April 15, 2008
Psychiatric Times.
No. 5
The Complex Interrelationships of Menstrual Cyclicity and Anxiety Disorders
Premenstrual Exacerbation of Anxiety Disorders
Miki Peer, Claudio N. Soares, MD, PhD, and Meir Steiner, MD, PhD
Ms Peer reports that she has no conflicts of interest concerning the subject matter of this article. Dr Soares reports that he has received grant/research support from AstraZeneca and GlaxoSmithKline; he is a consultant for Sepracor, GlaxoSmithKline, Wyeth-Ayerst, and Neurocrine; and he is on the Promotional Speakers' Bureau of GlaxoSmithKline, Wyeth-Ayerst, Forest Laboratories, and Pfizer. Dr Steiner reports that he has received grant/ research support from Wyeth, Pfizer, and AstraZeneca; he is a consultant for Eli Lilly, Pfizer, GlaxoSmithKline, Lundbeck, Novartis, Wyeth, OrthoMcNeil, AstraZeneca, and Azevan Pharmaceuticals; he is on the advisory board of Eli Lilly, GlaxoSmithKline, Pfizer, Lundbeck, OrthoMcNeil, Wyeth, Schering, Ferring, and Azevan Pharmaceuticals; and he is on the Speakers' Bureau of AstraZeneca, GlaxoSmithKline, Eli Lilly, and Wyeth.
Protein binding
a1-Glycoprotein levels are decreased by estrogen, resulting in highest levels during menses.9,20 Most anxiolytic medications are moderately to highly protein bound. More specifically, the binding of SSRIs is mostly to a1-glycoprotein, and some antidepressants (particularly tricyclic antidepressants) have a relatively narrow therapeutic index, putting women at an increased risk for adverse effects or toxicity.2
Hepatic metabolism Sex differences in hepatic metabolism of a number of drugs have been reported.2,11,20 Peak rates at mid cycle cause lower blood levels of drugs in the luteal phase and higher drug levels in the follicular phase.8 There is no evidence that benzodiazepine metabolism is altered across the menstrual cycle.10 The estrogenic component of oral contraceptive pills is known to increase conjugation activity.9
Cytochrome P-450 enzyme system The enzyme cytochrome 3A4 (CYP 3A4) is involved in the metabolism of more than 50% of drugs in clinical use,20,55 and it is responsible for hydroxylation of steroid hormones.56 Sex differences have been reported for CYP 3A4 and CYP 2C19, with higher activity levels in women resulting in lowered plasma levels of some antidepressants and other drugs (sertraline, carbamazepine, citalopram, clomipramine, imipramine, diazepam, propranolol).2,8,20,55 Evidence points to higher clearance rates of nonspecific CYP substrates at ovulation and prolonged clearance during the luteal phase, but the clinical relevance of these observations is unknown.9
Elimination
Women have lower renal clearance rates and concomitant increases in plasma levels of some but not all anxiolytic medications,6 possibly due to lower glomerular filtration rates, although limited evidence suggests no change in glomerular filtration rates across the menstrual cycle.2,9 There is no information to date on P-glycoprotein changes across the menstrual cycle, but the influence of sex ste- roids on P-glycoprotein is suggested by studies with pregnant animals.20 An increase in vasopressin and aldo- sterone plasma levels, and in renin activity during the luteal phase has been demonstrated but the clinical influence of these findings remains unknown.9
Limited evidence suggests that clinical effects of buspirone are not affected by sex.57 Sex differences in pharmacological parameters of a number of b-blocking agents (eg, metoprolol, propranolol) have been demonstrated in healthy subjects, suggesting that women may require lower than standard doses of these medications to avoid adverse effects.58 Similar studies in women with anxiety disorders are still needed and the effects of menstrual cycle-related hormonal fluctuations on b-blockers remain to be explored.
Oral contraceptives
Oral contraceptives are hepatically metabolized and can interfere with metabolism of a number of drugs, increasing clearance of those metabolized by conjugation and glucuronidation and decreasing clearance of drugs metabolized by oxidation.4,6 Antidepressants significantly metabolized by the liver are likely to be affected by oral contraceptive use (eg, imipramine). Oral contraceptives also affect disposition and dose requirements of antidepressants.
Women who take oral contraceptives may have higher blood concentrations and longer half-lives of drugs and therefore experience potentially more adverse effects and drug toxicity than men.6 Furthermore, drugs that increase hepatic enzyme induction may increase metabolism of contraceptives and cause failure of their contraceptive action.4 One study found that users of oral contraceptives who took a standard dose of diazepam were relatively "intoxicated" during menses because of pharmacodynamic changes of this benzodiazepine across the menstrual cycle,4,11 possibly due to progesterone's effects on the GBRC amplifying the pharmacological effects of diazepam.2 Despite these findings, the concomitant use of oral contraceptives and antidepressants appears to be relatively safe.
Overall, there is potential for women to have higher plasma levels of psychoactive drugs than men (especially if taken with oral contraceptives); therefore, women require lower doses and/or semi-intermittent dosing to minimize unwanted adverse effects.2,6,11,29 Generalizations about pharmacological parameters across the menstrual cycle are not possible. The pharmacodynamics and pharmacokinetics of different psychoactive agents need to be studied across the menstrual cycle; generalization of data derived from one drug can be misleading and should be interpreted cautiously, even for drugs within the same class.11
Recommendations for Clinical Practice
A better clinical practice to manage anxiety disorders would include:
• A careful assessment of sex-specific triggers of anxiety.
• A clinical interview performed on 2 consecutive occasions (1 in the luteal phase and 1 in the follicular phase of the menstrual cycle).
• The use of a diary for at least 1 menstrual cycle to prospectively chart anxiety symptoms and help identify temporal associations with hormonal changes or possible comorbid disorders.
Once treatment is initiated, women with anxiety disorders should be evaluated during the course of the menstrual cycle for continuous effectiveness of their medications. Women who exhibit premenstrual exacerbation of anxiety disorders may respond to increased doses immediately preceding or during the luteal phase.48,59 Progesterone augmentation may be a therapeutic option for women with anxiety disorders who do not respond, or who respond only partially, to standard therapeutic regimens.2,38
• Kaspi SP, Otto MW, Pollack MH, et al. Premenstrual exacerbation of symptoms in women with panic disorder. J Anx Disord. 1994;8:131-138.
• Vulink NCC, Denys D, Bus L, Westenberg HG. Female hormones affect symptom severity in obsessive-compulsive disorder. Int Clin Psychopharmacol. 2006;21: 171-175.
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