 years). Yet, age-by-sex interaction indicated that sex differences in dose-adjusted concentrations for quetiapine increase with age. At the age of 80, dose-adjusted concentrations for quetiapine are 33% higher in women compared to men.

A similar TDM study by Jönsson and colleagues [45•] included 26,833 patients (47% women) and reported significantly higher dose-adjusted concentrations in women for 10 out of 12 antipsychotics compared to men. The largest increases were found for olanzapine and clozapine, showing higher dose-adjusted concentrations of, respectively, 59% and 40% in women. For quetiapine, no significant differences were found, with dose-adjusted concentrations in women being 6.4% lower. For sertindole, the absence of a significant difference between men and women was possibly due to the small sample size included for this antipsychotic, as sex differences were numerically similar to the other evaluated antipsychotics.

An observational study by Tveito and colleagues [48] investigated long-acting injectable formulations of paliperidone (once-monthly) in 1158 patients (36% women, 3394 samples). They found significantly higher dose-adjusted concentrations in women (14% higher than in men), while men were prescribed 10% higher dosages than women. Dose-adjusted concentrations in older women (≥ 50 years) were increased by 29%, 30%, and 41%, compared to older men (≥ 50 years), younger women (≤ 49 years), and younger men (≤ 49 years), respectively (all p’s < 0.001).

An RCT by Hoekstra and colleagues [47] examined dose-adjusted concentrations in 144 patients (35.4% women), randomized to receive either amisulpride, aripiprazole, or olanzapine. The sample sizes of this study were much smaller as compared to the other studies, with 12 women (29%) in the olanzapine group, 12 women (24%) in the aripiprazole group, and 27 (51%) in the amisulpride group. No significant differences were found for olanzapine, while dose-adjusted serum levels were significantly higher in women for aripiprazole (56%) and amisulpride (72%). Hoekstra and colleagues also reported significantly higher prolactin levels in women than in men, especially for amisulpride, and a significantly higher BMI increase in women on this antipsychotic as compared to the two other antipsychotics.

Table 1 Studies investigating sex differences in serum concentrations of antipsychotic drugsHormonal Augmentation TherapiesEstrogen Augmentation

No high-quality meta-analyses were performed on this topic in the last 5 years. We found seven RCTs examining the effects of estrogen augmentation therapy on symptom severity (Fig. 3 in supplement), which were all performed in premenopausal women or in women of premenopausal age (Table 2). Types of estrogen augmentation that were examined were augmentation with estradiol (E2), conjugated equine estrogens (CEE), ethinyl estradiol (EE), and estradiol valerate (EV). In most studies, estrogens showed to be superior compared to placebo in reducing total symptomatology and symptomatology subscales (i.e., positive, negative, and general symptoms) as measured by the Positive and Negative Syndrome Scale (PANSS) [49]. However, Louzã and colleagues [50] did not find a significant effect of CEE on symptom severity compared to placebo in a sample of 40 women (age range 18–49, menopause status unknown), although a trend towards improvement was visible. It is important to highlight that the most recent meta-analysis concerning estrogen augmentation dates back to 2014 [26]. There have not been any meta-analyses on this subject within the last 5 years, possibly due to the limited availability of recent RCTs published on this topic, as only one additional RCT has been published [63]. The meta-analysis performed by Heringa and colleagues [26] found positive effects of estrogen augmentation, with effect sizes ranging from moderate to high for total symptom severity (Hedges’ g = 0.83, p = 0.001), positive symptoms (Hedges’ g = 0.48, p = 0.001), and negative symptoms (Hedges’ g = 0.39, p = 0.011), based on a sample of 427 women with SSD. Overall, these studies show that estrogenic augmentation therapies reduced PANSS total, positive, negative, and general scores specifically in premenopausal women with SSD.

Table 2 Randomized controlled trials investigating the effects of estrogen augmentation therapy on symptoms in women with SSDRaloxifene Augmentation

We found three meta-analyses that were published less than 5 years ago [51•, 52, 53]. Our search retrieved no original/novel RCT since these meta-analyses, apart from a subgroup analysis in a subsample of the RCT by Usall and colleagues [54, 55]. All original and relevant RCTs are summarized in Table 3.

