Premenstrual dysphoric disorder (PMDD) is a cyclical illness characterized by mood, behavioral, and physical symptoms that occur exclusively in the luteal phase of the menstrual cycle and remit with the onset of menses. PMDD is differentiated from premenstrual syndrome (PMS) by the number and specificity of symptoms that are required to make the diagnosis. Several studies have focused on the lifetime comorbidity of mood and anxiety disorders in women with PMDD. However, most PMDD studies have examined populations of women without current comorbid psychiatric disorders, making it difficult to estimate the true rate of psychiatric comorbidity in this group.
This article focuses on diagnostic and treatment dilemmas encountered in women with PMDD and psychiatric comorbidity.
PMDD occurs in about 3% to 8% of women with regular ovulatory cycles (Table 1).1 PMS, on the other hand, is experienced by about 20% of menstruating women who have at least 1 physical or emotional symptom during the 5 days before menses.2 In PMDD, symptoms must not merely be an exacerbation of another disorder,3 which makes understanding and diagnosing this condition in women who complain of PMS and who already have another Axis I disorder a challenge.
Although the term “PMDD” implies a focus on dysphoria, the most common affective symptoms are irritability and tension. PMDD is associated with a level of impairment that is similar to major depressive disorder and poorer quality of life compared with community norms and should therefore be considered a serious health condition.4
PMDD and psychiatric comorbidity
Despite the diagnostic criteria that comorbid illnesses must be excluded, studies report a higher rate of comorbid mood and anxiety disorders in women with PMDD than in the general population. It is important to distinguish the concept of comorbidity from premenstrual exacerbation (PME) of an underlying Axis I disorder.
The prevalence of PMEs of Axis I disorders is unknown, but it is probably common in women with mood and anxiety disorders. Kornstein and associates5 found that 63% of premenopausal women with major depression (N = 1500) self-reported PME of their symptoms. Cyclic exacerbations occur when the primary symptoms of the Axis I disorder worsen during the luteal phase of the menstrual cycle. This can be difficult to diagnose if the patient is seen monthly at similar phases of her menstrual cycle. Patients may not realize their symptom pattern is menstrually influenced, so it is important to ask directly about symptom and menstrual cycle patterns. Affected patients may be symptomatic throughout the month or, if treated, may have breakthrough symptoms only during the luteal phase. The key concept in PME is that the symptom profile is similar throughout the month.
In contrast with PME, PMDD is diagnosed as a comorbid condition when the specific constellation of symptoms occurs during the luteal phase, ceases in the follicular phase, and does not replicate the comorbid condition’s main symptoms. As an example, PMDD may be diagnosed in a woman who experiences symptoms of depression characterized by sadness, anhedonia, insomnia, and decreased appetite who reports significant irritability and hypersomnia that occur only premenstrually.
PMDD and mood disorders
Our recent review suggests that unipolar depression is more common in women with PMDD than in controls.6 Among studies in which PMDD was retrospectively diagnosed, depressive disorders (dysthymia, minor depression, and major depression) occurred in 18% to 69% of women with PMDD.6 In studies in which PMDD was prospectively diagnosed, depressive disorders occurred in 12% to 25% of women with PMDD.6 This phenomenon appears to be similar across cultures. In a recent study of 410 Nigerian university students, depression was the most frequent comorbid diagnosis in women with PMDD; it was present in 24% versus 3.6% of women without PMDD (odds ratio [OR], 8.37).7 Although PMDD was diagnosed retrospectively in this cross-sectional study, the researchers made attempts to distinguish between PME and comorbid PMDD.
Cohen and colleagues8 found that 57.6% of their community sample who had prospectively received a diagnosis of PMDD had a history of major depressive disorder, which is consistent with other reports. In general, severe dysphoria during the luteal phase suggests a comorbid depressive disorder.
Suicidality is routinely evaluated in patients with depression but not in the assessment of PMDD. However, suicidal ideation may be more frequent in women with PMDD than expected. Yonkers and associates9 reported that of 426 women in 6 outpatient obstetrics clinics with a current psychiatric disorder who reported premenstrual complaints, 24% with possible PMDD reported suicidal thoughts at any level (several days, more than half the days, or every day); and 20% reported suicidal thoughts for at least several days.
