Absorption and bioavailability

Distribution

The total blood volume in women is smaller than in men, meaning that there is less volume available for a drug to be distributed. However, men have more lean muscle mass and less body fat than women, with young adult women having, on average, 15% more body fat than their male counterparts. Antipsychotic medications are lipophilic, so readily enter the body fat. With the more fat-soluble compounds, such as many depot antipsychotics, this results in greater distribution of antipsychotic in a woman’s body compared with a man for the same dose of drug. Over time, more depot antipsychotic will accumulate in a woman compared with a man. This implies that women may need a longer interval between depot doses than a man to reduce the side effect burden (Smith 2010).

This effect is magnified in women of South Asian or Chinese origin. People from these ethnic groups have a higher body fat to lean mass ratio than other groups. Thus, women of South Asian heritage are more likely to experience antipsychotic accumulation than both South Asian men and men and women of other ethnic groups (Lear et al. 2007, 2009).

Metabolism

Intra-individual differences in antipsychotic metabolism account for much of the variability in drug response. The bulk of drug breakdown takes place in the liver, largely through the cytochrome P450 (CYP450) enzyme system. All antipsychotic medications are metabolized by the CYP450 system, which is dominated by three main pathways – CYP1A2, CYP2D6 and CYP3A4 (see Table 23.1). Genetic variations in CYP450 enzymes govern the rate of drug metabolism, and both gender and ethnic differences have been found. Men generally have higher CYP1A2 activity compared with women, while the reverse is the case for CYP3A4 activity (Anthony & Berg 2002, Wolbold et al. 2003, Scandlyn et al. 2008).

The role of the drug transporter P-glycoprotein is also relevant. This is the main transporter of substrates across the intra- and extracellular membrane and men have more than twice as much of this as women in their hepatocytes. This results in lower levels of drug in the serum of women because more drug substrate is bound to this protein carrier (Meibohm et al. 2002, Fleeman et al. 2010).

A number of psychotropic and non-psychotropic medications, as well as naturally occurring substances, interfere with CYP metabolism by either inhibiting or inducing the enzymes. The ability of medications such as antidepressants and mood stabilizers to induce or inhibit CYP enzymes is particularly relevant in women because women are prescribed more of these drugs than men. Many selective serotonin reuptake inhibitor (SSRI) antidepressants are inhibitors of the CYP2D6. Fluoxetine and paroxetine are potent inhibitors, while fluvoxamine, sertraline and citalopram are weak inhibitors. Co-prescription of these drugs will exert a considerable influence on the metabolism of those antipsychotics that are substrates for this system, such as risperidone, clozapine and olanzapine. These drugs are more likely to accumulate when given concomitantly with certain SSRIs, increasing the risk of side effects and toxicity. As women with serious mental illness (SMI) are more likely to be receiving concomitant antidepressants, they are more likely to be exposed to this possibility.

The CYP enzymes, such as CYP1A2 and 3A4, are also affected by diet. Ethnicity and gender influence dietary choices. This is most likely to be of relevance when treating women with protein-rich diets and South Asian women who have adapted to a more protein-rich Western diet, as this results in faster metabolism of drugs in this population (Alvares 1976).

The hydrocarbons in tobacco smoke act as enzyme inducers and, given that a large proportion of people with SMI smoke, this has implications for drug metabolism and response. Smokers taking clozapine or olanzapine have lower plasma levels of the drug than non-smokers taking the same dose as the hydrocarbons in cigarette smoke induce CYP1A2, accelerating breakdown of the dibenzodiazepines; (Tang et al. 2007, Lane et al. 1999). The rates of smoking in the general population vary considerably by gender, although it is not clear if the same effect is seen in men and women with psychosis. In terms of attitudes to smoking, although there are no major gender differences in smokers with psychosis regarding reasons for smoking/quitting or smoking outcomes, female smokers with psychosis are more likely than males to report that they smoke to prevent weight gain. Therefore, in practice, it will help to focus specifically on weight in helping women smokers with psychosis to quit (Filia et al., 2014).

Renal clearance

Women have a lower glomerular filtration rate, renal tubular secretion and reabsorption than men, which means that the elimination of antipsychotics is slower in women than in men. This further increases the likelihood of drug accumulation within the body.

The multiple factors that affect drug handling in women are not simply countered by dosing on a mg/kg basis as multiple mechanisms underlie the gender-based pharmacokinetic differences. Thus, a man of the same weight will clear a drug quicker and have lower plasma levels than a woman; for example, men clear olanzapine 38% faster than women. Women are therefore at greater risk of a range of adverse drug reactions from antipsychotics because the drug stays in the body for longer (Smith 2010). The main factors influencing adverse effects are pharmacodynamic and are related to the receptor binding profiles of these drugs. For antipsychotic receptor binding profiles and related adverse effects see Tables 23.2 and 23.3.

