859973 review-article20192019 TPP0010.1177/2045125319859973Therapeutic Advances in PsychopharmacologyA González-Rodríguez and MV Seeman Therapeutic Advances in Psychopharmacology Review The association between hormones and Ther Adv Psychopharmacol 2019, Vol. 9: 1–20 antipsychotic use: a focus on postpartum DOI: 10.1177/ https://doi.org/10.1177/2045125319859973 https://doi.org/10.1177/2045125319859973 2045125319859973 and menopausal women © The Author(s), 2019. Article reuse guidelines: sagepub.com/journals- permissions Alexandre González-Rodríguez and Mary V. Seeman Abstract: During the postpartum and menopausal periods of women’s lives, there is a well- established and significant drop of circulating estrogens. This may be the reason why both these periods are associated with an increased risk for onset or exacerbation of psychiatric disorders. Whether symptoms are mainly affective or mainly psychotic, these disorders are frequently treated with antipsychotic medications, which calls for an examination of the relationship between hormone replacement and antipsychotic agents at these time periods. The aim of this narrative review is to summarize what is known about the association of hormones and antipsychotics in the postnatal period and at menopause. In the review, we focus on estrogen and oxytocin hormones and include, for the most part, only papers published within the last 10 years. Both estradiol and oxytocin have at various times been implicated in the etiology of postpartum disorders, and estrogens, sometimes combined with progesterone, have been tested as potential treatments for these conditions. The role of estradiol as an adjunct to antipsychotics in the prevention of postpartum relapses is currently controversial. With respect to oxytocin, studies are lacking. Psychosis in menopausal and postmenopausal women has been successfully treated with estrogens and selective estrogen- receptor modulators, mainly raloxifene, in addition to antipsychotics. Some symptoms appear to respond better than others. No oxytocin study has specifically targeted postmenopausal women. Because of feedback mechanisms, there is a theoretical danger of therapy with exogenous hormones interfering with endogenous secretion and disturbing the balance among inter-related hormones. When used with antipsychotics, hormones may also affect the metabolism and, hence, the brain level of specific antipsychotics. This makes treatment with antipsychotics plus hormones complicated. Dose, timing and route of intervention may all prove critical to efficacy. While much remains unknown, this literature review indicates that, within standard dose ranges, the combination of hormones and antipsychotics for postnatal and menopausal women suffering severe mental distress can be beneficial, and is safe. Keywords: antipsychotics, hormones, menopause, postpartum Received: 17 November 2018; revised manuscript accepted: 1 April 2019. Correspondence to: Mary V. Seeman Introduction these periods in a woman’s life, postnatal and Department of Psychiatry, University of Toronto, 260 Following expulsion of the placenta after child- perimenopausal, are times of special vulnerabil- Heath Street West, Suite birth, estradiol and progesterone levels in women ity. Psychiatric morbidity characteristic of these 605, Toronto, Ontario M5P 3L6, Canada drop precipitously from their peaks at the end of periods can sometimes manifest as psychotic mary.seeman@utoronto. pregnancy. The sharpness of the drop is in con- symptoms (delusions, hallucinations, and cogni- ca Alexandre González- trast to the more gradual and fluctuating decline tive distortions), which are generally treated with Rodríguez of estrogens at perimenopause. It is also time lim- antipsychotic medications. Nonpsychotic affec- Department of Mental Health, Autonomous ited, in contrast to the permanent withdrawal of tive symptoms during these periods also, at times, University of Barcelona, gonadal hormones in menopausal women. Both respond to antipsychotics. Several questions arise Barcelona, Spain journals.sagepub.com/home/tpp 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Psychopharmacology 9 from this conjunction of hormone deficiency, been reported. Other studies, however, found no mental distress, and antipsychotic agents: polymorphisms of either ESR1 or ESR2 that were associated with postpartum psychosis.10 1. Does hormone replacement work and, if so, for which symptoms? Postpartum psychoses fall into three categories: 2. Is hormone replacement able to reduce the mania or mixed episodes with psychotic features, dose of antipsychotics? depressive episodes with psychotic features, and 3. Are some antipsychotics more compatible nonaffective psychotic episodes.3 These can occur with adjunctive hormones than others? after one birth (usually the first) and never again 4. Are hormone/antipsychotic combinations or they can recur with every birth (25–50% of the safe and well tolerated and, if so, within time). They can represent exacerbations of what dose range? chronic depressive, bipolar, or schizophrenic ill- ness. The incidence of first-time postpartum psy- The aim of this narrative, nonsystematic review chosis varies from 0.25 to 0.6 per 1000 births, 23 was to synthesize what is known about the asso- times higher within the first 4 weeks of delivery ciation of hormones (estrogens and oxytocin for than at any other time of a woman’s life. The clin- the most part) and antipsychotics in the puerperal ical picture is characterized by cognitive dysfunc- period and at menopause. tion: disorientation, confusion, derealization, and depersonalization, with mood-incongruent delu- sions centered on the theme of chilbirth.3 Method We reviewed the clinical literature on estrogens The literature suggests both estradiol11 and oxy- and oxytocin use in the postpartum and at meno- tocin12 may be implicated in postpartum psychosis. pause, with an emphasis on studies published within the last 10 years. We also reviewed the effi- cacy of hormonal treatments as adjuncts to antip- Estrogen and postpartum psychosis sychotics in these same time periods, and address Estrogen modulates dopaminergic, serotonergic, issues of therapeutic safety and tolerability. glutaminergic, noradrenergic, and cholinergic sys- tems believed to be relevant to psychosis.13 The estrogen-protection hypothesis suggests that estra- Postpartum psychotic disorders diol exerts antipsychotic effects through its many Hormonal involvement in the causation of post- varied actions in the central nervous system.14 partum psychiatric disorders has long been sus- Judging by these actions and by the results of clini- pected but never precisely understood.1,2 This cal and epidemiological studies, estradiol appears much is known: over the course of pregnancy, to play a protective role against the manifestations levels of