Low mood and depressive symptoms during perimenopause – Should General Practitioners prescribe hormone replacement therapy or antidepressants as the first-line treatment?

Mandy Leonhardt

First Published June 27, 2019 Research Article https://doi.org/10.1177/2053369119847867

Article information

Abstract

Perimenopausal women have an increased risk of developing new onset and recurrent mental health conditions such as anxiety, low mood and depressive symptoms. General Practitioners frequently prescribe antidepressants as the first-line treatment for these symptoms, despite clear lack of evidence for their efficacy and their unfavourable side effect profile. This article, written by a General Practitioner, gives a practical overview of the mental health symptoms which women may report to their General Practitioners during the menopausal transition and discusses underlying causes, assessment, risk factors and treatment options based on current evidence.Keywords Antidepressants, anxiety, depression, hormone replacement therapy, menopause, perimenopause

Perimenopause and mental health

The perimenopause is defined as the transitional period prior to menopause and features clinical, biological and endocrinological changes. The perimenopause ends 12 months after the last menstrual period.¹ The median age of onset of perimenopausal symptoms is 47.5 years.² The average duration of the menopause transition is four years (defined by menstrual cycle irregularity), but the individual variation for this phase ranges from 0–11 years.³

The risk of depression increases during the menopause transition.⁴ In my own clinical practice as a General Practitioner (GP), I find that from the age of 40 onwards, even while periods are still regular, women may experience a variety of different mental health symptoms. These symptoms may be new and out of character, or they may be recurrent, or cyclical, such as exacerbated perimenstrual syndrome (PMS). Heightened anxiety, tearfulness, loss of confidence, low mood or mood swings are common symptoms perimenopausal women report in my day-to-day practice. Many women report that they don’t feel continuously depressed as such, but that they ‘just don’t feel like themselves anymore and don’t recognise the person they have become’. These mental health symptoms during the menopausal transition may occur with or without vasomotor symptoms (VMS). In the absence of VMS, irregular or missed periods, or in women deemed ‘too young’ for being menopausal, health care practitioners often don’t consider hormonal changes as a causative factor and this can affect the treatment options offered to these patients.

There is evidence that episodes of depression associated with reproductive events are triggered by hormonal fluctuations. Some authors have argued that hormone modulated reproductive affective disorders such as PMS, perimenstrual dysphoric disorder (PMDD), pre/postnatal depression and climacteric depression are distinct forms of depression and could be categorised as subtypes of Reproductive Depression.^5,6 The term ‘Reproductive Depression’ was first introduced by Nappi et al.,⁷ and it implies that whilst symptoms may be similar, the underlying biological mechanisms differ from other forms of depression. The term helps to acknowledge that there are types of depression which are specifically linked to the biology of the female sex and this could lead to a more individualised approach to treatment. Currently, the term ‘Reproductive Depression’ is not yet widely acknowledged by the medical profession and it is not included in Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM 5) 5 or International Classification of Disease, Eleventh Revision (ICD-11).

Supporting the position that perimenopausal depression is a subtype of reproductive depression has important clinical implications for the treatment and/or prevention of perimenopausal depression.

Hormone replacement therapy (HRT) can be an effective and safe treatment for low mood that arises as a result of the menopause,^8–10 but a recent survey has shown that more than half of the GPs questioned prescribed antidepressants instead of HRT for the management of mood-related menopausal symptoms,¹¹ even though the NICE guidelines state that HRT and/or cognitive behavioural therapy (CBT) can be considered for low mood symptoms related to the menopause.¹² The incorrectly interpreted Women’s Health Initiate Study (WHI) from 2002 may still be to blame for the reluctance of some health care practitioners to prescribe HRT.¹³ A Canadian Study from 2005, which looked at changes in prescribing patterns related to HRT/antidepressants in Canada, confirmed that a significant decrease in the number of HRT prescriptions after 2002 was associated with a statistically significant increase in prescriptions for selective serotonin reuptake inhibitors (SSRIs) during the years after the WHI was published. They concluded that women who were previously prescribed HRT to control their (physical and psychological) menopausal symptoms were now given SSRIs instead.¹⁴

