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      Generalized Anxiety Disorder: What is it? What pharmaceutical methods are used to treat it, and to which is the most efficacy attributed?

 Katherine Delisio

date: 10/14/2006

 

     Generalized Anxiety Disorder (GAD) is a common, chronic, and recurrent psychiatric condition that affects nearly 5.1% (lifetime prevalence rate) of the population today.  Although there are a variety of physical and psychological symptoms associated with the disorder, research agrees that GAD is primarily characterized by at least 6 months of frequent worry and at least 3 of the following 6 symptoms on any given day: fatigue, restlessness, poor concentration, irritability, muscle tension, and unsatisfying sleep (Southern Medical Journal, 2003).  Generalized Anxiety Disorder is twice as common in women as in men and is known to be concomitant with other psychological disorders, including (but not limited to) major depressive disorder, dysthymia, alcoholism, phobias, and panic disorder (Southern Medical Journal, 2003). If GAD goes untreated, it is unlikely that the patient will recover from the disorder, and the recurrence rate of untreated cases is quite high (New England Journal of Medicine, 2004).

      The purpose of this site is to present collected research about the condition itself (including its diagnostic criteria, symptoms and characteristics, and epidemiology) and to describe and assess the pharmacological treatments commonly ascribed to after GAD has been diagnosed.

 

I.  What is Generalized Anxiety Disorder?

     The criteria for diagnosis of generalized anxiety disorder, according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association, 2000), is shown in the table below.

     This encompasses the defining psychological and physical symptoms of generalized anxiety disorder.  However, in addition to these traits, other important behaviors and characteristics exhibited by GAD individuals have been noted.  These include difficulty solving problems, completing a task, processing new info, and confusion, as well as the physical symptoms of increased heart rate, chest pain, palpitations, dyspnea, diaphoresis, dizziness, frequent urination, and nausea (Southern Medical Journal, 2003).                         

     

     An important distinction between GAD and mild (what is considered “normal”) anxiety is that GAD consistently interferes with an individual’s day-to-day living.  The affected individual becomes so overcome by anxiousness that they are consumed by thoughts of their own anxiety and are less able to interpret their daily interactions in a normal manner (European Psychiatry, 2004).  According to the Southern Medical Journal (2003), "Communication and daily living activities (of GAD individuals) are dysfunctional and self-absorbed.  Feelings of anger, fear, or helplessness may emerge explosively and are directed toward self or others in a fight-or flight reaction."  This preoccupation with anxiety also restricts the individual’s ability to perceive external stimuli.  As anxiety heightens, the individual's senses of sight, hearing, touch, etc. become progressively narrower and weaker, in essence causing their perception of daily stimuli and events to become distorted.  At this point, according to the Fundamentals of Nursing: Caring and Clinical Judgement  (2000), when anxiety becomes moderate or severe and interferes with a person's ability to function in everyday life, it is considered a disorder and should be treated.   

     One of the fundamental characteristics of GAD is its comorbidity with other psychological disorders (European Psychiatry, 2004).  In other words, GAD has been proven to have a high coexistence rate with other psychological disorders. A study done by Carter, Wittchen, Phister, and Kessler (2001) revealed that half the patients with anxiety symptoms met full criteria for another psychiatric disorder.  GAD has the highest comorbidity with major depressive disorder (62.4%), followed by dysthymia (39.5%), alcoholism (37.6%), simple phobia (35.1%), drug abuse (27.6%), and panic disorder (23.5%) (Southern Medical Journal, 2003).  It has also been shown that there is an increased prevalence of GAD among patients with hyperthyroidism. Although it is never certain whether GAD is the primary disorder or not, prospective studies have shown that anxiety almost always appears to be the primary disorder (New England Journal of Medicine, 2004).

     Since these linked disorders can interfere with the proper diagnosis of GAD, it is crucial that each patient with a pending case of GAD be given a comprehensive diagnostic assessment to determine whether symptoms are arising from GAD or from another associated disorder.