Table 3 Randomized controlled trials investigating the effects of raloxifene augmentation therapy on symptoms in men and women with SSD

The publication by De Boer and colleagues in 2018 was the most comprehensive meta-analysis, including nine studies in 561 patients with SSD, of which seven studies in postmenopausal women, one study in premenopausal women and men, and one study in men [51•]. Raloxifene was superior to placebo in improving total symptom severity (N = 482; Hedges’ g = 0.57, p = 0.009), as well as positive (N = 561; Hedges’ g = 0.32, p = 0.02), negative (N = 561; Hedges’ g = 0.40, p = 0.02), and general (N = 526; Hedges’ g = 0.46, p = 0.01) subscales, as measured by the PANSS.

The other meta-analyses specifically included RCTs in postmenopausal women, of which Wang et al. was the most comprehensive one [52, 53]. Corroborating the findings of de Boer and colleagues, Wang and colleagues found a superior effect of raloxifene as compared to placebo on PANSS total symptom severity, positive, negative, and general symptom severity (standard mean difference (SMD) − 0.22 to − 0.55, 95% confidence interval (CI) − 1.01 to − 0.02, p = 0.04–0.01; I2 = 74–79%). Overall, these studies indicate that adjunctive raloxifene improved PANSS positive, as well as total, negative, and general scores relative to placebo in women with SSD. As most studies have been conducted in postmenopausal women, there is most evidence for the beneficial effects of raloxifene for this group of women.

Safety and Tolerability of Hormonal Augmentation

Attitudes towards therapy with hormone-like agents tend to be negative due to the harmful effects that have been associated with its use in the past [56]. Although the prevalence of hormone replacement therapy for menopausal symptoms was high until the start of the current century, its use decreased due to two landmark studies who reported severe adverse effects. Current literature indicates that hormone replacement therapy is an acceptable and safe option for women before or within 10 years of menopause [57]. However, the safety of estrogen augmentation therapy in premenopausal women, and especially the safety of its long-term use (> 10 years) is still unknown.

Raloxifene has agonistic effects on the brain and bones, while having antagonistic effects on the breasts and uterus [28,29,30]. A recent review compared breast cancer risks in a sample of 116,317 raloxifene nonusers versus 1223 regular users of raloxifene and concluded that breast cancer-specific survival in raloxifene users was not worse than in nonusers, providing indirect evidence that raloxifene reduces breast cancer-related mortality [28]. In addition, a systematic review showed that the use of raloxifene is not associated with higher risks of endometrial cancer [30]. However, like all estrogens, raloxifene is associated with an increased risk of venous thromboembolic events (VTE). VTE risk seems highest at initiation and tends to decline with long-term use [30]. Overall, raloxifene can be considered more suitable for long-term use compared to estrogens.

Augmentation with Combined Contraceptives

We found no RCTs investigating the effects of combined contraceptives on symptom severity in women with SSD. Combined contraceptives (oral, patches, and vaginal ring) are widely prescribed to premenopausal women, including women with SSD. Despite the accumulating evidence of a beneficial effect of exogeneous estrogens on symptom severity in premenopausal women with SSD (Table 2), no studies investigated the effect of estrogenic contraceptives in premenopausal women with SSD. However, a recent meta-analysis evaluated psychotic exacerbations across the menstrual cycle in women with a psychotic disorder and showed that the rate of admissions during the perimenstrual phase was 1.48 times higher than expected (95% CI 1.31 to 1.67), indicating that hormonal fluctuations can negatively affect clinical outcome [22•]. By providing a regular daily dose of exogenous hormones, estrogenic contraceptives may have a stabilizing effect on endogenous sex hormone levels [27], especially when the stopping week is avoided. As estrogens are also known to affect the metabolism of several antipsychotics [17], the permanent use of a combined contraceptive may also help to stabilize the dose concentrations of antipsychotics. Instead, permanently lowering endogenous estrogen levels may also have a negative impact on symptom severity, considering the protective effects of estrogens. However, there are no studies that endorse any of these potential effects of combined contraceptives in women with SSD.