Symptoms

Mental health-related symptoms during the perimenopause and the early menopausal years are common and particularly these symptoms and not necessarily VMS can be the main reason why women seek help from their GP. Epidemiological studies have shown that between 45% and 68% of perimenopausal women report elevated depressive symptoms.¹⁵ In 15%–30% of perimenopausal women, symptoms are severe enough to be regarded as a depressive disorder.¹⁶

It is important that GPs have an awareness about these symptoms (Table 1) and their possible underlying causes in women in this age group. Every woman will experience this time in her life differently and every woman has a different range and severity of symptoms at a different age, before her periods stop for more than 12 months and she is postmenopausal. From my own experience as a menopause care provider, I find that women from their early 40s onwards frequently report that they feel more anxious, irritable and insecure, that they feel easily irritated, angry and that there are times when they feel like they are losing control over their life. Some women say that they feel overall less confident, less resilient to stress and that they have become indecisive and insecure for no reason. These symptoms often come and go during the day or they can last continuously for extended periods of time. Frequently, women also report that symptoms are exacerbated during the days before their period start. Depending on the severity and frequency of these symptoms, they can have a major detrimental effect on the way women function at work, on their relationship with their partner and on their family.

Table 1. Mental health symptoms women report during the perimenopause.17–19

Table 1. Mental health symptoms women report during the perimenopause.^17–19

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Aetiology

Animal studies have shown that ovarian steroids have a direct impact on neurotransmitter system activities, including regulation of metabolic enzyme production as well as receptor and transporter protein activity. The pattern of effects of ovarian steroids on the serotonin system in humans is similar to those observed in animals. There is also evidence that reproductive steroids influence the serotonergic regulation of the hypothalamic-pituitary-adrenal (HPA) axis.³ Neurobiological evidence indicates that estradiol has neuromodulary and neuroprotective effects in the hypothalamus, amygdala and the hippocampi, which are directly relevant to mood symptomatology. Estrogen acts as a serotonergic agonist and is implicated in multiple mood regulating mechanisms in different brain regions. It increases serotonergic postsynaptic responsivity, increases the number of serotonergic receptors and enhances serotonergic transport and uptake.²⁰ A clinical study from 2015 demonstrated that the sudden (blinded) withdrawal of estradiol, which was given to participating perimenopausal women as a transdermal patch, precipitated depressive symptoms in those women who had a history of perimenopausal depression. The women in the control group, who also had a history of perimenopausal depression, but who continued to receive estradiol, had no recurrence of their depressive symptoms. The depression inducing effects of estradiol withdrawal in this study only affected women with a history of perimenopausal depression, which suggests that perimenopausal changes in estradiol levels can trigger depression in a susceptible subgroup of women.²¹ Results from another clinical trial suggest that estradiol variability in the menopause transition enhances emotional sensitivity to psychosocial stress and this increased sensitivity may contribute to the development of depressed mood. These effects of estradiol fluctuation on stress sensitivity and mood appear to be independent of estradiol levels and VMS.²² There is substantial evidence now that fluctuations of estradiol levels during the menopause transition trigger alterations in the HPA axis and changes in cortisol levels, which further supports the idea that perimenopausal depression is unique in its aetiology and that affected women could benefit from interventions to stabilize estradiol levels, such as HRT.^23,24

Risk factors

There are risk factors which make a subgroup of women more vulnerable to developing depressive symptoms during the perimenopause (Table 2). Women who have a history of increased sensitivity to hormonal fluctuations and to reproductive endocrine changes, such as PMS/PMDD or postnatal depression (PD), but also women with a history of oral contraceptive-induced dysphoria have a higher risk of developing depressive symptoms during the perimenopausal years.³ Perimenopausal women with a history of PMS are three times more likely to report symptoms of depression during the menopausal transition compared to premenopausal women.¹⁷ But even in women with no history of depression, the risk of new onset depression during the perimenopausal years is still twice as high as in premenopausal women.³