     GAD is a chronic disorder, with average duration of 20 yrs (British Journal of Psychiatry, 1996).  There is significant disagreement about the life stage at which the onset of the disease occurs.  The New England Journal of Medicine (2004) dictates that the onset of GAD typically occurs before age 25, while other sources argue that the disease is usually most commonly diagnosed at age 35 for women and age 45 for men (British Journal of Psychiatry, 1996).  Common risk factors for generalized anxiety include a family history of the disease, increase in stress, and a history of emotional or physical trauma. (British Journal of Psychiatry, 1996).

      

 

II. What medical treatments exist for Generalized Anxiety Disorder?

    Once diagnosed, GAD is most commonly treated by pharmacological methods. The different classes of medications used for the treatment of anxiety are listed in a chart below, along with the recommended doses and possible side effects of each (American Psychiatric Association, 2000).  The substances on which the most pharmacological research has been done are the ones which will be discussed in this website; these include benzodiazepines (BZDs), tricyclic antidepressants (TCAs), selective serotonin-reuptake inhibitors (SSRIs), and serotonin norepinephrine-reuptake inhibitors (SNRIs) (specifically venlafaxine).   

        Benzodiazepines are known for their fast-acting effects, which may be the primary reason that their use has been so widespread in the past (New England Journal of Medicine, 2004).  In fact, the results of a randomized trial in which the relative efficacies of benzodiazepine, paroxetine, and imipramine were compared revealed that benzodiazepine produced the most successful results among GAD patients within the first two weeks (Acta. Psychiatry Scand., 1997).  This can be especially helpful in alleviating some of the intense anxiety experienced by newly diagnosed patients who are undergoing treatment for an anxiety disorder.      

         However, the negative consequences of taking BZDs are numerous.  BZDs have little to no sustained effect and thus are ineffective for long-term therapy (Southern Medical Journal, 2003).  In fact, in the same randomized trial study that compared benzodiazepines with paroxetine and imipramine (Acta Psychiatry Scand, 1997), it was found that after 8 weeks, benzodiazepine was less effective than either of the other two medications.  The side effects of BZDs are generally considered to be worse than those experienced by patients on other types of anxiety medications.  These side effects include physical dependence, depression of respiratory functions, withdrawal symptoms, sedation, ataxia, and memory impairment (Southern Medical Journal, 2003).  Also, it is unclear whether BZDs “fail to prevent depression in GAD patients or if they contribute to the development of depression when used on a long-term basis” (Southern Medical Journal, 2003).

      Antidepressants (TCAs, SSRIs, and SNRIs in the form of venlafaxine) are becoming an increasingly popular treatment for GAD, perhaps due in part to the comorbidity of GAD with major depressive disorder.  Tricyclic antidepressants are an effective treatment for the condition, both for patients with major depressive disorder and for those without it (New England Journal of Medicine, 2004).  A comparative study of imipramine, trazodone, and diazepam vs. placebo performed by Rickels et. al. (Archives of General Psychiatry, 1993) proved imipramine to be the most effective tricyclic antidepressant treatment for GAD.  These researchers found that all three antidepressant medications produced better results than the placebo, but that the success rate of imiprazine (73%) was significantly higher than that of trazodone (69%) or diazepam (66%) (Archives of General Psychiatry, 1993).  A potential downside to using TCAs is that they are associated with adverse side effects, most notably heart arrhythmia, orthostasis, and weight gain, which may influence the patient to quit the medication regimen and thus hinder the treatment process (Southern Medical Journal, 2003).

     Selective serotonin-reuptake inhibitors (SSRIs) have efficacy similar to tricyclic medications, but have more favorable side effects (New England Journal of Medicine, 2004). Reportedly, “in an eight-week, randomized, placebo-controlled trial involving 326 outpatients, those who received paroxetine had a significantly higher response rate (defined as much or very much improved, with a reduction in anxiety and better functioning) than those who received placebo (72 percent vs. 56 percent)” (New England Journal of Medicine, 2004).  The patients in this study who received paroxetine also had a significantly higher rate of remission (42 percent vs. 26 percent for individuals taking placebos) and a much lower rate of relapse (11 percent as compared to the 41 percent relapse for individuals given the placebo) (New England Journal of Medicine, 2004).  Although paroxetine and other SSRIs can potentially worsen anxiety symptoms for 1-2 weeks, individuals are encouraged to withstand these effects in order to benefit from the long-term efficacy of these medications (Southern Medical Journal, 2003).