estrogen and progesterone significantly of both schizophrenia and bipolar psychosis.15,16 rise. After birth, they fall steeply and do not nor- malize until approximately 3 weeks after deliv- Because of the abrupt decline of estrogen tempo- ery.3 The potential for psychosis at this time is rally associated with the emergence of postpar- attributable to an increased sensitivity of dopa- tum psychosis, and because of the known central mine receptors due to the abrupt change in estro- nervous system actions of estrogens, different gen levels at this time.4,5 Recent reports point to forms of estrogen therapy have been used for this the induction of psychosis by dopamine agonists condition, sometimes as pretreatment, adminis- such as bromocriptine, used to suppress lactation tered immediately after delivery to prevent relapse in women who decide against breastfeeding.6 in women who have experienced a previous epi- Studies on postpartum experimental animals sode or who have a history of psychotic illness.17 have also shown alterations in dopamine func- Different formulations of hormones used for the tion.7,8 Women already vulnerable as a result of treatment of postpartum disorders are presented genetic makeup or stressful environmental expo- in Figure 1.18–25 sure are thus susceptible to mental distress at times of low estrogen. This has led to the explora- A team from Finland20–22 treated 14 women suf- tion of estrogen-receptor polymorphisms as a fering from postpartum psychosis with sublingual potential source of genetic vulnerability9 and an estradiol and measured estradiol concentrations association with postpartum psychosis and one in the serum. The participants in this trial had variant of the estrogen-receptor alpha (ESR1) has failed to respond to antipsychotic treatment 2 journals.sagepub.com/home/tpp A González-Rodríguez and MV Seeman Postpartum depression Postpartum Non-affective Psychosis - Conjugated estrogen + medroxyprogesterone19 Gonadal hormones - Transdermal estradiol [E2]18 - 17-beta-estradiol20 (Estradiol +/- Progesterone) - 17-beta-estradiol21 - Sublingual 17-beta-estradiol22 - Intrapartum synthetic oxytocin23 Oxytocin - Peripartum synthetic oxytocin24 No evidence to date - Intranasal oxytocin25 Figure 1. Different formulations for gonadal hormones and oxytocin for the treatment of postpartum affective disorders and nonaffective postpartum psychosis. alone. The investigators used the Brief Psychiatric postpartum psychosis. Table 1 shows the main Rating scale (BPRS) to evaluate improvement characteristics of recent studies focusing on the and reported that symptoms decreased within use of gonadal hormones for the treatment of psy- 2 weeks for all women who complied with treat- chotic illness during the puerperium. ment. In at least one woman, symptoms recurred when estrogen treatment was discontinued. Prevention. In an effort at prevention of recurrent postpartum psychosis, Hamilton and Sichel26 In 2008, Huang and colleagues19 reported a case gave 50 patients injections of 10 mg of estrone from Taiwan of a woman with postpartum psy- immediately after delivery, followed by conju- chosis who improved after 2 weeks of combined gated estrogen for 12 days. No patients relapsed, estrogen and progesterone treatment. The patient although the usual expected rate of recurrence is had a long history of episodic psychotic mania 25–50%. Sichel and colleagues27 gave 11 women and was maintained on lithium plus an antipsy- with a history of postpartum depression or post- chotic. When she became pregnant, she stopped partum psychosis oral estrogen 5 mg twice daily her medications to avoid the risk of teratogenesis. starting at delivery and reducing the dose every She breastfed her infant. At 1 month after deliv- 14 days. Two women received additional intrave- ery she developed an episode of mania and was nous estrogen 25 mg three times daily for the first prescribed mood stabilizers and haloperidol. 2 days. Ten women complied with treatment and Serum levels were adequate but her symptoms none of them relapsed postpartum. did not respond. Conjugated estrogen 0.625 mg/ day and medroxyprogesterone 2.5 mg/day were A more recent study was carried out by Kumar added and the patient responded within 3 weeks. and coworkers in 2003.28 This was an open-label She remained stable when the hormones were study of 29 postpartum women with a previous stopped 2 months later. Research Diagnostic Criteria (RDC) diagnosis of bipolar I disorder, bipolar II disorder or schizoaf- Selective estrogen-receptor modulators (SERMs) fective disorder. All patients had been in remis- have not been tested in postpartum disorders. sion and had received no medication throughout their pregnancies. None of the women breastfed When reading the reports of treatment with estro- their infants for fear of exogenous hormones gens in postpartum psychosis, it is difficult to be entering the breast milk. Transdermal estradiol confident of their specific therapeutic effective- was administered within 48 h of delivery at three ness, since antipsychotics or mood stabilizers dose levels. Thirteen women received starting were also being administered to the patients doses of 200 µg/day; three received 400 µg/day, simultaneously. It is, however, possible to inter- and thirteen received 800 µg/day. All doses were pret the results as supportive of an adjunctive reduced by half every 4 days for a total of 12 days. therapeutic role of estrogens in treating The results of this study were not encouraging. journals.sagepub.com/home/tpp 3 Therapeutic Advances in Psychopharmacology 9 Table 1. Recent studies focused on the use of gonadal hormones and oxytocin for the treatment of nonpsychotic and psychotic illness in the puerperium. Authors and year Study design Sample (n) Comparison Assessment Results of publication groups Non-psychotic illness Gonadal hormones Wisner et al.18 8-week, n = 85 Transdermal E2 SIGH-ADS29 Efficacy of E2 compared randomized, (postpartum (n = 26) Asberg Side-Effects to placebo could not be placebo- depression) Sertraline (n = 30) Scale explored due to non- controlled trial Placebo (n = 29) significant E2 concentration difference between groups Oxytocin Takács et al.23 Prospective n = 260 (data Oxytocin EPDS Synthetic oxytocin observational collection exposure administration at study available; intrapartum did not have postpartum an immediate impact on maternal mood) maternal mood Kroll-Desrosiers Retrospective n = 46,732 Oxytocin exposed MiCARD Peripartum synthetic et al.24 population- (depressive (n = 9684) oxytocin exposure was based study and anxiety Oxytocin associated with higher disorders) nonexposed depressive or anxiety (n = 37,048) symptoms Mah et al.25 Within-subject n = 25 Oxytocin EPDS Severe physical abuse double-blind (postnatal Placebo Conflict Tactic Scale: during childhood did not