Table 2. Factors which increase the risk for depressive symptoms during the perimenopause.25,26

Table 2. Factors which increase the risk for depressive symptoms during the perimenopause.^25,26

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Assessment

GPs have usually 10 min to take a history, make a diagnosis and discuss treatment options. It is not realistic to carry out a thorough mental health assessment during 10 min and often it requires several visits to enable the GP to make a diagnosis and for women to make an informed decision about the best possible treatment option. Blood tests such as FSH levels may be considered in symptomatic women aged 40–45 and of course if premature ovarian insufficiency is suspected in women below the age of 40.²⁷ The GP should ask the patient about a history of depression including PD, PMS/PMDD, quality of sleep, periods (flooding, pain, frequency), contraception, as well as VMS (hot flushes, night sweats). Validated instruments such as the beck depression inventory, Hamilton Depression Rating Scale or the Patient Health Questionnaire-9 can be used to measure and monitor the severity of depressive symptoms. The Greene Climacteric Scale is a specific assessment tool for menopausal symptoms, which includes physical as well as psychological parameters.²⁸ Another useful tool is the Meno-D questionnaire. This is a relatively new rating scale (2018), which was specifically developed and validated to assess the rate and severity of the characteristic symptoms of perimenopausal depression (Table 3). The concept of the Meno-D scale is based on a five-factor model: self; somatic; cognitive; sleep; sexual. It is designed to be used by clinicians, researchers and as a self-assessment tool for perimenopausal women. The questionnaire asks 12 questions and each question has five answer options, each graded from 0 to 4, according to severity.¹⁹ Unfortunately, the paper does not provide scoring thresholds which would help to practically define normal from abnormal results. It may therefore be more useful as a symptom monitoring tool rather than a diagnostic tool.

Table 3. Clinical areas which are assessed by the Meno-D questionnaire.19

Table 3. Clinical areas which are assessed by the Meno-D questionnaire.¹⁹

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Treatment

Untreated depressive symptoms greatly affect the quality of life, relationships and the ability to function in the workplace. Depression is associated with an increased risk of heart disease, diabetes, osteoporosis and in the worst case, suicide.¹⁶ Treatment should be personalised and tailored to each individual woman and her needs. Treatment progress needs to be monitored, and women should be reviewed frequently. A careful risk assessment and history taking prior to starting treatment is essential. Personal health beliefs, ideas, concern and expectations should be considered, and doctors should work in partnership with the patient, giving relevant evidence-based information to help women to make an informed decision about the best treatment option. Advice about healthy lifestyle measures like smoking cessation, reducing alcohol intake, healthy eating, exercise and managing stress should be included during the discussion about treatment. CBT and mindfulness-based therapies can be offered in addition to medication depending on severity and preferences.²⁹

Hormone replacement therapy

Fluctuating estradiol levels have been shown to contribute to the development of depressive symptoms and low mood during the perimenopause. Stabilising estradiol levels with HRT has been shown to be an effective treatment for mild to moderate depressive symptoms.^9,30,31 One recent clinical study showed that the combination of transdermal estradiol in combination with micronized progesterone helped to prevent clinically significant depressive symptoms among initially euthymic perimenopausal and early postmenopausal women.⁸

The NICE guidelines state that HRT should be considered as a treatment for low mood that arises as a result of the menopause. The guidelines also state, that due to lack of evidence, SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) are not recommended to treat low mood in menopausal women who have not been diagnosed with clinical depression.¹² It is important that health care professionals who are involved in the care of menopausal women are mindful to distinguish between severe major depressive episodes and less severe depressive symptoms and low mood. Women who diagnostically fulfil the criteria for major depression and clinical depression should still be treated with antidepressants as the first-line treatment.

