In a period in which they keep on struggling for equal chances in several fields, women still need to strive for a medical treatment which takes sex differences into account. Medical practice has long been implicitly led by the notion that only reproductive organs differ between the sexes. Yet, significant sex differences have been clearly documented in blood, immune system, liver, kidneys, stomach, gut, heart and brain¹. Such differences can impact pharmacokinetic and pharmacodynamic mechanisms².

For example, women have a less acidic stomach³, which increases the absorption of weak acids but decreases that of weak bases. Gastric and colonic emptying is slower, lending pharmaceuticals more time to be absorbed. The levels of protein-transporter p-glycoprotein are two-fold lower in women of fertile age than in men: as this transporter pumps substances out of the cell, a lower activity increases absorption in the body and the brain, while decreasing renal excretion³. Blood volume and blood protein fraction are lower in women, decreasing dilution and binding capacity compared to men. Women, on average, have more fat tissue, which can lead to stacking of lipophilic pharmaceuticals. In gut and liver, many cytochrome P450 (CYP) enzymes are influenced by estrogens, which can lead to higher (for CYP3A4, and to a lesser degree for CYP2D6) or lower (for CYP1A2 and CYP2C19) metabolic activity in women of reproductive age. Renal blood flow, glomerular filtration, tubular secretion and resorption are all lower in women. These sex differences are not only numerous; they are also sizable – a 10-50% sex difference per mechanism – and can significantly affect the efficacy and tolerability of pharmacotherapy.

In 1977, the US Food and Drug Administration (FDA) recommended that women of childbearing age should be excluded from phase 1 and early phase 2 clinical trials. This directive, intended to protect women, did quite the opposite: it halted the understanding of pharmacotherapy in the female body and widened the knowledge gap in women's health. In 1993, the US National Institutes of Health policy made the inclusion of women and minorities in trials mandatory, but drugs already registered at that time were never retested in large female study populations. At present, only a handful of drugs (such as alosetron, desmopressin and zolpidem) have different dosing recommendations for women, while there are over 100 commonly prescribed drugs with unequal pharmacokinetics between men and women². This suggests that women are at high risk for both over- and under-dosing of many drugs across medical specialties.

For psychotropic drugs, sex differences in pharmacodynamics further contribute to inequalities in efficacy and tolerability. Dopamine release regulation and synaptic elimination are influenced by sex hormones and differ significantly between men and women⁴. Although less well studied, such sex differences in neurotransmitter trafficking are also described in the serotonergic, GABAergic and glutamatergic circuitry⁵.

Many of the above mechanisms – such as increased or reduced activity of CYP enzymes or p-glycoprotein, gastric acid production, gastric and colonic emptying, and dopaminergic and serotonergic trafficking – are estrogen-dependent^{3, 5}. This means that changes in pharmacokinetics and pharmacodynamics occur over the phases of the menstrual cycle, affecting the efficacy and tolerability of psychotropic drugs. Robust changes in efficacy and safety occur when hormonal changes are large, such as during pregnancy and menopause. With menopause, pharmacokinetic and pharmacodynamic mechanisms may both reduce the bioavailability of drugs, inducing a dramatic reduction in their efficacy. We recently demonstrated a massive increase in rehospitalization after menopause in women with schizophrenia spectrum disorders using commonly prescribed antipsychotics⁶.

Olanzapine is absorbed more readily from the gastrointestinal tract in women, whereas renal clearance is lower. As this antipsychotic is predominantly metabolized by CYP1A2, which is inhibited by estrogens, blood levels may be about two-fold higher in pre-menopausal women than in men with equal dosing⁷. In addition, the pre-menopausal female brain is more sensitive to olanzapine treatment, with women achieving similar receptor occupancy rates at a 50% lower dose than men³. After menopause, gastric acidity and emptying equals that of men, and CYP1A2 is no longer inhibited by estrogens, so that the blood levels of the drug decrease. At the same time, declining estrogen levels reduce the sensitivity of the brain to olanzapine³, which leads to much lower receptor occupancy and efficacy in post-menopausal women.

Quetiapine is mainly metabolized by CYP3A4, whose activity is induced by estrogens, while excretion in women is lower than in men. In pre-menopausal women, these mechanisms work in opposite directions, leading to approximately similar blood levels in men and women with the same dose of the drug⁷. After menopause, quetiapine metabolism slows down and blood levels rise, which may cause a rapid increase in side effects⁷.