randomized, depression) Parent Child version moderate OT effect placebo- Maternal Sensitivity controlled trial and Non- Intrusiveness Scale Psychotic illness Gonadal hormones Ahokas and Aito22 Case reports n=2 Sublingual 17- BPRS Higher estradiol levels were (postpartum beta estradiol associated with a decline of psychosis) (n = 2) psychotic symptoms Ahokas et al.21 Case series n = 10 17-beta estradiol BPRS Higher estradiol levels (6-week follow (postpartum (n = 10) were associated with an up) psychosis) improvement of psychiatric symptoms Ahokas et al.20 Case reports n=2 17-beta estradiol BPRS Elevation of serum estradiol (postpartum (n = 2) levels was associated psychosis) with decline in psychotic symptoms Huang et al.19 Case report n=1 Conjugated Clinical assessment Conjugated estrogen (postpartum estrogen + combined with mania) medroxy­ medroxyprogesterone progesterone improved manic symptoms (n = 1) Oxytocin No evidence is available BPRS, Brief Psychiatric Rating Scale; E2, Estradiol; EPDS, Edinburgh Postnatal Depression Scale; MiCARD, Massachusetts Integrated Clinical Academic Research Database; OT, oxytocin; SIGH-ADS20, Structured Interview Guide for the Hamilton Depression Rating Scale—Atypical Depression Symptoms Version. 4 journals.sagepub.com/home/tpp A González-Rodríguez and MV Seeman Fourteen (50%) of the women relapsed within E2 secretion could be suppressed by exogenous 90 days of delivery, as evaluated by scores on the dosing. In other words, they wondered about the Schedule for Affective Disorders and wisdom of (a) administering estrogen that would Schizophrenia (SADS); 12 of the women relapsed be eliminated before it could work and (b) that between 7 and 12 days of delivery while still on could suppress the secretion of a woman’s own their estrogen regimen. One woman committed estrogen. suicide 4 months after hospital discharge. The women who relapsed were placed on antipsy- Several problems have thus been identified in the chotic medication and it was discovered that preventive or therapeutic use of gonadal hor- those on 800 µg/day of estradiol recovered on mones for puerperal psychiatric disturbance. The lower doses of antipsychotics (chlorpromazine timing of administration matters because of elim- equivalents) than those on the lower doses of ination rates. The dose is also relevant because estrogen. Also, the 800 µg/day group was dis- suppression of endogenous hormones needs to charged from hospital sooner than the lower- be avoided. If women are breastfeeding, an added estrogen group. This suggests that although concern is that of infants absorbing maternal estradiol alone may not prevent postpartum hormones in breast milk. Table 1 summarizes relapse of serious mental illness in vulnerable recent studies focusing on the use of gonadal women, an effective dose of estradiol used as an hormones for the treatment of nonpsychotic adjunct to antipsychotic medication can be postpartum illness. therapeutic. Gonadal hormones for nonpsychotic illness in the Oxytocin and postpartum mood disorders postpartum period. Most postpartum conditions Mood disorders have been widely considered fall into the category of nonpsychotic affective capable of negatively influencing the adjustment disorders but these, too, are sometimes treated of new mothers and interfering with the establish- with antipsychotics29 to which replacement hor- ment of mother–infant bonding. Recent research mones can be added. The idea of treating affec- has implicated oxytocin in mediating this rela- tive illness with gonadal hormones comes from tionship.35,36 For instance, recent genetic studies the finding that a gonadotropin-releasing-hor- suggest that differential methylation of the oxy- mone agonist, leuprolide acetate, when given to tocin receptor gene can modulate the risk for healthy women, and especially to women with a postpartum depression and positively influence history of postpartum depression, can induce maternal behavior.37 A number of studies have depression.30 The resulting conclusion that the suggested that oxytocin plays an important role in drop in either estrogen or progesterone, or both, mood regulation and that oxytocin plasma levels is responsible for postpartum depression is con- are associated with the development of postpar- troversial, however, as an association between tum mood disorders. hormone withdrawal and mood symptoms is not always found.31 This suggests that estrogen/pro- Oxytocin effect in postpartum depression. At gesterone levels, though they probably play a 8 weeks postpartum, Cox and colleagues12 part, do not totally explain postpartum mood assessed mood symptoms in 39 women who then disorders. Maternal stress plays an important underwent a standard stress test immediately role as well,32 as, probably, do many related, after breastfeeding. The surge of oxytocin that interactive hormones.33,34 accompanies breastfeeding buffered the subse- quent stress induced by the test, but only in the An 8-week randomized controlled trial that set women who were asymptomatic. The authors out to compare the efficacy of transdermal estra- concluded that this was putative evidence that diol (E2), sertraline and placebo in women with oxytocin plays a role in the genesis of postpartum postpartum major depressive disorder18 was depression. Niwayama and coworkers,38 in partial stopped because E2 serum concentrations in the confirmation, demonstrated a calming effect on E2 arm of the study were found to be lower than mood disturbance of relatively high salivary oxy- expected. The authors hypothesized that the tocin levels in 24 primiparous breastfeeding induction of liver enzyme CYP3A4 during preg- mothers. Another study found a correlation nancy had led to an increased E2 rate of elimina- between relatively low levels of oxytocin and tion that continued after delivery. The other depressive symptoms at 8 weeks postpartum in possibility they entertained was that endogenous women who had stopped breastfeeding.39 The journals.sagepub.com/home/tpp 5 Therapeutic Advances in Psychopharmacology 9 same group also found that oxytocin levels signifi- These studies await replication. There are no cantly decreased from the prenatal to the postpar- studies that assessed the efficacy of oxytocin in tum period in their whole sample of women, but the treatment of bipolar disorder with onset in the women who were depressed or anxious at 6 weeks postpartum period. postpartum exhibited persistently higher mean oxytocin levels over time.40 Oxytocin effect in nonaffective psychosis. Both social cognition and neurocognition in schizo- With respect to exogenous oxytocin, in a prospec- phrenia have been examined in relationship to tive observational design,23 the administration of plasma oxytocin levels.47 Low levels of oxytocin intrapartum synthetic oxytocin was found to not were associated with cognitive