The Complex Interrelationships of Menstrual Cyclicity and Anxiety Disorders

Retrospective studies have found an increase in anxiety and panic symptoms during the premenstrual phase in a substantial portion of women with PD, while the majority of prospective studies have not been able to document these changes.^1,3,23,41,42 Kaspi and colleagues,⁴³ however, found that retrospective reports of premenstrual exacerbations of PD were confirmed in a subsample studied prospectively. They found a worsening of panic symptoms and an increase in panic frequency in half their sample during the premenstruum.⁴³

Gonadal steroid hormones may influence PD through effects on respiration sensitivity. Panic attacks provoked by the inhalation of 35% car- bon dioxide were more frequent and the anxiety significantly more severe in the early follicular phase than in the mid luteal phase in patients with PD, but no difference was seen in controls.⁴⁴ This suggests that in some women with PD, the reactivity to carbon dioxide and/or the suffocation alarm threshold may be impaired.^23,44

Social anxiety disorder (social phobia)
The impact of female reproductive hormones on the course and severity of social anxiety disorder (SAD) has yet to be investigated.^1,4 To our knowledge, there are no studies to date on possible premenstrual exacerbation of SAD.

Noradrenergic and dopamine(Drug information on dopamine)rgic abnormalities have been consistently observed in social phobia, including dysfunction of a₂-adrenoreceptors²⁴ and decreased dopamine binding and dopamine reuptake sites in the striatum.¹⁷ No abnormalities in HPA axis function have been identified in SAD.¹⁷ Serotonergic dysfunction (particularly in females with social phobia) was reported in one study.⁴⁵ Serotonergic medications are first-line treatment for patients with social phobia,^24,46 and benzodiazepines are also effective.^28,46 Allopregnanolone and dehydroepiandrosterone (DHEA) levels were reportedly normal in patients with SAD, while pregnanolone sulfate levels were significantly lower in male patients with generalized social phobia.^23,47 Information on other steroids in SAD is lacking.

Obsessive-compulsive disorder
Clinical studies suggest that there are serotonergic mechanisms in obsessive-compulsive disorder (OCD), especially in women.^1,48,49 However, increased dopamine neurotransmission has also been implicated.¹⁹ Recent retrospective studies have found that almost half of a sample of women with OCD reported experiencing premenstrual worsening of OCD symptoms.^48,50 Findings from another study, with a greater percentage of women of reproductive age, showed that 20% of those with OCD reported premenstrual exacerbation.⁴⁹ Labad and colleagues⁴⁹ also found that patients with an onset or worsening of OCD postpartum more frequently reported premenstrual exacerbation of this condition, as well as premenstrual mood symptoms and a history of depressive disorders.The authors therefore suggest that there may be a continuum of vulnerability in some female patients with OCD to anxiety and mood symptoms during periods of abrupt hormonal variability, such as the premenstruum and postpartum periods.⁴⁹ Similarly, Vulink and colleagues⁵⁰ found that OCD was comorbid with PMDD but that this association only partially explained premenstrual exacerbation of OCD in their study.

Overall, evidence points to menstrual cycle-related sex steroid influences on the course of OCD in some women, possibly via serotonergic mechanisms,^1,7,48 and serotonergic antagonism on dopamine neurotransmission (causing increased dopamine activity and consequent exacerbation of OCD).^19,50 Treatment studies examining efficacy of semi-intermittent dosing (ie, dosage increases during the late luteal phase) in women with documented premenstrual exacer- bation of OCD symptoms would be particularly beneficial in informing treatment practices.⁴⁸ Furthermore, identification of premenstrual exacerbation of OCD may serve as a predictor of postpartum OCD exacerbation, but prospective verification of this association would be useful.

Posttraumatic stress disorder
Decreased hippocampal volume, and decreased hippocampal blood flow in tandem with increased blood flow to cortical areas in patients with posttraumatic stress disorder (PTSD) have been attributed to stress effects.¹⁸ A hyperreactive HPA axis, with exaggerated cortisol responses to stressors, is characteristic of PTSD.^18,51,52 Rasmusson and colleagues⁵² found that DHEA levels at baseline and in response to ACTH were increased in women with PTSD. Further findings showed normal baseline progesterone(Drug information on progesterone) levels and normal progesterone levels in response to stress in women with PTSD.⁵² Another study reported low cerebrospinal fluid allopregnanolone levels in women of reproductive age with PTSD.⁵³

Serotonergic antidepressants are the treatment of choice because they show efficacy in both PTSD and comorbid disorders.⁵⁴ Benzodiazepines should be used with caution in PTSD but may be effective as adjunctive therapy to SSRIs.²⁸

Effects of Female Sex Steroids
Information on physiological changes across the menstrual cycle in the absence of drug therapy is lacking,⁹ so it is not surprising that research on changes in drug action across the menstrual cycle is scarce as well.^10,29 Sex differences in the pharmacodynamics and pharmacokinetics of a number of drugs have been described^9,20,29 and are probably caused (at least in part) by differences in hormone concentrations, body size and fat composition, liver metabolism, gastric absorption and emptying, and cerebral blood flow.^{1,2,6,9,10,55} Interactions between psychoactive drugs and cyclical fluctuations in anxiety disorders might be expected because of the similar neural pathways activated,^12,22 and may be particularly critical for psychoactive drugs with a narrow therapeutic index.^2,8

Absorption
Decreased secretion of gastric acid and progesterone in the luteal phase results in slower gastric emptying and could consequently lower drug levels in the blood; study results, however, have shown conflicting results.^6,8-11 Dilution of drugs via fluid retention in the luteal phase could result in lowered drug levels but the amount of fluid retained would have to be fairly large.^8,11 Gonadal hormones may affect bioavailability through changes in absorption rates, necessitating luteal-phase increases of some medications in certain women.^10,11

Distribution
Cyclical, menstrual-related changes in body weight and water metabolism may theoretically alter distribution properties of drugs in some women, although this has not been shown to be clinically relevant.^2,9 Many psychotropic medications (eg, benzodiazepines) are lipophilic and therefore gravitate to adipose tissue, where accumulation may prolong half-life; however, there is no information on whether these parameters vary significantly with menstrual-cycle phase.^2,10,11