No studies have examined rates of PMDD in women with a current diagnosis of depression, but because depression is common in women with PMDD, all women with mood disorders should be assessed for PMS and vice versa. In addition, some women appear to be more sensitive to hormonal fluctuations than other women. This is highlighted by the evidence that suggests that PMDD may be a risk factor for postpartum depression.10
PMS can be seasonally exacerbated.11 The similarity of the cyclical symptomatology and propensity for hypersomnia and hyperphagia in both seasonal affective disorder (SAD) and PMDD highlights the possibility of an overlapping pathophysiology. In one study, PMDD was found in 46% of women with SAD during a summer remission period and in 2% of women in a control group.12 A possible genetic vulnerability for developing the conditions comorbidly has also been suggested by a recent study that found an increased prevalence of affective disorders in first-degree relatives of patients with both SAD and PMDD compared with patients with SAD alone.13
The exact nature of the relationship between PMDD and depression is still uncertain, but both disorders have been linked to serotonin (5-HT) dysregulation. In women with PMDD, whole blood 5-HT levels and platelet uptake of 5-HT are decreased.14-16 In addition, PMS is exacerbated by the depletion of tryptophan, the precursor to 5-HT.17
Animal experiments suggest that 5-HT has inhibitory effects on aggression and irritability—predominant symptoms of PMS. For example, fluoxetine reduced aggressive behavior elicited by estradiol and progesterone in ovariectomized rats.18 These animal models suggest links between serotonergic transmission and cycle-dependent behaviors that are associated with steroid hormones. The main evidence that links PMDD and unipolar depression to 5-HT dysregulation is the efficacy of the serotonergic antidepressants.19 While PMDD is not relieved by nonserotonergic antidepressants, depression may be. Whether women who respond to nonserotonergic antidepressants are less likely to suffer from PMS is not known but would be of interest.
PMDD and anxiety disorders
Like mood disorders, our recent review of the data suggests that anxiety disorders are more common in women with PMDD than in controls.6 The evidence suggests that panic disorder co-occurs in 25% of women with PMDD. Social phobia is comorbid in approximately 20% of women with PMDD, and obsessive-compulsive disorder is comorbid in 12%. Rates of comorbid PMDD and generalized anxiety disorder range from 4% to 38%.
There appears to be a relationship between trauma and PMDD. In a sample of 42 women with prospectively assessed PMS, 95% reported at least 1 sexual abuse event.20 In a longitudinal community study of 1251 women with retrospectively diagnosed PMDD, traumatic events were a stronger predictor for the onset of PMDD than depressive disorders (OR, 5.1).21 Although the biggest predictor of a later diagnosis of PMDD was subthreshold PMDD symptoms, previous trauma and a diagnosis of an anxiety disorder were also factors. Women with a history of trauma should be questioned about PMS carefully.
There may be a physiological overlap between PMDD and anxiety disorders. The rate and intensity of carbon dioxide–induced panic attacks are similar in patients with panic disorder and PMDD, while patients with depression have panic attacks similar to controls.22 Differences in g-aminobutyric acid (GABA) plasma levels in women with PMDD have been found, and serial proton magnetic resonance spectroscopic measurements show decreased cortical GABA levels during the follicular phase in women with PMDD compared with controls.23,24 Allopregnanolone—a metabolite of progesterone—has been implicated in the regulation of the GABAA receptor and may provide a link between neurosteroid function and anxiety symptoms.
PMDD and other Axis I disorders
While PME has been reported in women who have schizophrenia, there are few data to support a link between these 2 disorders. Moreover, studies do not support a strong association between PMDD and bipolar disorder.
As we have highlighted, it is important to elucidate the cyclicity of mood and anxiety symptoms in women. Inquire about the regularity of menstrual cycles, use of hormonal contraception, and use of herbal remedies during the diagnostic interview. If cyclicity is reported, prospective symptom charting should be prescribed, in which the patient must record her daily symptoms for 2 consecutive months.
There are numerous daily symptom rating charts available to help patients record their PMDD symptoms (eg, Daily Symptom Report).25 If there is a 50% change between the premenstrual and postmenstrual symptoms, a diagnosis of comorbid PMDD should be considered. Patients who have PME of their underlying Axis I disorder should be evaluated in a similar manner, even though there are no validated daily rating scales to support the diagnosis. However, clinical studies have used the Beck Depression Inventory and Hamilton Depression Rating Scale; elevated luteal phase scores indicate PME.
The serotonergic antidepressants, particularly the SSRIs, are the first-line treatment for severe PMS and PMDD. In their expert guidelines, Steiner and colleagues19 recommend the following treatment for PME of depression or anxiety:
• Treat the underlying Axis I disorder with full antidepressant dosages.
• If luteal symptoms persist, increase the dosage of the antidepressant for the whole cycle.