deficits.48 Asocial- correlate with mood symptoms at 6 weeks, nor at ity in schizophrenia has also been associated with 9 months postpartum. Another recent study low levels of oxytocin.49 found that women exposed to peripartum oxy- tocin administration were more likely than con- The administration of intranasal oxytocin has trol women to receive depression and anxiety been suggested as a potential treatment for social diagnoses and to be prescribed antidepressants or cognition and neurocognition in patients with anxiolytics.24 Finally, in a randomized, double- schizophrenia50 on the basis of study results blind, placebo-controlled trial of intranasal oxy- obtained by Woolley and colleagues,51 and Davis tocin in women with postnatal depression,25 the and colleagues.52 A meta-analysis by Bürkner results showed that women receiving oxytocin and coworkers53 found intranasal oxytocin to be were more likely than controls to choose a harsh more effective for high-level social cognition caregiving strategy in response to prerecorded (mentalizing and theory of mind) than for low- infant crying. On the evidence of these results, the level social cognition, highlighting the need for authors recommended that oxytocin not be given research focused on specific cognitive targets. to depressed mothers. Oxytocin study results are Two meta-analyses,54,55 however, found no sig- presented in Table 1. nificant effect of adjunctive oxytocin either on symptoms or on cognition in schizophrenia. Oxytocin effect in postpartum mania. The relation- Sasayama and colleagues56 investigated oxytocin ship between oxytocin levels and bipolar disorder levels in relation to antipsychotic doses in schizo- has been extensively examined for several phrenia. Cerebrospinal fluid oxytocin levels were decades.41 Relatively recent research has shown significantly and negatively correlated with doses high oxytocin levels to be specifically associated of second-generation antipsychotics, but not with manic episodes in male and female patients with doses for first-generation antipsychotics, a diagnosed with bipolar I disorder, when com- finding that is difficult to interpret. pared to those with other mood disorders and also when compared to healthy subjects.42 Oxyto- No studies have explored the use of oxytocin as cin levels decreased once symptoms had an adjunct to antipsychotic medication in post- responded to treatment.42 These researchers sug- partum psychosis, which is surprising given the gested that oxytocin level could even be used as a tie of oxytocin to parturition, lactation and trait marker for bipolar disorder. Lien and col- mother–child interaction and well-being.57,58 It leagues43 confirmed these results, but a previous has been suggested that the timing of oxytocin study44 had found no statistically significant dif- intervention may be critical to its effect, but, thus ference in oxytocin levels between depressed and far, the oxytocin story in relation to psychosis bipolar patients. remains confusing. A population-based birth cohort study found a disturbing 2.4-fold increased odds of later bipolar Antipsychotics in the postpartum period disorder in children of women who had been Antipsychotic treatment has been shown to be given oxytocin to induce labor.45 A study of 161 highly effective in preventing postpartum relapse children born to mothers in whom oxytocin had of women with a prior history of postpartum dis- been used for this purpose found that mothers order or ongoing psychotic illness.29,59,60 reported their children as showing a relative lack of interest at 3 months of age, crying or turning Because postpartum mothers may also be breast- away when picked up at 6 months of age, and feeding mothers, several authors have systemati- showing withdrawal behavior at 1.5 years of age.46 cally reviewed the topic of safety of antipsychotic 6 journals.sagepub.com/home/tpp A González-Rodríguez and MV Seeman use during lactation,61–64 but criticism has been level to rise. The opposite can be expected when leveled at some aspects of the reviewed studies.65 the antipsychotic is mainly metabolized by The issues are the short- and long-term effects of CYP3A4 (quetiapine is an example), in which antipsychotics in breastfeeding mothers on chil- case the antipsychotic level will fall.71 It may be dren’s physical, cognitive, and psychosocial the antipsychotic level rather than the hormone health, and also the antipsychotic side effects on that determines symptom response. mothers’ abilities to care for their neonates. The most recent systematic review in this field Hormones and menopause recommends that quetiapine and olanzapine be A recent publication reported on a study of over considered first-line treatments in breastfeeding 5000 women who had been diagnosed with an women.63 The review considers risperidone to be acute psychotic disorder.72 The women were acceptable under conditions of medical monitor- divided into two groups: (a) age 18–45; (b) over ing, and both clozapine and amisulpride to be age 55. The investigators wanted to know whether contraindicated. Klinger and coworkers61 had also the advent of menopause (somewhere between found olanzapine and quetiapine to be acceptable age 45 and 55 in most women) induced measur- for breastfeeding, and chlorpromazine, haloperi- able changes in the characteristics of their psy- dol, zuclopenthixol, and risperidone as possible chotic illness. One finding was that the younger under medical supervision. They could make no group of women, when compared with same-age recommendations with respect to aripiprazole, men with psychosis, was hospitalized half as clozapine or paliperidone, as adequate informa- often. In contrast, women in the older group were tion was lacking. Uguz64 addressed issues of rela- 1.5-fold more often hospitalized than their same- tive infant dose, milk-to-plasma ratio, infant drug age male peers. Another finding was that in a sub- plasma levels, and adverse events, and found group of the sample (n = 192) who were on antipsychotic plasma levels to be undetectable in clozapine, the under 45s were maintained on most exposed neonates. With respect to clozapine lower clozapine doses than their male controls, in breast milk, the potential risks for infants are while the over 55s were maintained on relatively largely unknown. Imaz and coworkers66 did not higher doses. These findings suggest that psycho- find any acute toxicological effect in newborns sis gets worse after menopause. exposed to clozapine in pregnancy. The alterna- tive in women who are unresponsive to other A recent study along the same lines that included antipsychotic drugs is stopping antipsychotic patients with schizophrenia and healthy controls treatment altogether and this, of course, confers investigated the effects of catechol-O-methyl- risks of its own.67 With respect to