Neuroimaging premenstrual dysphoric disorder: A systematic and critical review

Endocrine organizational and activational influences on cognitive and affective circuits are likely critical to the development of premenstrual dysphoric disorder (PMDD), a sex-specific hormone-dependent mood disorder. An overview of the anatomical and functional neural characterization of this disorder is presented here by means of neuroimaging correlates, identified from eighteen publications (n = 361 subjects). While white matter integrity remains uninvestigated, greater cerebellar grey matter volume and metabolism were observed in patients with PMDD, along with altered serotonergic and GABAergic neurotransmission. Differential corticolimbic activation in response to emotional stimuli distinguishes the PMDD brain, namely enhanced amygdalar and diminished fronto-cortical function. Thus far, the emotional distress and dysregulation linked to PMDD seem to be defined by structural, chemical and functional brain signatures; however, their characterization remains sparsely studied and somewhat inconsistent. Clear and well-replicated neurobiological features of PMDD are needed to promote timely diagnoses and inform development of prevention and treatment strategies.     

Assessment of sexual drive and desire in women with premenstrual dysphoric disorder who have been treated with fluoxetine

Objective

To explore the impact of treatment with fluoxetine on sexual drive and desire (SDD) in women with premenstrual dysphoric disorder (PMDD).

Methods

Data were collected during a randomised, controlled, double-blind trial evaluating the efficacy of fluoxetine 20 or 60 mg/day versus placebo in the treatment of women with PMDD. Study subjects rated their SDD on the Premenstrual Tension Scale, Self Rating (PMTS-SR) during their follicular and luteal phases of the placebo run in cycles and the double-blind treatment cycles. Data were analyzed using chi-square test.

Results

Data were available for 184 subjects who rated their SDD during the follicular and luteal phases of two baseline (placebo) cycles and the following two treatment cycles. There was a trend for more women on fluoxetine to report improvement in luteal phase SDD compared to women on placebo (P=0.057).

Conclusions

Our data, contrary to expectations, suggest that fluoxetine treatment may restore SDD in women who experience decreased SDD as part of a cluster of symptoms associated with PMDD. Future trials with SSRIs should include specific measures of sexual functioning to further examine the potential beneficial versus side effects of these medications as they relate to phases of the menstrual cycle.     

Reduced parasympathetic activity during sleep in the symptomatic phase of severe premenstrual syndrome

OBJECTIVE: Severe premenstrual syndrome (PMS) is a common distressing disorder in women that manifests during the premenstrual (late-luteal) phase of the ovulatory menstrual cycle. There is some evidence that altered autonomic function may be an important component of PMS, but few studies have used heart rate variability (HRV) as a sensitive marker of autonomic activity in severe PMS, and findings are conflicting. METHODS: We investigated HRV during sleep, a state that is relatively free of external disruptions, in 9 women with severe PMS and 12 controls. RESULTS: The normal-to-normal (NN) RR interval was shorter during the sleep period in women with PMS than in controls in both the follicular and the late-luteal phases of the menstrual cycle. The standard deviation of all NN intervals, a measure of total variability in the interbeat interval, was lower during the sleep period in the late-luteal phase than in the follicular phase in women with PMS. The square root of the mean of the sum of the squares of differences between adjacent NN intervals, a measure reflecting high-frequency (HF) activity, showed a similar pattern. HF power, a marker of parasympathetic activity, was lower during non-rapid eye movement (non-REM) and REM sleep in the late-luteal phase than in the follicular phase in women with severe PMS. Controls had a shorter NN interval, but similar HRV measures, in the late-luteal phase compared with the follicular phase. CONCLUSION: These results suggest that women with severe PMS have decreased parasympathetic activity during sleep in association with their premenstrual symptoms in the late-luteal phase compared with the follicular phase when they are symptom-free.     

Predicting response to leuprolide of women with premenstrual dysphoric disorder by daily mood rating dynamics