Imipramine is absorbed better in women than in men. Its main metabolizing enzyme, CYP2C19, is inhibited by estrogens and, with equal dosing, blood levels in women may be much higher. In practice, toxic serum levels are often corrected, as therapeutic drug monitoring is the standard of care for imipramine. After menopause, CYP2C19 inhibition stops and, with the same dose, bioavailability of imipramine decreases significantly, increasing the risk for relapse of depression.

Fluoxetine is transported by p-glycoproteins and metabolized by several CYP enzymes, including CYP2C19. In pre-menopausal women, serum levels are much higher than in men receiving the same dose. As therapeutic drug monitoring is not the standard for this medication, many young female patients are expected to be overdosed.

Zolpidem yields an about 30% higher exposure in women, especially after menopause⁸. The risk of morning drowsiness prompted the FDA to request sex-specific dose recommendations. The manufacturers now recommend prescribing half the male dose for women, without taking menopausal status into account⁸.

Simply treating women with half the male dose of a psychotropic drug, as the manufacturers of zolpidem recommend, is not sufficient, as sex differences can be hormone-dependent and drug-specific. In order to provide women with a dose that fits their body and hormonal status, each psychotropic drug would need to be examined for its sex- and hormone-specific pharmacokinetic and pharmacodynamic mechanisms. Detailed knowledge of sex-specific dosing for all psychotropic drugs should be expanded rapidly, to stop over- and under-treatment of female patients, which now occurs for many of these drugs².

Female patients are a heterogeneous group. As many mechanisms are estrogen-dependent, hormonal status – especially during pregnancy and menopause – needs to be considered. We currently cannot oversee all sex- and hormone-dependent pharmacokinetic and pharmacodynamic mechanisms for each psychotropic drug, as this is a quite complicated matter. Therefore, therapeutic drug monitoring – when available – is recommended for female patients, especially during pregnancy and menopausal transition.

There are factors – such as age, body mass index, percentage of fat tissue, and genetic polymorphism of CYP enzymes – whose importance in determining the correct dosage of psychotropic drugs is widely acknowledged. However, sex and hormonal status also have a large impact on the efficacy and tolerability of many psychotropic drugs. It is now time to take them into account.

在女性不断在多个领域争取平等机会的时期，女性仍然需要争取考虑到性别差异的医疗。长期以来，医学实践一直隐含着这样一种观念：两性之间只有生殖器官不同。然而，在血液、免疫系统、肝脏、肾脏、胃、肠道、心脏和大脑中都清楚地记录了显着的性别差异¹。这些差异可能会影响药代动力学和药效学机制²。

例如，女性的胃酸性较低³，这会增加弱酸的吸收，但会减少弱碱的吸收。胃和结肠排空较慢，使药物有更多时间被吸收。育龄女性的蛋白质转运蛋白 p-糖蛋白水平比男性低两倍：由于这种转运蛋白将物质泵出细胞，较低的活性会增加身体和大脑的吸收，同时减少肾脏排泄³。与男性相比，女性的血容量和血液蛋白分数较低，稀释度和结合能力较低。平均而言，女性有更多的脂肪组织，这可能导致亲脂性药物的堆积。在肠道和肝脏中，许多细胞色素 P450 (CYP) 酶受到雌激素的影响，这可能导致育龄妇女的代谢活性升高（CYP3A4 和 CYP2D6 程度较低）或降低（CYP1A2 和 CYP2C19）。女性的肾血流量、肾小球滤过、肾小管分泌和吸收均较低。这些性别差异不仅数量众多，而且数量巨大。它们也相当大——每种机制存在 10-50% 的性别差异——并且可以显着影响药物治疗的功效和耐受性。

1977年，美国食品和药物管理局（FDA）建议将育龄妇女排除在1期和早期2期临床试验之外。这项旨在保护女性的指令却适得其反：它阻止了对女性身体药物治疗的理解，并扩大了女性健康方面的知识差距。1993年，美国国立卫生研究院的政策强制要求将女性和少数族裔纳入试验，但当时已经注册的药物从未在大量女性研究人群中进行重新测试。目前，只有少数药物（如阿洛司琼、去氨加压素和唑吡坦）对女性有不同的剂量建议，而超过 100 种常用处方药物的男女药代动力学不同²。这表明女性在医学专业中的许多药物服用过量或不足的风险很高。