aripiprazole, transferase (COMT) haplotypes with ValMet Cuomo and colleagues68 have suggested that its polymorphisms and their potential interplay on potential benefits in lactating women suffering cognitive functions in menopause.73 The findings from bipolar disorder or schizophrenia may be were that functional COMT mutations modulate higher than its potential risks. Case-by-case shared cognitive functions in schizophrenia according to decision making has been recommended when hormonal status, for example, pre/postmeno- deciding on the use of antipsychotics during the pause. The authors suggested that genetics, hor- puerperium.69 Importantly, the long-term effects monal status and sex interact with each other and of antipsychotic agents on infants of breastfeeding need to be taken into account when exploring women are not known. There are known short- changes in cognition at menopause. term sedating effects on mothers, however, and these can interfere with a new mother’s ability to look after her infant and can sometimes contribute What is menopause? to a mother losing custody of her child.70 The onset of menopause (from the Greek ‘meno’ meaning month, and ‘pausis’ meaning cessation), With regards to the pairing of hormones and defined as 1 year of amenorrhea, is usually identi- antipsychotics, the success of therapy may fied retrospectively. It marks the end of fertility depend on the specific antipsychotic agent that and is attributed to the loss of ovarian follicular is being used. For instance, olanzapine and clo- function (although approximately 1000 oocytes zapine are mainly metabolized by liver enzyme are still present in most women at the time of CYP1A2, which is inhibited by estrogen, so that menopause).74 The 2011 STRAW+10 staging adding estrogen will cause the antipsychotic system for reproductive aging in women divides journals.sagepub.com/home/tpp 7 Therapeutic Advances in Psychopharmacology 9 the menopausal period into early and late stages increase the speed of bone resorption.81 Moreover, of menopausal transition or perimenopause, fol- oscillations in estradiol levels during perimeno- lowed by four stages of postmenopause, all stages pause contribute to emotional lability during this based on progressive changes in follicle-stimulat- period, probably because of estrogen effects on the ing hormone (FSH), anti-Müllerian hormone serotonin system.82,92,93 In addition, women of (AMH), and the ovarian protein, inhibin-B.75 menopausal age can become increasingly depend- ent on alcohol, anxiolytics, and hypnotics. Throughout a woman’s reproductive life, estradiol, Discontinuation of these substances may produce progesterone and ovarian regulatory proteins con- withdrawal symptoms such as sweating, tremor, trol gonadotropin secretion from the anterior pitui- dizziness, headache, insomnia, rebound anxiety, tary through a complex mechanism of feedback tachycardia, and elevated blood pressure, which and feedforward. Pulses of FSH are stimulated by are often impossible to distinguish from true men- the protein activin and inhibited by estradiol and opausal symptoms.83,84 inhibin B.74 As the number of oocytes remaining in the ovaries drop, inhibin B levels decline and FSH Menopausal women can experience subjective levels rise. Low inhibin B and high FSH is the hor- cognitive impairment in attention, new learning, monal signature of menopause. More recently, and memory.85,86 Further, menopausal women progressively decreasing levels of AMH has become experience both pain on intercourse and urinary a further marker of approaching menopause. incontinence. When estrogen levels decline, the Although the ovary loses its capacity to produce tissues lining the vagina, vulva, bladder, and ure- estrogen and progesterone at menopause, andro- thra atrophy, leading to vaginal dryness, dyspare- gen (testosterone, dehydroepiandrosterone, and unia, vulvar pruritus, and urinary problems.87,88 androstenedione) production continues far longer. Androgens produced by the ovary and the adrenal Metabolic syndrome, defined as insulin resistance gland are aromatized to estrogen in adipose tissue plus any two of the following: central obesity, so that estrogens continue to circulate in postmen- hypertriglyceridemia, low high-density lipopro- opausal women, but at relatively low levels (higher tein (HDL) cholesterol, hypertension, high fast- in women with more adipose tissue).76 ing glucose, or microalbuminuria, has also been associated with menopause.89 In addition to increasing the risk for cardiovascular disease and Menopausal symptoms type 2 diabetes mellitus, metabolic syndrome is In general, women’s menopausal symptoms vary associated with nonalcoholic fatty liver disease, across different stages of menopause; they are a hyperuricemia, polycystic ovarian syndrome, and consequence of estrogen deficiency and also of the obstructive sleep apnea.90,91,93,94 aging of estrogen target organs.77 Inadequate estro- gen and the process of aging work hand in hand and it is often difficult to determine which of the Effect of antipsychotics on menopausal two is responsible for which symptom. Correlations symptoms of menopausal symptoms, hormones, and antipsy- In women with psychosis (schizophrenia, delusional chotic use are presented in Figure 2.78–91 disorder, or mood disorder with psychotic features), side effects of the antipsychotic medication such as Most women experience a variety of symptoms at weight gain and hyperprolactinemia,95 intensify nat- this time, many of which, such as hot flushes, urally occurring menopausal symptoms. For markedly interfere with quality of life. Hot flushes instance, weight gain increases muscle and joint interfere with sleep and increase in frequency pain and heat intolerance. It also increases the inci- during periods of psychological stress.78 dence of sleep apnea,96 which, in turn, heightens Furthermore, changes in the distribution of body sleep difficulties and leads to daytime sedation.97 fat lead to obesity that, among other health risks, Most importantly, antipsychotic-induced obesity increase the risk for sleep apnea in menopausal adds to the risk of metabolic and cardiovascular women and contribute to sleep disturbance.79 In problems of postmenopausal women.98 turn, short sleep duration has itself been associated with obesity, especially central obesity.80 Muscle Furthermore, antipsychotic-induced hyperprol- and joint aches often start at this time, perhaps as a actinemia increases the likelihood of developing result of acceleration in the rate of bone loss due to osteoporosis99 and intensifies urogenital problems both estrogen loss and to high levels of FSH, which and sexual dysfunctions such as diminished libido. 