Strategies to Reduce Antipsychotic-Induced Hyperprolactinemia

We found two large recent meta-analyses on prolactin-lowering strategies for antipsychotic-induced prolactin elevation [41•, 70•]. Zhang and colleagues [70•] specifically summarized studies on adjunctive therapies, while Lu and colleagues [41•] summarized both addition and switching strategies. Our search retrieved one additional clinical trial on adjunctive metformin (Fig. 4 in the supplement) [71].

Addition Strategies

The network meta-analysis of Zhang and colleagues [70•] included RCTs on adjunctive therapies with aripiprazole (k = 53), paeoniae–glycyrrhiza decoction (PGD) (k = 5), and metformin (k = 4), including 5550 patients (66% female). They composed nine different treatment groups based on treatment type and different dosing regimens. There were 23 RCTs that specifically included women, whereas 7 RCTs specifically included men. Aripiprazole of < 5 mg/day was found to be the most effective adjunctive therapy for reducing prolactin levels as compared to placebo and all other treatment groups, followed by aripiprazole at > 10 mg/day and aripiprazole 5–10 mg/day. Adjunctive PGD was associated with the least all-cause discontinuation rate, but since the quality standardization of PGD preparation is still lacking, this can currently not be considered as a treatment strategy and needs further research. Importantly, a subgroup analysis revealed a sex difference in the efficacy of the adjunctive treatments, showing a 25% smaller decrease in women as compared to men.

Lu and colleagues [41•] performed a series of meta-analyses including single-armed studies on adjunctive aripiprazole (k = 15), single-armed studies on adjunctive dopamine agonists (k = 9), RCTs on adjunctive aripiprazole (k = 12), and RCTs on adjunctive PGD (k = 3). All conducted meta-analyses contained high levels of heterogeneity. Based on their findings, it can also be concluded that adjunctive aripiprazole was the augmentation strategy with the best level of evidence, while the effect of PGD on prolactin levels was not significant.

Similar conclusions could be drawn from their network meta-analysis, which also included RCTs on adjunctive metformin (k = 2), adjunctive vitamin B6 (k = 1), adjunctive PDG (k = 5), and adjunctive dopamine agonists (k = 2). Although they found a significant effect of adjunctive vitamin B6, this was based on one study (n = 200) in which only males were included. In another network meta-analysis, they compared different dosing categories of adjunctive aripiprazole and concluded that aripiprazole doses of 5, 10, and > 10 mg/day were similarly effective, while prolactin elevation above 100 ng/ml was only significantly reduced at a dose of 5 mg/day. Aripiprazole at > 10 mg/day was associated with a higher incidence of side effects.

Our search retrieved one additional RCT on this topic. Zhu and colleagues [71] evaluated the effect of metformin addition on amisulpride-induced hyperprolactinemia (n = 86, 47% women). Prolactin levels in the metformin group were significantly lower compared to the placebo group after 8 weeks; this effect was observed in the whole group as well as in women separately.

Switching Strategies

Lu and colleagues evaluated the efficacy of switching strategies in a comprehensive meta-analysis of single-armed studies and a network meta-analysis on RCTs on switching strategies [41•]. The meta-analysis included 26 studies, of which 15 with aripiprazole, whereas other strategies included switching to quetiapine, clozapine, olanzapine, and brexpiprazole. The network meta-analysis included 6 RCTs on switching to aripiprazole, and one RCT on switching to quetiapine. Based on both analyses, switching to another antipsychotic appears to be an effective strategy to lower prolactin levels. When comparing different switching strategies, changing antipsychotic therapy to aripiprazole in titration and reducing the previous antipsychotic in titration has the best level of evidence, whereas switching to other antipsychotics (olanzapine or quetiapine) reached a low level of evidence.