Beyond the stabilisation of estradiol fluctuations to treat low mood, HRT is also the first choice for the treatment of VSM in woman who don’t have contraindications. HRT improves overall quality of life, energy levels and sleep and it does not negatively affect libido or cause sexual dysfunction.³² In addition, HRT is licenced for the prevention and treatment of osteoporosis,^32,33 and can help to prevent cardiovascular disease if started early enough.³⁴ HRT, preferably transdermal estradiol (gel or patch) should be offered as the first-line treatment to women with mild perimenopausal depressive symptoms.³⁵ Women with a uterus need endometrial protection when using estrogen replacement; however, many women with a history of PMS/PMDD and oral contraceptive-induced dysphoria are sensitive or even intolerant to synthetic progestins. Micronized progesterone (orally or vaginally) given continuously or cyclically or the Mirena coil (IUS) have been shown to be better tolerated than other progestogens with regard to mood-related side effects.³⁶

Antidepressants

In a large metanalysis, antidepressants have been shown to be more efficacious than placebo in adults with major depressive disorder, but this analysis did not specifically look at perimenopausal women.³⁷ In 2018, the North American Menopause Society (NAMS) issued a consensus statement about the evaluation and treatment of perimenopausal depression. These guidelines recommend that antidepressants, CBT and other psychotherapies should remain the front-line treatments for major depressive episodes during the perimenopause, despite also stating that there is evidence that estrogen therapy has antidepressant effects of similar magnitude to that observed with classic antidepressant agents when administered to depressed perimenopausal woman with or without concomitant VMS.¹⁵ The NAMS statement does not provide a treatment recommendation for less severe menopause-related depressive symptoms or low mood, but focuses on major depressive episodes. The NICE menopause guideline on the other hand does make this recommendation by stating that there is no clear evidence for SSRIs or SNRIs to ease low mood in menopausal women who have not been diagnosed with clinical depression.¹²

With regard to the best choice of antidepressant, only Desvenlafaxine has been studied in two large randomised placebo controlled trials and proven efficacious in the treatment of depressed perimenopausal women. Most other antidepressants have been trialled in cohorts of younger premenopausal or older postmenopausal women.^38,39 Clinical trials have shown that compared to placebo, antidepressants can help to reduce the frequency of VMS^40,41; however, compared to HRT they are much less effective. HRT has been shown to reduce the severity and frequency of VMS by up to 83%, whereas antidepressants reduced the severity by up to 50%.⁴² In addition to that, only Paroxetine 7.5 mg (Brisdelle) has so far been approved by the FDA for the treatment of VMS, no other antidepressant is licenced for this purpose.⁴³

Another very important consideration with regard to prescribing antidepressants in perimenopausal women is the unfavourable side effect profile. While HRT is licenced for the prevention and treatment of osteoporosis, SSRIs have been shown to significantly increase fracture risk in perimenopausal women if taken longer than five years.⁴² Menopausal symptoms can last much longer than five years and the long-term use of antidepressants can further add to an already increased risk of osteoporosis in women. In addition to an increased fracture risk, antidepressants are also associated with cardiovascular side effects, gastrointestinal side effects, increased risk of suicidal behaviour during the first weeks of treatment, weight gain, headache and insomnia.⁴⁵ More than 50% of women who take SSRIs will experience sexual dysfunction, including low libido, anorgasmia and decreased arousal, which greatly affects quality of life.⁴⁶