8 journals.sagepub.com/home/tpp A González-Rodríguez and MV Seeman Symptoms Main explanation Peripheral vasodilation Vasomotor symptoms Hot flushes (interfere with sleep)78 (lack of estrogens) Fat redistribution and Weight gain79 Decrease in energy expenditure weight gain Obesity (mainly central)80 (lack of estrogens and antipsychotic use) Hot flushes lack of estrogens) Sleep apnea79 Sleep disturbance Obesity (lack of estrogens and Insomnia antipsychotic use) Muscles, joints, Muscle and joints atrophy Estrogen loss at menopause and bones Accelerated bone loss81 hyperprolactinemia (antipsychotic use) Emotional lability82 Mood changes and Anxiety and insomnia Oscillations in estrogen levels drug dependence Use of anxiolytics and hypnotics Use of psychotropic medications Withdrawal symptoms83,84 Impairment in attention, learning Estrogen loss and Cognitive impairment and memory85,86 psychotropic use Urinary incontinence Dyspareunia Estrogen loss effect on estrogen- Genitourinary Vaginal dryness dependent tissues Vulvar pruritus Urogenital atrophy87,88 Central obesity89 Hypertriglyceridemia Low high-density lipoprotein (HDL) Lack of estrogens Metabolic syndrome cholesterol Antipsychotic use Hypertension High fasting glucose Microalbuminuria Lack of estrogens Cardiovascular Vasoconstriction - Increased Antipsychotic use (endothelial disease coronary heart disease90,91 hypothesis) Figure 2. Correlation of main symptoms of menopause with hormones and antipsychotic use. Antipsychotics can aggravate other menopausal symptoms experienced by these women were symptoms, as well. With time, they have been feeling depressed, anxious, tired, lacking energy, reported to lead, for instance, to a decrease in cog- and experiencing poor memory.103 nitive abilities.100 Side effects diminish women’s sense of attractiveness,101 further undermining Using magnetic resonance imaging (MRI), Fukuta self-esteem and sexual satisfaction, already at a and coworkers104 investigated the influences of low ebb at menopause.102 menopause on brain morphological changes in 20 premenopausal and 20 postmenopausal women with schizophrenia (as well as 50 control women). Changes in psychosis symptoms at menopause The gray matter of postmenopausal patients was Women with schizophrenia, psychotic affective significantly smaller than that of premenopausal disorder, and delusional disorder report that patients in the left middle frontal gyrus, suggesting their psychotic symptoms worsen at menopause an impact of estrogen loss on brain structure, and that their medications no longer work as which could explain the changes in positive symp- well as previously. In a study by Sajatovic and toms105 and cognitive symptoms.106 Environmental colleagues,103 over half of 86 women with schiz- events such as parents dying, social supports ophrenia reported that menopause had a nega- dwindling, motherhood becoming permanently tive effect on their emotional state. The top five impossible, children leaving home, and health journals.sagepub.com/home/tpp 9 Therapeutic Advances in Psychopharmacology 9 declining77 play a partially causative role, but, Weickert and colleagues115 had previously shown according to Jacobs and Goldstein,107 many of the that the effect of raloxifene on cognition in schiz- symptom changes experienced at this time are ophrenia may depend on a person’s estrogen-­ attributable to the decline of sex hormones. receptor genotype. Furthermore, Labad and colleagues,116 in a pharmacogenetic analysis of a double-blind, randomized, parallel, placebo-­ Treatment response to estrogen and SERMs controlled study of 24 weeks’ duration of raloxifene Following the clinical evidence that psychotic in 65 postmenopausal women with schizophrenia, symptoms worsen after menopause and the epi- examined four single nucleotide polymorphisms demiological evidence that, in contrast to men, (SNPs): rs9340799, rs2234693 and rs1801132 in the incidence of psychosis in women increases the estrogen-receptor 1 (ESR1) gene, and after age 40,108 estrogens and selective estrogen- rs1042597 in the UDP-glucuronosyltransferase receptor modulators (SERMS, mainly raloxifene) 1A8 (UGT1A8) gene. They found that the have been used as adjuncts to antipsychotic agents rs1042597 variant was associated with response of for postmenopausal women with psychosis. Two negative symptoms, while the rs2234693 variant excellent reviews of these strategies for women was associated with response in general psychopa- (and also men) with schizophrenia109,110 summa- thology scores. It appears, therefore, that estrogen rize the findings thus far. Taking all available ran- agonists may help at least some postmenopausal domized controlled trials into account, estrogens, women with schizophrenia, but that the results especially estradiol, were found to be superior to depend on several factors such as severity of ill- placebo for positive, negative and general symp- ness, menopausal stage, genetic profile, and target toms. Raloxifene was also found to be superior to symptoms, as well as estrogen/antipsychotic placebo for positive, negative, and total symp- interaction. toms, but not for affective symptoms or cognitive function. In a meta-analysis that included five Table 2 shows the main characteristics of recent randomized controlled trials (RCTs) comparing studies of the effect of raloxifene on clinical symp- raloxifene augmentation at 60 or 120 mg/day with toms and cognition in postmenopausal women placebo in 240 postmenopausal women, ralox- with schizophrenia.115–121 ifene again outperformed placebo.111 Included in the meta-analysis was a multicenter Antipsychotic/estrogen interaction negative trial by Weiser and colleagues,112 a It is possible that response to estrogen agonists may 16-week, double-blind, randomized, placebo-con- partly depend on the specific antipsychotic with trolled study of 200 severely ill, postmenopausal which the hormone is paired. With the loss of estro- women with schizophrenia that used 120 mg ralox- gen postmenopause, olanzapine and clozapine lev- ifene/day in addition to antipsychotics. The results els decrease and exogenous estrogens or SERMs showed no differences between groups either in will raise their level. The levels of most other antip- Clinical Global Impression Scale-Severity scores sychotics could, by contrast, rise after menopause; or Composite Brief Assessment of Cognition in replacement hormones or SERMs could bring Schizophrenia scores. A further meta-analysis that these levels down,71 thus dampening the therapeu- also included the Weiser et al. trial113 concluded tic effect. The pharmacokinetics and pharmacody- that adjunctive raloxifene did have positive effects namics of antipsychotics help to explain why in postmenopausal women with schizophrenia, but response of psychotic symptoms diminishes with especially in those whose psychotic symptoms time postmenopausally.122 were relatively less severe. Severity of symptoms might account for discrepancies among