Medication treatment response

Antipsychotic drugs are the mainstay of the medical treatment of people with schizophrenia. However, women with schizophrenia on average have a slightly later age of onset (although see Chapter 22), complicated reproductive and hormonal considerations, frequent affective symptoms and a greater likelihood of prior or ongoing victimization This is related to a common requirement for concomitant antidepressant and mood stabilizing medications, as well as being more likely to be co-prescribed hormonal preparations such as the combined oral contraceptive pill and hormone replacement therapy.

Even where antipsychotics are prescribed alone, there are considerable gender differences that should be borne in mind when prescribing. For example, for the same dose of clozapine or olanzapine, women will achieve much higher blood levels than men. They are likely to start showing a therapeutic response at a lower dose than men; if the dose is not modified to take account of gender, it may well lead to a much higher rate of side effects (Salokangas 2004, Tang et al. 2007b, Usall et al. 2007).

Adverse reactions to medication

There are two situations whereby women may experience adverse drug reactions. One, as alluded to earlier, is where the plasma levels of the medication are higher than intended by virtue of gender, leading to a greater likelihood of dose-related side effects.

The other type of side effect is where the effect is either specific to, or amplified in, women. An obvious example is drugs where there is a risk of teratogenicity in women of childbearing age. This is dealt with in Chapter 11 of this book. Many psychotropic medications affect the reproductive cycle or female sexual function, and may increase the risk of disorders that are more common in women in the general population, such as osteoporosis.

Antipsychotics

There are no specific antipsychotics used preferentially in women rather than men, but it should be noted that women are more at risk of the hormonal and metabolic side effects of antipsychotic medication, with men being more likely to suffer with the neurological side effects of these medications (Van Os 1999, Christodoulou & Kalaitzi 2005, Zhang et al. 2009). There is some limited evidence that women may experience a greater side effect burden with the newer second generation antipsychotics (SGAs), in particular clozapine and olanzapine, which is most likely related to the effects of these drugs on metabolic parameters (Aichhorn 2006).

Hyperprolactinemia

The most common cause of amenorrhea in women with psychosis is not pregnancy, but rather antipsychotic induced hyperprolactinemia – although for safety’s sake, the old medical school adage, “every woman is pregnant until proven otherwise” still applies. The antipsychotic most at fault here are those with strong affinity to the dopamine D2 receptor, especially amisulpride, risperidone and paliperidone. As dopamine is the main prolactin inhibitory factor, antagonism of this receptor may cause a large and clinically meaningful rise in prolactin. This can result in amenorrhea, galactorrhea, enlarged breasts, and, in the longer term, an increased risk of osteoporosis and fractures (Abel et al. 2008; Inder & Castle, 2011). Up to 75% of women taking prolactin-raising medications (those with significant D2 blocking effects) experience hyperprolactinemia (Smith et al. 2002, Wieck & Haddad 2003).

The use of antipsychotic medication is commonly associated with sexual dysfunction (in both women and men). However, because of the complex nature of female sexuality, the significant negative impact on women’s sexual function of antipsychotic medication may be missed. Studies indicate that antipsychotic-related sexual dysfunction is more common in women than men with up to 90% of women taking antipsychotics experiencing sexual dysfunction (MacDonald et al. 2003). Unlike with men (for whom there are multiple underlying mechanisms driving sexual dysfunction), the main cause of sexual dysfunction in women taking antipsychotic medication is hyperprolactinemia (Smith et al. 2002, Harley et al. 2010). Low libido is often the first sign of antipsychotic-induced hyperprolactinemia, but this symptom must be directly inquired about as patients are unlikely to report it spontaneously (Smith 2002, Baggaley 2008).

Hyperprolactinemia is not the only cause of amenorrhea or oligomenorrhea in women with severe mental illness. The use of the mood stabilizer sodium valproate not only results in a far greater risk of teratogenicity than other anticonvulsants, but also confers a risk of polycystic ovarian syndrome (PCOS), which adds to cardiac risk in the longer term (Wild et al. 2010, Hillman et al. 2014). Given the shortened life expectancy already experienced by people with psychosis, this additive risk is a substantial concern. The anti-diabetic drug metformin has been shown not just to help reduce weight, but also to improve amenorrhea in women with schizophrenia (Wu et al., 2012).