HRT in combination with antidepressants

What needs to be taken into consideration, is the range of severity of perimenopausal mental health symptoms from mild to moderate and severe which is different for each woman. The most severe symptoms may fulfil the criteria of a major depressive episode as diagnosed according to the DSM 5 criteria.⁴⁷ Women are two to four times more likely to experience major depression during the perimenopausal or early postmenopausal phase.⁴⁸ Women who fulfil the criteria for major depression should be offered antidepressants as the first-line treatment. In addition, they can be offered HRT if they also experience other menopause-related symptoms. In women with mild to moderate low mood who don’t achieve sufficient symptom control on HRT alone, antidepressants can be an important adjunct medication and there is some evidence that HRT can augment and enhance the efficacy of some antidepressants. HRT can be added to an antidepressant and vice versa.^15,17,46 In women with a history of several depressive episodes, who have been stable for many years while taking antidepressants (SSRIs) and who are experiencing a worsening of depressive symptoms together with VMS, the antidepressant dosing may need to be adjusted and add-on hormone therapy should be considered.⁴² Clinical decisions about treatment should be made on a personalised case-by-case evaluation.

Summary

A growing body of research provides evidence that perimenopausal depression is a subtype of Reproductive Depression. Women with a history of depression or hormone-related mood changes seem to be particularly sensitive to perimenopausal estradiol fluctuations and have a higher risk of developing anxiety and depression. It is important that GPs have an awareness of Reproductive Depression and support women who enter and go through the menopausal transition appropriately and effectively. A thorough history of the woman’s mental health, which also includes questions about the menstrual cycle, PMS, PD and side effects to hormonal contraception should be taken. Women should be given relevant information about the benefits and side effects of HRT, as well as antidepressants, so that they can make an informed decision about the best treatment option. Those women who do not have contraindications, such as breast cancer and are not diagnosed with clinical depression, should be offered HRT as the first-line treatment for low mood during the perimenopause and GPs who practice in the UK should follow the NICE guidelines. In more severe cases, such as major depressive episodes, a combination of antidepressants and adjunct HRT should be considered.

Acknowledgements

None.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Not applicable.

Contributorship

ML is the sole author of this work.