trials. Pharmacokinetics. Women increasingly accumu- Another possible explanation of discrepant results late adipose tissue after menopause, which expands is raised by Gurvich and colleagues.114 They show the volume of distribution of lipophilic drugs such that the menopausal raloxifene effect as it relates to as antipsychotics, thus decreasing the amount of cognition depends not only on the specific cogni- drug that enters the brain.123 The main liver tive parameter studied but also on menopausal enzyme that metabolizes olanzapine and clozap- stage (perimenopause versus postmenopause). The ine, CYP 1A2, is inhibited by estrogen; when specific antipsychotic drug used can also influence estrogen levels drop at menopause, the enzyme the results, as can concomitant drugs that affect becomes more active so that higher doses of drugs the amount of raloxifene that reaches the brain. metabolized by this enzyme are required to achieve 10 journals.sagepub.com/home/tpp A González-Rodríguez and MV Seeman Table 2. Recent studies focusing on the effect of adjunctive raloxifene on clinical and cognitive symptoms in postmenopausal women with schizophrenia. Authors and Study design Sample Groups Assessment and Conclusions reference outcomes citation Psychopathological assessment Labad et al.116 24-week, double- n = 65 Raloxifene Psychopathology: Genetic variants in UGT1A8 blind, randomized, 60 mg/day PANSS and ESR1 genes may influence parallel placebo- Placebo Genetic analyses: response to raloxifene controlled trial ESR1 gene (rs9340799, rs2234693 and rs1801132) and UGT1A8 gene (rs1042597) Usall et al.117 24-week, double- n = 70 Raloxifene Psychopathology: Raloxifene (60 mg daily) blind, randomized 60 mg/day PANSS and SANSS improved negative and parallel placebo- Placebo general psychopathological controlled trial symptoms Kianimehr 8-week, parallel- n = 46 Risperidone Psychopathology: Risperidone combined with et al.118 group, placebo- 6 mg/day + PANSS raloxifene (120 mg daily) was controlled trial raloxifene more effective than placebo in 120 mg/day positive symptomatology Risperidone 6 mg/day + placebo Usall et al.119 12-week, double- n = 33 Raloxifene Psychopathology: Raloxifene (60 mg daily) blind, randomized 60 mg/day PANSS improved positive, negative, placebo-controlled, Placebo and general psychotic trial symptoms Kulkarni 12-week, double- Current Raloxifene Psychopathology: Raloxifene (120 mg daily) et al.120 blind, randomized trial: 26 120 mg/day PANSS and MADRS was associated with better controlled trial Pilot: 9 Raloxifene recovery in total and general 60 mg/day symptoms compared to Placebo 60 mg/day and placebo Cognitive assessment Weiser et al.112 16-week, double- n = 200 Raloxifene Psychopathology: No significant improvement blind, randomized 120 mg/day PANSS, CGI in severely ill decompensated placebo-controlled, Placebo Cognition: Composite patients receiving raloxifene trial Brief Assessment of adjunct to antipsychotic cognition medications Weickert 13-week, n = 478 Raloxifene Psychopathology: Adjunctive raloxifene (120 mg et al.115 randomized, 120 mg/day PANSS, DASS daily) may have beneficial double-blind, Placebo Cognition: WAIS-III, effects on attention and crossover, placebo- WTAR processing speed and memory controlled trial for men and women Huerta-Ramos 12-week, double- n = 33 Raloxifene Psychopathology: Adjunctive raloxifene (60 mg et al.121 blind, randomized, 60 mg/day PANSS daily) was associated with placebo-controlled Placebo Cognition: improvement in memory and trial neuropsychological executive functioning battery CGI, Clinical Global Impression Scale; DASS, Depression and Anxiety and Stress Scale; ESR1, estrogen-receptor 1; MADRS, Montgomery-Asberg Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale; SANSS, Scale for the Assessment of Negative Symptoms; UGT1A8, UDP- glucuronosyltransferase 1A8; WAIS-III, Wechsler Adult Intelligence Scale: third edition; WTAR: Wechsler Test of Adult Reading. journals.sagepub.com/home/tpp 11 Therapeutic Advances in Psychopharmacology 9 the prior effect. The opposite is true for drugs spray or saline nasal spray for 8 weeks. Oxytocin metabolized mainly by CYP 3A4, quetiapine for spray was administered as 20 IU (five sprays) twice instance, whose activity is enhanced by estrogen. a day for the first week followed by 40 IU (10 After menopause, this enzyme becomes less active, sprays) twice a day for the following 7 weeks. The so that lower doses of the antipsychotics con- patients on placebo received the same amount of cerned may be sufficient.71 The use of concurrent nasal sprays. By week 8, the patients in the oxy- drugs is another important issue. Because of sleep tocin group showed significantly greater improve- problems and pain problems and depression, ment than the placebo group on positive, negative, women at menopause often take more varieties of and general psychopathology scores of the medication than previously, which affects protein PANSS. The investigators concluded that, though binding of concurrent antipsychotics and may, the improvement was statistically significant, it thus, enhance or inhibit the ability of individual was unlikely to be clinically significant. Ota and drugs to enter the brain.124 colleagues129 administered daily intranasal oxy- tocin for 3 months to 16 patients with schizophre- Pharmacodynamics. The loss of estrogens at the nia who stayed on their regular medication period of menopause may eventually lead to throughout the trial. MRI was performed on 15 of increased vulnerability for psychotic relapse, poor the study participants. Positive and negative clinical outcome, and a need for increased antip- symptoms, but especially negative symptoms, sychotic dose.122,125,126 were improved. There was also an improvement in verbal fluency. From the MRI results, the inves- Women show more D2 receptor binding sites tigators concluded that improvement was related than men, particularly in the frontal cortex, tem- to gray matter volume in the right insula and left poral cortex and thalamus125 and estrogens aug- cingulate cortex of the brain. In reviewing the ment the antipsychotic action of antipsychotics at studies of oxytocin as an augmenting strategy in dopamine D2 receptors.125 Declining levels of schizophrenia, Ettinger and coworkers47 con- estrogens at menopause thus diminish D2 recep- cluded that the evidence was inconsistent. tor occupation by antipsychotics, the basis for their effect on psychotic symptoms.124,125 No oxytocin study has specifically targeted post- menopausal women with schizophrenia. Oxytocin and schizophrenia in menopausal-age women Other hormones potentially relevant to Oxytocin has been less implicated in menopau- postpartum disorders and menopause sal symptoms than in puerperal symptoms in While most of the recent literature about treat- schizophrenia. Both oxytocin and vasopressin