Approximately 60-70 percent of women with premenstrual dysphoric disorder (PMDD) show symptomatic improvement in response to the GnRH agonist leuprolide acetate, which suppresses ovarian function. However, it has been very difficult to either predict or understand why some women respond, while others do not. We applied several complementary statistical methods to the dynamics of pre-treatment mood rating data to determine possible predictors of response for women with PMDD. We compared responders (n = 33) to nonresponders (n = 12) in clinical trials of leuprolide (three months in duration) as a treatment for PMDD, on the basis of pre-trial daily self-ratings of sadness, anxiety, and irritability. We analyzed both sequential irregularity (approximate entropy, ApEn) and a quantification of spikiness of these series, as well as a composite measure that equally weighted these two statistics. Both ApEn and Spikiness were significantly smaller for responders than nonresponders (P ≤ 0.005); the composite measure was smaller for responders compared with nonresponders (P ≤ 0.002) and discriminated between the subgroups with high sensitivity and specificity. In contrast, mean symptom levels were indistinct between the subgroups. Relatively regular and non-spiky pre-trial dynamics of mood ratings predict a positive response to leuprolide by women with PMDD with high probability, moreover based on typically less than 3 months of daily records. The statistical measures may have broad and direct applicability to behavioral studies for many psychiatric disorders, facilitating both accurate diagnosis and the prediction of response to treatment.     

Patients with adverse mood effects from combined oral contraceptives have lower levels of prepulse inhibition than healthy controls

BACKGROUND: Negative mood symptoms remain one of the major reasons for discontinuation of oral contraceptive pills. The aim of this study was to compare acoustic startle response and prepulse inhibition (PPI) in women with different experience of oral contraceptive pills. METHODS: Thirty women currently on combined oral contraceptives (COCs) with no reports of adverse mood symptoms, 28 women currently on COCs and experiencing mood-related side effects from treatment, 27 women who had discontinued COC use for reasons other than adverse mood symptoms and 32 women who had discontinued COC use due to adverse mood effects were included. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of musculus Orbicularis Oculi. Twenty pulse-alone trials (115dB 40ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115dB 40ms noise burst preceded at a 100ms interval by 20ms prepulses that were 72, 74, 78, or 86dB. RESULTS: Patients with adverse mood effects of COCs exhibited lower levels of PPI with 86dB prepulse compared to COC users with no adverse effects of COCs (p<0.05). There was no difference in PPI between the two groups of prior COC users. No significant difference was found between the groups regarding acoustic startle response. CONCLUSION: Relative to COC users with no reports of adverse mood symptoms, subjects suffering from COC-induced negative mood displayed deficits in PPI of acoustic startle. The fact that there was no difference in PPI between the two groups of prior COC users indicates that deficient PPI is related to adverse mood effects caused by COCs.     

Altered sensitivity to alcohol in the late luteal phase among patients with premenstrual dysphoric disorder

BACKGROUND: Affective disorders, and possibly also premenstrual dysphoric disorder (PMDD) are risk factors for alcohol abuse in women. Although the majority of prior studies have indicated that alcohol sensitivity does not differ between menstrual cycle phases, patients with PMDD have thus far not been studied. METHODS: We have evaluated the functional sensitivity to a low dose of alcohol in 12 women with and 12 women without PMDD in the mid-follicular and late luteal phases of the menstrual cycle, by comparing the effects of an intravenous alcohol infusion on a number of saccadic eye movement measures, including saccadic eye velocity (SEV), saccade deceleration, and self-rated levels of intoxication. RESULTS: PMDD patients displayed blunted SEV (p<0.01) and saccade deceleration responses (p<0.01) to alcohol infusion in the late luteal phase compared to the mid-follicular phase. Control subjects, on the other hand, did not change their SEV or saccade deceleration responses to alcohol between cycle phases. CONCLUSION: These findings are compatible with altered saccadic eye movement sensitivity in response to alcohol among PMDD patients, particularly in the late luteal phase of the menstrual cycle.     

No correlation of depression and anxiety to plasma estrogen and progesterone levels in patients with premenstrual dysphoric disorder

A number of studies have demonstrated the correlation of depression and anxiety to estrogen and progesterone in premenstrual dysphoric disorder (PMDD), but the findings are still controversial. The purpose of this study was to determine the correlation of depression and anxiety to estrogen and progesterone concentrations in blood plasma in Taiwanese women with PMDD. A total of 43 women who met the 4th edition of the Diagnostic and Statistical Manual diagnostic criteria for PMDD were enrolled in this study. Blood samples were obtained for determination of estrogen and progesterone levels, and depression and anxiety ratings were summed for each subject during one menstrual cycle to obtain a premenstrual result (2-6 days before menses) and a postmenstrual result (menstrual cycle days 7-11). Anxiety was assessed using the 14-item Hamilton Anxiety Scale-A and was also assessed by the patients themselves using the Trait Anxiety Inventory. Depression was rated using the 21-item Hamilton Anxiety Scale-D. Calculations were made to determine the relationships between hormonal changes and mood changes. There were no statistically significant correlations between depression or anxiety ratings and estrogen or progesterone concentrations.     