References

1.	Hillard, T, Abernethy, K, Hamoda, H, et al. Management of the menopause. 6th ed. UK: British Menopause Society, 2017, p.2. Google Scholar
2.	McKinlay, SM, Brambilla, DJ, Posner, J. The normal menopause transition. Maturitas 1992; 14: 103–115. Google Scholar | Crossref | Medline | ISI
3.	Schmidt, PJ, Rubinow, DR. Sex hormones and mood in the perimenopause. Ann N Y Acad Sci 2009; 1179: 70–85. Google Scholar | Crossref | Medline | ISI
4.	Cohen, LS, Soares, CN, Vitonis, AF, et al. Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry 2006; 63: 385–390. Google Scholar | Crossref | Medline
5.	Studd, J, Nappi, RE. Reproductive depression. Gynecol Endocrinol 2012; 28: 42–45. Google Scholar | Crossref | Medline | ISI
6.	Payne, JL, Teitelbaum-Palmer, J, Joffe, H. A reproductive subtype of depression: conceptualizing models and moving toward etiology. Harv Rev Psychiatry 2009; 17: 72–86. Google Scholar | Crossref | Medline | ISI
7.	Nappi, RE, Tonani, S, Santamaria, V, et al. Luteal phase dysphoric disorder and premenstrual syndrome. Ital J Psych 2009; 28: 27–33. Google Scholar
8.	Gordon, JL, Rubinow, DR, Eisenlohr-Moul, TA, et al. Efficacy of transdermal estradiol and micronized progesterone in the prevention of depressive symptoms in the menopause transition: a randomized clinical trial. JAMA Psychiatry 2018; 75: 149–157. Google Scholar | Crossref | Medline
9.	Soares, CN, Almeida, OP, Joffe, H, et al. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001; 58: 529–534. Google Scholar | Crossref | Medline
10.	Schmidt, PJ, Nieman, L, Danaceau, MA, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 2000; 183: 414–420. Google Scholar | Crossref | Medline | ISI
11.	Newson L, Mair R. and Lass A. Br J of Fam Med 2018, https://www.bjfm.co.uk/results-from-the-bjfm-menopause-survey (accessed 30 December 2018). Google Scholar
12.	NICE . Menopause: diagnosis and management. UK: NICE, 2015. Google Scholar
13.	Writing Group for the Women’s Health Initiative Investigators . Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled Trial. JAMA 2002; 288: 321–333. Google Scholar | Crossref | Medline | ISI
14.	McIntyre, RS, Konrski, JZ, Grigoriadis, S, et al. Hormone replacement therapy and antidepressant prescription patterns: a reciprocal relationship. CMAJ 2005; 4: 172. Google Scholar
15.	Maki, P, Kornstein, SG, Hadine, J, et al. Guidelines for the evaluation and treatment of perimenopausal depression: summary and recommendations. Menopause 2018; 25: 1069–1085. Google Scholar | Crossref | Medline
16.	Toffol, E, Heikinheimo, O, Partonen, T. Hormone therapy and mood in perimenopausal and postmenopausal women: a narrative review. Menopause 2015; 22: 564–578. Google Scholar | Crossref | Medline
17.	Parry, BL. Optimal management of perimenopausal depression. Int J Womens Health 2010; 2: 143–151. Google Scholar | Crossref | Medline
18.	Soares, CN, Frey, BN. Challenges and opportunities to manage depression during the menopausal transition and beyond. Psychiatr Clin N Am 2010; 33: 295–308. Google Scholar | Crossref | Medline | ISI
19.	Kulkarni, J, Gavrilidis, E, Hudaib, AR, et al. Development and validation of a new rating scale for perimenopausal depression – the Meno-D. Transl Psychiatry 2018; 8: 123–131. Google Scholar | Crossref | Medline
20.	Wharton, W, Gleason, CE, Olson, SR, et al. Neurobiological underpinnings of estrogen-mood relationship. Curr Psychiatry Rev 2012; 8: 247–256. Google Scholar | Crossref | Medline
21.	Schmidt, PJ, Ben, DR, Martinez, PE, et al. Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry 2015; 72: 714–726. Google Scholar | Crossref | Medline | ISI
22.	Gordon, JL, Rubinow, DR, Eisenlohr-Moul, TA, et al. Estradiol variability, stressful life events and the emergence of depressive symptomatology during menopause transition. Menopause 2016; 23: 257–266. Google Scholar | Crossref | Medline | ISI
23.	Gordon, JL, Eisenlohr-Moul, TA, Rubinow, DR, et al. Naturally occurring changes in estradiol concentrations in the menopause transition predict morning cortisol and negative mood in perimenopausal depression. Clin Psychol Sci 2016; 4: 919–935. Google Scholar | SAGE Journals | ISI
24.	Gupta, S, Mukherjee, A, Biswas, S, et al. Evaluation of endocrine parameters as predictor of major depressive disorder. Indian J Psychol Med 2017; 39: 766–769. Google Scholar | Crossref | Medline