ment of postpartum and menopausal psychosis have, however, been associated with symptom concerns estrogens, other hormones have, at severity and cognition in middle-aged women times, been considered as potential players. The with schizophrenia.127 role of stress hormones has been well summarized elsewhere.130 Progesterone is of interest because it Depending on the gender distribution of the exerts effects on the dopaminergic system.131 study sample, some studies report positive find- Progesterone levels fall dramatically postpartum ings when administering oxytocin to schizophre- and this could theoretically contribute to postpar- nia patients, whereas other studies report negative tum disorders.132 A retrospective study explored results. A potential explanation is that oxytocin the effect of depot medroxyprogesterone acetate affects reproductive-age women differently than it given for contraception immediately postpartum; does postmenopausal women or men. The most 55 women received the injection and 192 women representative studies are summarized below. did not.133 At 6 weeks postpartum, scores on the Edinburgh Postnatal Depression Scale (EPDS) Modabbernia and coworkers128 conducted an were the same in the two groups. In contrast to 8-week, randomized, double-blind, placebo-con- these findings, Lawrie and colleagues134 had trolled study in two hospitals in Iran. They found that long-acting norethisterone enanthate, recruited 40 male and female patients with schizo- a progestogen contraceptive, increased the risk of phrenia aged 18–50. All were on a stable dose of postpartum depression when administered post- risperidone (5–6 mg/day) for at least 1 month. The partum. The suppression of endogenous secre- patients were randomly assigned to oxytocin nasal tion of ovarian hormones was hypothesized as the 12 journals.sagepub.com/home/tpp A González-Rodríguez and MV Seeman cause of the increased risk. Misiak and cowork- antipsychotics required to reverse psychotic symp- ers135 have postulated a role for androgens in psy- toms during the postpartum and menopause peri- chosis. Luteinizing hormone136 alone, or in ods. It is also still not clear which psychiatric relation to FSH,137 has also come under scrutiny, symptoms may be most responsive to hormones. especially in regard to the cognitive symptoms of We do have evidence, however, that combinations menopause. Also, the high prolactin levels of hormones and antipsychotics, when used at induced by antipsychotics have been suspected of standard doses, are generally safe and well toler- further impairing cognition at the time of meno- ated. Research continues so that these and related pause,138 perhaps especially so when the antipsy- questions will be answered in the near future. chotic used, risperidone for instance, is metabolized by the CYP2D6 enzyme.139 Neurosteroids (steroids synthesized in the brain) Key points such as pregnenolone, dehydroepiandrosterone, 1. Hormonal decline at postpartum and at and allopregnanolone modulate neural plasticity menopause is temporally related with the and may have therapeutic potential for psychotic onset and exacerbation of both psychotic illness.140,141 Thyroid hormone is important in the disorders and affective disorders in women. postpartum period because this time period is 2. The potential use of estradiol and oxytocin associated with an increased risk for autoimmune has been tested in postpartum depression. thyroid disorder.142 Thyroid hormone is also The results have been lackluster. Trials in important at menopause in that menopausal postpartum psychosis and postpartum mania symptoms may, at times, mask thyroid disease.143 are sparse. Another hormone, melatonin, may be therapeuti- 3. The results of adjunctive use of estrogens cally useful during the menopause to counteract and raloxifene in postmenopausal psycho- sleep disturbance and, also, as has been shown sis have been promising. SERMs other recently, to prevent metabolic side effects induced than raloxifene have been insufficiently by antipsychotic drugs.144–149 investigated. 4. The use of oxytocin as a potential interven- Although the evidence for the treatment potential tion for schizophrenia at menopause has of hormones added to antipsychotics at postpar- not yet been investigated. tum or at menopause is only beginning to accu- 5. Treatment with a hormone can suppress mulate, it is worthwhile keeping such options in endogenous secretion of the hormone and mind and also appreciating that what may be sig- affect endogenous synthesis. Dose and tim- nificant in achieving good response are not levels ing of intervention are potentially critical to of individual hormones but the balance of levels efficacy. of several different hormones.137 6. Gonadal hormones can inhibit or enhance the action of drug-metabolizing enzymes and thereby affect the level of specific con- Summary and Conclusion comitant antipsychotic drugs, depending In this narrative review, we attempted to sum- on the metabolizing pathways involved (e.g. marize evidence bearing on the association of CYP1A2 and CYP3A4). estrogens and oxytocin with antipsychotic use in 7. The results of hormones added to antipsy- the postpartum period and menopause. Estradiol chotic medication in the treatment of psy- and oxytocin have been implicated in postpartum chotic and affective symptoms partially psychosis; however, their use as potential treat- depend on their effect on protein binding of ments is controversial and critical information is antipsychotics drugs, thus modulating their still lacking. Estradiol and SERMs show promise entry into the brain. as potential adjuncts to antipsychotics for post- menopausal women with psychosis, whereas oxy- Funding tocin-augmentation strategies in menopausal The author(s) received no financial support for women are lacking. the research, authorship, and/or publication of this article. In response to the questions raised at the outset of this review, it should be noted that the jury is Conflict of interest statement still out.150 We still do not know whether adjunc- MVS has been a consultant for Clera Inc. tive hormones are able to reduce the dose of Alexandre González-Rodríguez has received journals.sagepub.com/home/tpp 13 Therapeutic Advances in Psychopharmacology 9 honoraria or travel costs from Pfizer, Janssen, 12. Cox EQ, Stuebe A, Pearson B, et al. Oxytocin Lundbeck-Otsuka and Ferrer. and HPA stress axis reactivity in postpartum women. Psychoneuroendocrinology 2015; 55: ORCID iD 164–172. Mary V Seeman https://orcid.org/0000-0001- 13. Gogos A, Sbisa AM, Sun J, et al. A role 6797-3382 for estrogen in schizophrenia: clinical and preclinical findings. Int J Endocrinol 2015; 2015: 615356. References 14. McGregor C, Riordan A and Thornton J. 1. Schiller CE, Meltzer-Brody S and Rubinow DR. 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