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Anita H. Clayton, MD
 Primary Psychiatry. 2003;10(10):27-30

Dr. Clayton is professor of psychiatric medicine at the University of Virginia in Charlottesville.

Disclosure: Dr. Clayton receives grants from Bayer, Boehringer-Ingelheim, Eli Lilly, Forest, GlaxoSmithKline, Organon, Pfizer, Pharmacia, Pherin, and Merck; is a consultant for Bayer, Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Pharmacia, and Vela; and is on the Speaker’s Bureau of Bristol-Myers Squibb, GlaxoSmithKline, Organon, and Pfizer.


United States population surveys1 suggest a lifetime prevalence rate for anxiety disorders of 25%, with nearly one third of women experiencing an anxiety disorder during their lifetime. Women are 2–3 times more likely than men to meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition2 criteria for most anxiety disorders, the exceptions being obsessive-compulsive disorder, social anxiety disorder, and specific phobia (Table).1 Unfortunately, recognition rates are low, leading to undertreatment.


Because anxiety disorders are often associated with prominent somatic complaints that can represent a serious medical condition, consideration of an anxiety disorder diagnosis often does not occur until all other diagnoses have been excluded. In addition, when a comorbid medical illness is in fact present, the anxiety disorder is much less likely to be recognized. Anxiety disorders also frequently occur comorbid with other psychiatric diagnoses including affective disorders (present in approximately 60% of anxiety disorder patients), other anxiety disorders, substance abuse disorders, somatization disorders, and eating disorders. The anxiety disorder is usually the primary diagnosis, and it markedly increases the risk for secondary depression.3 The presence of more than one disorder can complicate diagnosis, and subsequently, treatment. To add to the diagnostic difficulty in women, anxiety symptoms may be increased in the late luteal phase,4 during the menopausal transition, and during pregnancy and the postpartum period, much like mood disorders.

Anxiety disorders may be classified in the following three ways:

Generalized—those that affect multiple situations, such as generalized anxiety disorder and social anxiety disorder.
Specific—those that are specific in time (eg, discrete attacks), are a response to a specific stimulus (eg, phobias), or are a response to a specific distressing situation (eg, posttraumatic stress disorder).
With behaviors—those that occur comorbid with behaviors such as compulsions (obsessive-compulsive disorder) and avoidance (agoraphobia).

Clinical Course

Physical symptoms of anxiety may include motor tension, autonomic hyperactivity, and hyperarousal (vigilance and scanning). Most anxiety disorders have a chronic, persistent course, although some women experience episodic exacerbations of anxiety symptoms, often associated with reproductive life events. The presence of an anxiety disorder often leads to extreme sensitivity to and magnification of somatic symptoms. This may be interpreted by the patient as an indication of the presence of a serious medical condition. Thus, they may frequently present to their physicians with symptoms that cannot be medically explained, and they may be extremely sensitive to adverse events associated with any recommended procedure or treatment. As a result, morbidity and functional impairment may be high.5


Genetic factors appear to be more important than environmental factors in the etiology of most anxiety disorders. The exceptions are specific phobia6 and posttraumatic stress disorder (PTSD)7; a history of childhood abuse7 or sexual assault8 puts women at increased risk for the development of PTSD. Serotonin, norepinephrine, γ-aminobutyric acid (GABA), and dopamine systems play a role in the symptoms associated with anxiety disorders, although the specific effect(s) may vary by anxiety diagnosis.

Changes in sex hormones associated with reproductive life events may also contribute to onset or exacerbation of anxiety symptoms. Allopregnanolone, a progesterone metabolite, enhances GABA tone and causes subsequent antianxiety effects.9 However, progesterone increases monamine oxidase (MAO) activity, which may cause dysregulation of neurotransmitters leading to anxiety and/or affective disturbance. Thus, in some women (especially those with panic disorder), when progesterone levels drop, anxiety may increase. Levels may drop during the late luteal phase of the menstrual cycle, postpartum,10 during the menopausal transition, or with abrupt cessation of ovarian function; the latter may occur with the use of ovarian suppressants11 or after surgical menopause.

