Understanding Premenstrual Exacerbations of Psychiatric Illnesses

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Anxiety and Depression Association of America (ADAA).

PME affects many women, yet it remains under-recognized in clinical practice and in research.

uterus, menstruation

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What Is PME?

Research on premenstrual disorders has become increasingly common, particularly with the addition of premenstrual dysphoric disorder (PMDD) to the DSM-5 in 2013.1 While the majority of women experience premenstrual symptomatology, only a subset of these women has a premenstrual disorder (ie, premenstrual symptoms that cause significant distress or functional impairment).2 The premenstrual disorders include PMDD and premenstrual syndrome (PMS), which are overlapping disorders defined by different organizations, and premenstrual exacerbation (PME) (Table).1,3

Table. Summary of Diagnostic Criteria for Premenstrual Disorders

Table. Summary of Diagnostic Criteria for Premenstrual Disorders

There have been significant strides in the understanding of PMDD and PMS; however, PME has remained little studied,4 and the distinction between PMDD/PMS and PME is often not recognized in clinical practice. Women with PMDD and PMS do not experience symptoms throughout the menstrual cycle, but rather have symptoms premenstrually and have a period of time in the menstrual cycle when they are not suffering from symptoms. While PMDD and PMS are considered premenstrual (ie, late luteal phase) disorders, the specific timing of vulnerability to symptoms in the menstrual cycle varies between women.5 Nevertheless, these women have a period of time in the follicular phase when symptoms are absent or minimal. PME, in contrast, refers to the worsening of symptoms of another existing disorder during the premenstrual, or late luteal, phase.2 Women with PME may experience symptoms across the menstrual cycle, and have symptom exacerbation premenstrually. To date, there remains an inadequate understanding of PME; yet studies have shown it affects many women.

What Conditions Can Be Premenstrually Exacerbated?

PME can be seen in a variety of preexisting psychiatric disorders and nonpsychiatric disorders such as Meniere’s disease and atopic dermatitis.6,7 Here, we will focus on PME of preexisting psychiatric disorders. The prevalence of PME is not well estimated, both because it has been studied little and because many prior studies failed to prospectively evaluate subjects. Prospective symptom ratings over a minimum of 2 symptomatic menstrual cycles is crucial for the accurate diagnosis of premenstrual disorders and allows the differentiation of PME from PMDD/PMS and from intermittent symptoms without relationship to the menstrual phase.2 Retrospective recall of when symptoms occurred in relation to the menstrual cycle phase is inaccurate.

PME can be seen in a variety of mood disorders, including unipolar and bipolar depression; however, only a limited number of studies have prospectively examined the prevalence of PME. Data from the first 1500 participants of The National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study showed that, among 433 premenopausal women not taking oral contraceptives, 64% retrospectively reported premenstrual worsening of their depression.8 A post-hoc analysis of data from the same trial with all included participants reported a prevalence of 66% for retrospective premenstrual exacerbation.9 This study also found that women with PME had longer index episodes, more anxiety, and shorter time to relapse after remission with citalopram.8,9 Overall, these findings suggest that PME is associated with a more severe illness course in major depressive disorder. However, in both studies, premenstrual symptomatology was based on retrospective recall and not prospective monitoring of symptoms.

PME has also been noted in bipolar disorder. A review found that, in retrospective studies, 64% to 68% of women with bipolar disorder reported menstrual cycle-related mood changes while, in prospective studies, 44% to 65% reported menstrual cycle-related mood changes.10 Women with PME are more likely to report that their premenstrual symptoms interfered with work or school compared to those without PME.11 Bipolar disorder with PME is also associated with a more severe illness course.11

Women with borderline personality disorder can also experience PME, with symptoms worsening premenstrually and further worsening during menstruation.12 Certain women with obsessive-compulsive disorder (OCD) can experience premenstrual worsening of symptoms.13 Vulink et al found that 49% of patients reported an exacerbation of OCD symptoms during the premenstrual period, with a significant difference of 3 points on the Yale-Brown Obsessive Compulsive scale between the premenstrual phase and mid-menstrual phase.13 Lastly, a subset of women may also experience premenstrual worsening of certain anxiety disorders, such as generalized anxiety disorder and panic disorder, though this area has been less studied.14

It is important to point out that, while many psychiatric and nonpsychiatric illnesses can be exacerbated at particular times in the menstrual cycle, the pattern of exacerbation can vary between disorders. The premenstrual period is not the only menstrual phase when symptoms can be exacerbated for a disorder. For example, the early follicular, or menstrual phase, is a period of vulnerability for migraines.15 Depression in borderline personality disorder appears to peak during the perimenstrual (days around start of menstruation) and follicular phase.12 Psychotic disorders can also fluctuate across the menstrual cycle.16 The mechanism for exacerbation with hormonal change likely differs between illnesses.