Brain-derived neurotrophic factor plasma variation during the different phases of the menstrual cycle in women with premenstrual syndrome

Premenstrual syndrome (PMS) is characterized by a cluster of psychological and somatic symptoms that begin during the late luteal phase of the menstrual cycle and disappear after the onset of menses. Since PMS might be caused by an alteration in the cyclical hormonal modifications and ovarian steroids are directly involved in the regulation of mood, affective and cognitive functions and influence neurotrophins expression, in particular the brain-derived neurotrophic factor (BDNF), we aimed to evaluate whether plasma BDNF levels in women with PMS differ from those of normally menstruating women without PMS. Sixty-two women were divided into two groups: one group of women (n=35) with PMS and one group (n=27) composed by normally menstruating women. Plasma samples were collected at day 7 (follicular phase) and day 21 (luteal phase) of the menstrual cycle. Plasma BDNF of the control group significantly increased (p<0.001) from the follicular phase (402.90±74.41pg/ml) to the luteal phase (1098.79±146.49pg/ml). On the other hand, in the PMS group plasma BDNF levels significantly decreased (p<0.001) from the follicular phase (412.45±78.35pg/ml) to the luteal phase (233.03±75.46pg/ml) Luteal BDNF levels of the PMS women were significantly lower than those of the control group (p<0.001). In women with PMS, plasma BDNF followed a decreasing trend during the ovarian cycle, in opposition to the increasing trend observed in women without PMS. The lower luteal BDNF levels of the PMS women might be a consequence of an altered hormonal response and might play a role in the onset of the symptoms PMS related.     

Risk for premenstrual dysphoric disorder is associated with genetic variation in ESR1, the estrogen receptor alpha gene.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is a heritable mood disorder that is triggered by gonadal steroids during the luteal phase in susceptible women. METHODS: We performed haplotype analyses of estrogen receptors alpha and beta (ESR1 and ESR2) in 91 women with prospectively confirmed PMDD and 56 control subjects to investigate possible sources of the genetic susceptibility to affective dysregulation induced by normal levels of gonadal steroids. We also examined associations with the valine (Val)158methionine (Met) single nucleotide polymorphism (SNP) of the gene for catechol-O-methyltransferase (COMT), an enzyme involved in estrogen metabolism and prefrontal cortical activation. RESULTS: Four SNPs in intron 4 of ESR1 showed significantly different genotype and allele distributions between patients and control subjects. Significant case-control differences were seen in sliding-window analyses of two-, three-, and four-marker haplotypes but only in those haplotypes containing SNPs in intron 4 that were positive in the single-locus analysis. No significant associations were observed with ESR2 or with the COMT Val158Met polymorphism, although the significant associations with ESR1 were observed only in those with the Val/Val genotype. CONCLUSIONS: These are the first positive (albeit preliminary) genetic findings in this reproductive endocrine-related mood disorder and involve the receptor for a hormone that is pathogenically relevant.     

Cortisol circadian rhythms during the menstrual cycle and with sleep deprivation in premenstrual dysphoric disorder and normal control subjects.

BACKGROUND: In this study we extended previous work by examining whether disturbances in the circadian rhythms of cortisol during the menstrual cycle distinguish patients with premenstrual dysphoric disorder (PMDD) from normal control (NC) subjects. In addition, we tested the differential response to the effects of early and late partial sleep deprivation on cortisol rhythms. METHODS: In 15 PMDD and 15 NC subjects we measured cortisol levels every 30 min from 6:00 PM to 9:00 AM during midfollicular (MF) and late luteal (LL) menstrual cycle phases and also during a randomized crossover trial of early (sleep 3:00 AM-7:00 AM) versus late (sleep 9:00 PM-1:00 AM) partial sleep deprivation administered in two subsequent and separate luteal phases. RESULTS: In follicular versus luteal menstrual cycle phases we observed altered timing but not quantitative measures of cortisol secretion in PMDD subjects, compared with NC subjects: in the LL versus MF phase the cortisol acrophase was a mean of 1 hour earlier in NC subjects, but not in PMDD subjects. The effect of sleep deprivation on cortisol timing measures also differed for PMDD versus NC subjects: during late partial sleep deprivation (when subjects' sleep was earlier), the cortisol acrophase was almost 2 hours earlier in PMDD subjects. CONCLUSIONS: Timing rather than quantitative measures of cortisol secretion differentiated PMDD subjects from NC subjects both during the menstrual cycle and in response to early versus late sleep deprivation interventions.