对于精神药物，药效学的性别差异进一步导致疗效和耐受性的不平等。多巴胺释放调节和突触消除受到性激素的影响，并且男性和女性之间存在显着差异⁴。尽管研究较少，但神经递质运输中的这种性别差异也在血清素能、GABA 能和谷氨酸能回路中有所描述⁵。

上述许多机制——例如 CYP 酶或 p-糖蛋白活性的增加或减少、胃酸的产生、胃和结肠排空以及多巴胺能和血清素能运输——都是雌激素依赖性的^{3, 5}。这意味着药代动力学和药效学的变化发生在月经周期的各个阶段，影响精神药物的疗效和耐受性。当荷尔蒙变化较大时，例如在怀孕和更年期期间，功效和安全性会发生剧烈变化。绝经后，药代动力学和药效学机制都可能降低药物的生物利用度，导致其疗效急剧下降。我们最近证明，使用常用抗精神病药物治疗的精神分裂症谱系障碍女性绝经后的再住院率大幅增加⁶。

奥氮平在女性中更容易从胃肠道吸收，而肾脏清除率较低。由于这种抗精神病药主要由 CYP1A2 代谢，而 CYP1A2 受雌激素抑制，因此绝经前女性的血液水平可能比同等剂量的男性高约两倍⁷。此外，绝经前女性大脑对奥氮平治疗更敏感，女性以比男性低 50% 的剂量即可达到相似的受体占用率³。绝经后，胃酸度和排空量与男性相当，CYP1A2不再受到雌激素的抑制，从而使该药的血药浓度下降。同时，雌激素水平下降会降低大脑对奥氮平^{3 的}敏感性，从而导致绝经后女性的受体占用率和疗效显着降低。

喹硫平主要通过CYP3A4代谢，其活性由雌激素诱导，女性的排泄量低于男性。在绝经前女性中，这些机制以相反的方向发挥作用，导致服用相同剂量药物的男性和女性的血液水平大致相似⁷。绝经后，喹硫平代谢减慢，血药浓度升高，可能导致副作用迅速增加⁷。

女性比男性更容易吸收丙咪嗪。其主要代谢酶 CYP2C19 受到雌激素的抑制，在同等剂量下，女性血液中的水平可能要高得多。在实践中，有毒血清水平通常会得到纠正，因为治疗药物监测是丙咪嗪的护理标准。绝经后，CYP2C19 抑制作用停止，在相同剂量下，丙咪嗪的生物利用度显着降低，增加了抑郁症复发的风险。

氟西汀由 p-糖蛋白转运，并由多种 CYP 酶（包括 CYP2C19）代谢。绝经前女性的血清水平比接受相同剂量的男性高得多。由于治疗药物监测不是这种药物的标准，因此许多年轻女性患者预计会服用过量。

女性中唑吡坦的暴露量要高出约 30%，尤其是绝经后⁸。早晨嗜睡的风险促使 FDA 要求针对特定性别的剂量建议。制造商现在建议为女性开出男性剂量的一半，而不考虑更年期状况⁸。

正如唑吡坦制造商建议的那样，仅仅用男性剂量一半的精神药物治疗女性是不够的，因为性别差异可能是激素依赖性和药物特异性的。为了向女性提供适合其身体和激素状态的剂量，需要检查每种精神药物的性别和激素特异性药代动力学和药效机制。应迅速扩大对所有精神药物的性别特异性剂量的详细了解，以制止对女性患者的过度治疗和治疗不足，这种情况现在在许多此类药物中都发生过²。

女性患者是一个异质群体。由于许多机制依赖于雌激素，因此需要考虑荷尔蒙状态，尤其是在怀孕和更年期期间。我们目前无法监督每种精神药物的所有性别和激素依赖性药代动力学和药效机制，因为这是一个相当复杂的问题。因此，建议女性患者在可行的情况下进行治疗药物监测，尤其是在怀孕和绝经过渡期间。

年龄、体重指数、脂肪组织百分比和 CYP 酶的遗传多态性等因素在确定精神药物的正确剂量方面的重要性已得到广泛认可。然而，性别和荷尔蒙状态也对许多精神药物的疗效和耐受性产生很大影响。现在是时候考虑它们了。