Interestingly, anxiety symptoms during pregnancy follow the one-quarter rule: 25% of women will experience improvement, 50% will not have a significant change, and 25% will demonstrate wors
ening of anxiety symptoms.10 Anxiety and/or depressive symptoms often herald the onset of other perimenopausal symptoms, such as hot flashes, subsequent sleep disturbance, and fatigue. Hypothalamic-pituitary-ovarian hormones are usually within the normal range at this time; however, diagnosis and treatment of the anxiety disorder may reduce other symptoms of the menopausal transition, such as hot flashes.12



Most anxiety disorders can be effectively treated with selective serotonin reuptake inhibitors, MAO inhibitors, tricyclic antidepressants, and benzodiazepines. Acute use of benzodiazepines may improve tolerability and resulting compliance with an antidepressant. Benzodiazepines can usually be discontinued after acute relief of anxiety symptoms has been obtained. Discontinuation within 6 weeks of initiation may reduce the likelihood of benzodiazepine abuse or dependence.

Low-dose atypical antipsychotics have been used in addition to antidepressants in patients with treatment-resistant anxiety disorders. Buspirone may also be useful in the treatment of generalized anxiety disorder, and as an adjunctive agent in the treatment of obsessive-compulsive disorder and social anxiety disorder.13

Individuals with anxiety disorders are more sensitive to the side effects of all medications and may misinterpret side effects as a worsening of the disorder; thus, it is crucial that patients understand the process of treatment. Difficulties experienced early in treatment or with dose increases are due to acute adverse events that subside over time, while the therapeutic benefit of the medication treatment may not be realized until higher doses are tolerated for 4–6 weeks. As such, medication therapy in patients with anxiety symptoms must be initiated at the lowest possible dose; dosage increases should occur only after the acute adverse events have subsided, which may take up to 2 weeks in anxious patients. Thus, it may take many weeks to months to achieve an appropriate therapeutic dose, which is usually higher than doses required to treat depression.


Psychotherapy may be used instead of medications as well as with medications. Cognitive-behavioral therapy may be particularly effective for anxiety disorders, and should be initiated after the initial therapeutic response is seen with medications if combined therapy is used. Consideration of the pattern of anxiety symptoms, whether they are chronic versus episodic, should inform the length of treatment. Some patients may require lifelong treatment, especially if they have comorbid depressive disorders. PP


1. Kessler R, McGonagle K, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51:8-19.

2. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.


3. Wittchen HU, Kessler RC, Pfister H, Lieb M. Why do people with anxiety disorders become depressed? A prospective-longitudinal community study. Acta Psychiatr Scand. 2000;406(suppl):14-23.


4. Stein M, Jang K, Livesley W. Heritability of anxiety sensitivity: A twin study. Am J Psychiatry. 1999;2:246-251.


5. Roy Byrne P, Katon W. Generalized anxiety disorder in primary care: the precursor/modifier pathway to increased health care utilization.
J Clin Psychiatry. 1997;3:34-38.


6. Kendler KS, Neale MC, Kessler RC, et al. The genetic epidemiology of phobias in women: the interrelationship of agoraphobia, social phobia, situational phobia, and specific phobia. Arch Gen Psychiatry. 1992;4:273-281.


7. Breslau N, Davis GC, Andreski P, et al. Sex differences in posttraumatic stress disorder. Arch Gen Psychiatry. 1997;11:1044-1048.


8. Foa EB. Trauma and women: course, predictors, and treatment. J Clin Psychiatry. 1997;9:25-28.


9. Stahl S. Reproductive hormones as adjuncts to psychotropic medication in women. Essential Psychopharmacology. 1997;2:147-164.


10. Northcott CJ, Stein MB. Panic disorder in pregnancy. J Clin Psychiatry. 1994;12:539-542.


11. Warnock J, Bundren J. Anxiety and mood disorders associated with gonadotropin-releasing hormone agonist therapy. Psychopharmacol Bull. 1997;2:311-316.


12. Van-der Feltz-Cornelis CM. Hot flashes resistant to hormone replacement in menopausal women: Panic disorder? Nederlands Tijdschrift voor Geneeskunde. 1999;6:281-284.


13. Van Ameringen M, Mancini C, Wilson C. Buspirone augmentation of selective serotonin reuptake inhibitors (SSRIs) in social phobia. J Affect Disord. 1996;2:115-121.