Why Do Certain Women Experience PME?

The pathophysiology of PME has not been studied. However, studies suggest that women with PME may not respond or may not respond as well to certain treatments used for PMDD, such as suppression of ovulation and thus stabilization of hormonal fluctuations with leuprolide. This differential response provides evidence that the pathophysiology of PME may differ from that of PMDD.17 Furthermore, women are vulnerable to symptom exacerbation at different times of the menstrual cycle. The mechanisms involved in each pattern of exacerbation may be unique. Both PMDD and PME, however, appear to be due to a sensitivity to the same fluctuations of hormones as other women experience.18

How Do We Treat PME?

Treatment for PME remains understudied as well. Studies have shown that certain treatments for PMDD may not have the same efficacy in patients with PME. Previous studies have shown that PMDD-specific treatments, such as the addition of drospirenone-containing oral contraceptives to selective serotonin reuptake inhibitors (SSRIs)19 or gonadotropin-releasing hormone agonists analogues,17 are not effective in treating PME. In addition, symptoms in women with PME are not limited to the premenstrual period; consequently, intermittent luteal phase dosing of an SSRI, which is an effective treatment for PMDD and PMS, would not be appropriate alone for PME.

There are small studies that have provided preliminary evidence for the treatment of certain PMEs. Miller et al evaluated a small number of patients (n=9) with a double-blind crossover protocol. They found that, among patients with PME of major depressive disorder who exhibited continued PME on a constant dose of sertraline, the Hamilton Depression Rating Scale scores were significantly lower when on an increased dose of sertraline premenstrually compared to placebo.20 There is also preliminary evidence that mood stabilization throughout the menstrual cycle in women with bipolar disorder can improve premenstrual symptomatology.21

While there are small studies that have begun to shed light on the treatment of certain PMEs, we continue to understand little about how to approach medication management of PME. Future studies need to clarify whether premenstrual dosing of medications helps PME of psychiatric illnesses. Major depressive disorder takes weeks to respond to an SSRI. In contrast, PMS/PMDD improves immediately with SSRI initiation due to a different mechanism of action.22 This immediate symptom relief allows women with PMS/PMDD to respond to luteal phase dosing. If increasing medication in the luteal phase can relieve PME, we also need to understand what medication to select. In the luteal phase, would we select or increase the dose of the treatment for PMS/PMDD (ie, SSRI) or for the underlying diagnosis (ie, mood stabilizer for PME of bipolar disorder)? Lastly, we need to study treatment of PMEs of different psychiatric illnesses, as the pathophysiology and, thus, treatment response may differ.

Although there is some evidence to suggest that PME should be managed differently than PMDD and PMS, further research should clarify whether treating the underlying condition could help treat PME, whether luteal phase dosing of medications helps women with PME, and, if luteal phase dosing helps PME, which medication should be selected. Finally, to our knowledge, no studies have evaluated the efficacy of psychotherapy for PME of psychiatric disorders.

Why Do We Need to Understand PME Better?

We continue to understand little about who is vulnerable to PME, why they experience this vulnerability, and how to effectively treat their symptoms. Nevertheless, the studies that exist suggest that PME affects a large portion of women with psychiatric illness. In addition, the course of PME and the relationship between PME and reproductive depressions (ie, symptoms during reproductive transitions such as perinatal perinatal mood and anxiety disorders and symptoms in the menopausal transition) remain unclear. Perinatal depression and depression in the menopausal transition have both been associated with PMS.22,23 By understanding populations vulnerable to relapse during periods of hormonal fluctuation, women can be educated and monitored closely at these times to mitigate the effects.

PME is often not recognized in clinical practice. When premenstrual symptoms are reported, prospective evaluation of symptomatology across the menstrual cycle is rarely collected to clarify diagnosis. There is need for further education about what PME is and the importance of distinguishing it from PMS/PMDD and from intermittent symptoms with timing unrelated to the menstrual phase.

Concluding Thoughts

PME has been underrecognized in research despite its estimated prevalence and impact on women’s lives. Larger studies using prospective ratings to accurately estimate the prevalence of PME across different psychiatric illnesses are needed. Understanding the prevalence, pathophysiology, pattern with menstrual cycle, and treatment of PME across psychiatric illnesses can help decrease the burden of illness for women.

Dr Lin recently graduated from Weill Cornell Medicine and will be starting psychiatry residency at NYU Langone in July 2023. While at Weill Cornell Medicine, she served as a codirector for the women’s health division of the Weill Cornell Community Clinic, a student-led free clinic for uninsured New York City patients.She is interested in women’s mental health and has presented on the psychological impact of premenstrual symptoms at a national conference. Dr Susser is a reproductive psychiatrist and assistant professor of clinical psychiatry at Weill Cornell Medicine. She established a reproductive mental health clinic within the New York Presbyterian Hospital/Weill Cornell Medicine Westchester Behavioral Health Center, and now oversees this clinic. Through this program, she provides consultations to outpatient and inpatient teams; provides time limited specialized reproductive psychiatry care; and educates trainees, faculty, and staff.