• Alternatively, switch to semi-intermittent dosing by maintaining the follicular dosage and then increasing it during the luteal phase only.
A recent study of 9 women with PME of menstrual dysphoric disorder (MDD) showed that variable antidepressant dosing could be effective.26 In this study, the sertraline dosage was increased during the luteal phase by 50% from the follicular phase dosage.
In 5 patients with both PMDD and MDD, cyclical irritability and physical symptoms persisted during treatment with a tricyclic antidepressant.27 In a study of whole-cycle (continuous) versus luteal phase (intermittent) treatment with sertraline, there was a significant decrease in Hamilton Rating Scale for Depression scores in the subgroup that had both PMDD and depression.28
Although it is unlikely that PMDD is just a variant of depression, one might suppose that serotonergic antidepressants could address both the PMDD and major depressive symptoms. However, more controlled studies are needed. While patients with PMDD generally respond to dosages of SSRIs at the lower end of the effective range, it is our clinical experience that when there are comorbid Axis I disorders, higher dosages should be prescribed. If a patient is currently taking a nonserotonergic antidepressant, augmentation with an SSRI or switching to an SSRI should be considered.
There are no studies that examine maintenance treatment in women with PMDD and a comorbid psychiatric illness. PMDD is a chronic, recurrent disorder, so it can be assumed that long-term treatment is indicated. Further studies are warranted.
Alprazolam, a benzodiazepine, and buspirone, a 5-HT1A agonist, have shown modest efficacy in some, but not all, PMS studies. Berger and Presser29 found a poorer response to alprazolam in women with follicular phase anxiety and depression than in those with only luteal phase symptoms. Women took the medication regularly during the luteal phase and on an as needed basis during the follicular phase.
If a woman continues to experience significant premenstrual anxiety, despite treatment with an SSRI, luteal phase treatment with an anxiolytic can be considered.
Estradiol affects 5-HT synthesis and reuptake. Pharmacological suppression of ovulation has been shown to decrease symptoms in women with PMS. Young and colleagues30 reported in the analysis of the STAR*D that 1238 women with depression who took a combined oral hormonal contraception (OCP) report less severe depression. Yet, many women reported increased mood and anxiety symptoms while taking synthetic progestins; this needs to be carefully considered in women with comorbid Axis I disorders. OCPs in general do not improve PMS symptoms, although there may be benefit to the FDA-approved use of the OCP that contains drosperinone 3 mg and ethinyl estradiol 20 µg (DRSP/EE) or extended-cycle dosing (fewer hormone-free intervals). In an open-label trial, Joffe and associates31 found that an OCP that contains DRSP/EE given to women with prospectively diagnosed PME of depression was effective. Again, the possible effects of OCPs on women with an underlying mood disorder need to be considered.
Among the most effective hormonal treatments for PMS suppression is the gonadotropin-releasing hormone (GnRH) agonist leuprolide, which is administered by monthly injection in depot form, and intranasal buserelin. GnRH agonists decrease pituitary release of follicle-stimulating hormone and luteinizing hormone, thereby suppressing ovulation. One key note about the treatment of comorbid depression and PMDD is that the GnRH agonists are less effective when there is an underlying depressive disorder.32 In addition, GnRH agonists can be difficult for patients because of the resulting hypoestrogenism. Adverse effects of GnRH treatment include hot flashes, headaches, and osteoporosis.
Grigorova and colleagues33 reported a significant increase in Beck Depression Inventory scores in 26 previously asymptomatic women after 4 weeks of treatment with leuprolide. The mood-related adverse effects of a GnRH agonist should be monitored closely in all women; this is especially important in women who are predisposed to mood disorders.
Calcium carbonate reduces premenstrual depression, fatigue, edema, and pain significantly more than placebo in women with PMS.34 Although there are no data in women with Axis I comorbidity and PMDD, calcium is a reasonable first-line choice for women with mild PMS symptoms or as an adjunct for women with moderate to severe PMS. Calcium should be used carefully in patients with constipation or renal stones.
Table 2 describes the steps to diagnose PMDD or PME in the context of another psychiatric disorder.
In patients with PMDD there is a 30% to 70% and a 14% to 16% lifetime risk of major depression and anxiety, respectively. Patients with PMDD need to be screened for depression and anxiety and vice versa. There are few data to guide treatment in these patients, but the use of SSRIs should be considered first-line with various dosing strategies to increase effectiveness.
References1. Yonkers KA, O’Brien PM, Eriksson E. Premenstrual syndrome. Lancet. 2008;371:1200-1210.