25.	Freeman, EW, Sammel, MD, et al. Premenstrual syndrome as a predictor of menopausal symptoms. Obstet Gynecol 2004; 103: 960–966. Google Scholar | Crossref | Medline | ISI
26.	Bromberger, JT, Kravitz, HM. Mood and menopause: findings from the study of women’s health across the nation (SWAN) over 10 years. Obstet Gynecol Clin North Am 2011; 38: 609–625. Google Scholar | Crossref | Medline | ISI
27.	Hillard, T, Abernethy, K, Hamoda, H, et al. Management of the menopause. 6th ed. UK: British Menopause Society, 2017, p.36. Google Scholar
28.	Greene, J. A factor analytic study of climacteric symptoms. J Psychosom Res 1976; 20: 425–430. Google Scholar | Crossref | Medline | ISI
29.	Green, SM, Key, BL, McCabe, RE. Cognitive-behavioural, behavioural, and mindfulness-based therapies for menopausal depression: a review. Maturitas 2015; 80: 37–47. Google Scholar | Crossref | Medline
30.	Grazziottin, A, Serafini, A. Depression and the menopause: why antidepressants are not enough? Menopause Int 2009; 15: 76–81. Google Scholar | SAGE Journals
31.	Worsley, R, Davis, SR, Gavrilidis, E, et al. Hormonal therapies for new onset and relapsed depression during perimenopause. Maturitas 2012; 73: 127–133. Google Scholar | Crossref | Medline
32.	Newson, LR. Best practice for HRT: unpicking the evidence. Br J Gen Pract 2016; 66: 597–598. Google Scholar | Crossref | Medline
33.	Hillard, T, Abernethy, K, Hamoda, H, et al. Management of the menopause. 6th ed. UK: British Menopause Society, 2017, p.121. Google Scholar
34.	Newson, L. Menopause and cardiovascular disease. Post Reprod Health 2018; 24: 44–49. Google Scholar | SAGE Journals
35.	Soares, CN, Zitek, B. Reproductive hormone sensitivity and risk for depression across the female life cycle: a continuum of vulnerability? J Psychiatry Neurosci 2008; 33: 331–343. Google Scholar | Medline | ISI
36.	Panay, N, Studd, J. Progestogen intolerance and compliance with hormone replacement therapy in menopausal women. Hum Reprod Update 1997; 3: 159–171. Google Scholar | Crossref | Medline | ISI
37.	Cipriani, A, Furukawa, TA, Salanti, G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018; 391: 1357–1366. Google Scholar | Crossref | Medline
38.	Clayton, AH, Kornstein, SG, Dunlop, BW, et al. Efficacy and safety of desvenlafaxine 50 mg/d in a randomized, placebo-controlled study of perimenopausal and postmenopausal women with major depressive disorder. J Clin Psychiatry 2013; 74: 1010–1017. Google Scholar | Crossref | Medline | ISI
39.	Kornstein, SG, Jiang, Q, Reddy, S, et al. Shortterm efficacy and safety of desvenlafaxine in a randomized, placebo-controlled study of perimenopausal and postmenopausal women with major depressive disorder. J Clin Psychiatry 2010; 71: 1088–1096. Google Scholar | Crossref | Medline | ISI
40.	Hickey, M, Szabo, RA, Hunter, M, Non-hormonal treatments for menopausal symptoms. BMJ 2017; 23: 359–366. Google Scholar
41.	Stubbs, C, Mattingly, L, Crawford, SA, et al. Do SSRIs and SNRIs reduce the frequency and/or severity of hot flashes in menopausal women. J Okla State Med Assoc 2017; 110: 272–274. Google Scholar | Medline
42.	Tan O, Pinto A and Carr BR. Hormonal and non-hormonal management of vasomotor symptoms: a narrated review. J Endocrinol Diabetes Obes 2013; 1: 1009–1024. Google Scholar
43.	Ronald, J, Li, L, Kim, MJ, et al. FDA approval of paroxetine for menopausal hot flushes. N Engl J Med 2014; 370: 1777–1779. Google Scholar | Crossref | Medline
44.	Sheu, Yi-han, Lanteigne, A, Stürmer, T, et al. SSRI use and risk of fractures among perimenopausal women without mental disorders. Inj Prev 2015; 21: 397–403. Google Scholar | Crossref | Medline
45.	Andrews, PW, Thomson, JA, Amstadter, A, et al. Primum non nocere: an evolutionary analysis of whether antidepressants do more harm than good. Front Psychol 2012; 3: 117–136. Google Scholar | Crossref | Medline | ISI
46.	Kim, D, Joffe, H. Use of antidepressants during perimenopause. Womens Health 2006; 2: 627–637. Google Scholar | SAGE Journals
47.	American Psychiatric Association . Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association, 2013. Google Scholar | Crossref
48.	Bromberger, JT, Kravitz, HM, Chang, YF, et al. Major depression during and after the menopausal transition: study of women’s health across the nation (SWAN). Psychol Med 2011; 41: 1879–1888. Google Scholar | Crossref | Medline | ISI