Cardiovascular risk and metabolic syndrome

There is increasing evidence that in addition to being at risk of hormonally mediated side effects of psychotropic medications, women are at greater risk of the metabolic adverse effects of these drugs. The CATIE study found that 51% of women taking antipsychotic medication had metabolic syndrome compared with 36% of men (McEvoy et al 2005). The NIHR funded IMPaCT (IMProving health and ReduCing SubsTance Use in Psychosis) program in the UK found very high rates of central obesity, most marked in women (personal communication, Gaughran et al. 2013). Given the greater diabetes hazard ratio in women, that is, that women are more likely to develop diabetes complications and die from the cardiovascular disease related to their diabetes, this represents a major physical health burden for women. It is therefore incumbent upon prescribers to ensure that they choose antipsychotic medications that are less likely to worsen the cardiovascular status of women in the long term. This could help to improve the shortened life expectancy seen in this group.

Table 23.2 shows the side effects associated with different antipsychotic medications. It is apparent from this which medications are most likely to be troublesome in women and prescribers can use this information to tailor the medication to the individual in order to minimize the risk of short- and long-term side effects.

Other psychotropics used in the treatment of women with schizophrenia and psychotic disorders

Antidepressants – Depression is common in schizophrenia with prevalence rates estimated at 40% or more (Wassink et al. 1999, Micallef et al. 2006). Women with schizophrenia are more likely to have an affective component to their illness (Tang 2007b, Martin-Reyes 2011). Generally, women are more likely to be treated for depression than men, which may partly be due to differences in health-seeking behavior between the sexes. A recent study found that depression and psychotic depression were common amongst a group of women and men with schizophrenia, yet only one-third of the sample had received antidepressants. They recommended that prescribers could significantly improve the prognostic outcomes for their patients if they regularly reviewed depressive symptomatology and their prescribing practices (Nejtek et al. 2012).

There are no specific antidepressant medications which are felt to be more advantageous in women than men with schizophrenia, but it should be remembered that the SSRI medications may interfere with hepatic metabolism in a way that is likely to differentially affect women by interfering with antipsychotic metabolism, and that they may cause sexual dysfunction thus adding to any sexual dysfunction problems caused by co-prescribed antipsychotic medication (see Table 23.1).

Hypnotics (benzodiazepines and antihistamines) – Although not in and of themselves treatments for schizophrenia, these drugs are often used in the acute stages of treatment to manage agitation, anxiety and disturbed behavior. Benzodiazepines are both overprescribed to, and overused by, women and those of advancing age (Simoni-Wastila 2004). However, despite benzodiazepine use in schizophrenia being common, women with schizophrenia appear no more likely to receive these drugs than men with schizophrenia (Xiang et al. 2012). Antihistamines are often used instead of benzodiazepines as sedatives because they have a far lower addiction potential. These drugs are relatively safe and there are no significant gender differences in their handling; the main consideration should be that prescribers might consider using these rather than the more addictive benzodiazepines where possible, given that one-third of people are likely to continue benzodiazepines for 8 years or more after initial prescription and more recently benzodiazepine use has been linked with a significant increase in mortality (van Hulten et al. 2003, Weich et al. 2014).

Mood stabilizers

Schizophrenia in women often has an affective component and therefore, it should be expected that women with schizophrenia are often given concomitant mood stabilizing medications. With this in mind, prescribers should be aware of, and be cautious about, the following.

Sodium valproate – The significant adverse effects associated with sodium valproate have a disproportionate effect on women. This is dealt with in Chapter 21, but in brief, sodium valproate is associated with menstrual abnormalities and PCOS, and has a high risk of teratogenicity in the fetus. Therefore, great care should be given to ensuring it is not given to sexually active, reproductively able women. If there is no alternative to valproate, robust contraception plus folate is essential.

Lithium – Lithium use is well-known to be associated with thyroid abnormalities, in particular, goiter, hypothyroidism, hyperthyroidism and autoimmune thyroiditis. Lithium-associated thyroid dysregulation occurs more frequently in women (Bauer et al. 2014, Ozerdem et al. 2014) and therefore monitoring of thyroid function (serum thyroid stimulating hormone, free thyroid hormones – T3 and T4, and thyroid autoantibodies) and clinical assessment of thyroid size should be undertaken at initiation of lithium and annually.

There is evidence that over time lithium gradually reduces glomerular filtration rate (GFR), that is, it can compromise renal function. GFR has been estimated to decrease by 0.64ml/min (95% CI = 0.38 to 0.90, p = 0.00) for each year of lithium treatment (Bocchetta et al. 2013). This has disproportionately negative effects on women who already have slower GFRs than men. In a recent study, women treated with lithium not only had lower GFR to begin with but also had a higher rate of reduction in GFR. They were more likely to have an eGFR <60ml/min, which indicates chronic kidney disease stage 3–5 (Bocchetta et al. 2013). This means that lithium is more likely to be associated with renal disease in women.

In addition, lithium is exquisitely sensitive to changes in fluid balance, which are more likely to occur around the menstrual cycle. This can affect the volume of distribution of lithium, which has a narrow therapeutic range. Therefore prescribers must be vigilant and ensure adequate monitoring when prescribing to women.