References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

2. O'Brien PM, Bäckström T, Brown C, et al. Towards a consensus on diagnostic criteria, measurement and trial design of the premenstrual disorders: the ISPMD Montreal consensus. Arch Womens Ment Health. 2011;14(1):13-21.

3. Hofmeister S, Bodden S. Premenstrual syndrome and premenstrual dysphoric disorder. Am Fam Physician. 2016;94(3):236-240.

4. Tiranini L, Nappi RE. Recent advances in understanding/management of premenstrual dysphoric disorder/premenstrual syndrome. Fac Rev. 2022;11:11.

5. Eisenlohr-Moul TA, Kaiser G, Weise C, et al. Are there temporal subtypes of premenstrual dysphoric disorder?: using group-based trajectory modeling to identify individual differences in symptom change. Psychol Med. 2020;50(6):964-972.

6. Andrews JC, Honrubia V. Premenstrual exacerbation of Meniere's disease revisited. Otolaryngol Clin North Am. 2010;43(5):1029-1040.

7. Kemmett D. Premenstrual exacerbation of atopic dermatitis. Br J Dermatol. 1989;120(5):715.

8. Kornstein SG, Harvey AT, Rush AJ, et al. Self-reported premenstrual exacerbation of depressive symptoms in patients seeking treatment for major depression. Psychol Med. 2005;35(5):683-692.

9. Haley CL, Sung SC, Rush AJ, et al. The clinical relevance of self-reported premenstrual worsening of depressive symptoms in the management of depressed outpatients: a STAR*D report. J Womens Health (Larchmt). 2013;22(3):219-229.

10. Teatero ML, Mazmanian D, Sharma V. Effects of the menstrual cycle on bipolar disorder. Bipolar Disord. 2014;16(1):22-36.

11. Dias RS, Lafer B, Russo C, et al. Longitudinal follow-up of bipolar disorder in women with premenstrual exacerbation: findings from STEP-BD. Am J Psychiatry. 2011;168(4):386-394.

12. Eisenlohr-Moul TA, Schmalenberger KM, Owens SA, et al. Perimenstrual exacerbation of symptoms in borderline personality disorder: evidence from multilevel models and the Carolina Premenstrual Assessment Scoring System. Psychol Med. 2018;48(12):2085-2095.

13. Vulink NC, Denys D, Bus L, Westenberg HG. Female hormones affect symptom severity in obsessive-compulsive disorder. Int Clin Psychopharmacol. 2006;21(3):171-175.

14. Hsiao MC, Hsiao CC, Liu CY. Premenstrual symptoms and premenstrual exacerbation in patients with psychiatric disorders. Psychiatry Clin Neurosci. 2004;58(2):186-190.

15. Maasumi K, Tepper SJ, Kriegler JS. Menstrual migraine and treatment options: review. Headache. 2017;57(2):194-208.

16. Bergemann N, Parzer P, Nagl I, et al. Acute psychiatric admission and menstrual cycle phase in women with schizophrenia. Arch Womens Ment Health. 2002;5(3):119-126.

17. Freeman EW, Sondheimer SJ, Rickels K. Gonadotropin-releasing hormone agonist in the treatment of premenstrual symptoms with and without ongoing dysphoria: a controlled study. Psychopharmacol Bull. 1997;33(2):303-309.

18. Kuehner C, Nayman S. Premenstrual exacerbations of mood disorders: findings and knowledge gaps. Curr Psychiatry Rep. 2021;23(11):78.

19. Peters W, Freeman MP, Kim S, et al. Treatment of premenstrual breakthrough of depression with adjunctive oral contraceptive pills compared with placebo. J Clin Psychopharmacol. 2017;37(5):609-614.

20. Miller MN, Newell CL, Miller BE, et al. Variable dosing of sertraline for premenstrual exacerbation of depression: a pilot study. J Womens Health (Larchmt). 2008;17(6):993-997.

21. Robakis TK, Holtzman J, Stemmle PG, et al. Lamotrigine and GABAA receptor modulators interact with menstrual cycle phase and oral contraceptives to regulate mood in women with bipolar disorder. J Affect Disord. 2015;175:108-115.

22. Susser LC. Clinical implications of the neurosteroid allopregnanolone in reproductive depression. Harv Rev Psychiatry. 2023;31(1):37-45.

23. Freeman EW, Sammel MD, Rinaudo PJ, Sheng L. Premenstrual syndrome as a predictor of menopausal symptoms. Obstet Gynecol. 2004;103(5 Pt 1):960-966.

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