     The serotonin norepinephrine-reuptake inhibitor (SNRI) venlafaxine has recently been lauded for its successful treatment of GAD (Southern Medical Journal, 2003).  This is probably a direct consequence of its pharmacological complexity; its dual control of both serotonin and norepinephrine results in higher response rates among GAD-diagnosed individuals (European Psychiatry, 2004).  In a collective analysis of five different double-blind controlled studies of venlafaxine vs. placebo, it was found that 66% of all older adults responded successfully to venlafaxine, while only 41% of adults responded to the placebo (Katz et. al, Journal of American Geriatric Society, 2002).                                                                      

    

     Venlafaxine is not only effective as a short-term treatment—it has long-term efficacy superior to its competitors. Venlafaxine, sometimes called Effector, has a long-lasting form called venlafaxine XR (or Effector XR) in the form of an extended release capsule. This medication has been shown to dramatically lower relapse rates and increase remittance rates among GAD individuals (Southern Medical Journal, 2003). In a study comparing the effects of venlafaxine XR or buspirone with a placebo, groups of non-depressed GAD individuals treated with venlafaxine XR were significantly superior to their counterparts in the other two groups after two weeks, and remained as such for the duration of the 6-month study. (JAMA, 2000).  These results were later confirmed by a similar study performed by Allugander et. al.(European Psychiatry, 2004).  These studies also confirmed the high tolerability of venlafaxine (both short-term and long-term), as well as the “improved psychosocial functioning” resulting from the medicine’s seemingly therapeutic effect (European Psychiatry, 2004). 

 

    III. What treatments have the most efficacy?

         In collectively analyzing the available research on GAD, it becomes evident that the pharmacological treatment of the disorder is moving more towards the use of antidepressants and away from the use of benzodiazepines.  This conclusion is confirmed by the International Consensus Group on Depression and Anxiety (European Psychiatry, 2004). Probable reasons for declining support for BZDs can be summarized as: lack of sustained effect (ineffectiveness in preventing relapse with long-term treatment), adverse side effects such as physical dependence and painful withdrawal symptoms, and weak/inconclusive research concerning their long-term effects on the patient. As noted in European Psychiatry (2004), “controlled studies of BZDs in GAD have been mostly conducted over short periods of time (6-8 weeks).”  This is a shorter time frame than has been studied with other medications and is insufficient for determining whether or not there exist any harmful long-term effects associated with BZD’s.  The journal also notes that studies which have been done demonstrate a high rate of relapse (European Psychiatry, 2004).

     Furthermore, the undefined relationship between the use of BZDs and the development of depressive disorders is of great concern.  It does not seem rational to take the chance of developing depression from using BZDs,  considering that the majority of patients with GAD have already been afflicted with (or will likely develop) major depressive disorder as a result of the high correlation between these two disorders.    

     It has been noted in the Southern Medical Journal (2003) that a new favored treatment of generalized anxiety disorder involves the combined use of BZDs with antidepressants.  The planned regimen, in a general sense, is to begin treatment with a combination of both drugs and to taper the use of BZDs as time increases.  (The purpose of using BZDs temporarily in the treatment would be to lessen the undesirable effects of heightened anxiety that usually occur at the onset of a GAD patient’s treatment.)  Although research has clearly confirmed that BZDs do reduce anxiety in a fast-acting manner, not enough has been studied on the effects of medicine combination regimens to ensure the safety of co-treatment by these medicines. A possible substitute for the use of BZDs as an initial part of a patient’s treatment might be psychotherapy—a curative method not mentioned by this website but one which has been proven to add to the success of pharmacological treatments for GAD (New England Journal of Medicine, 2004). 

     Concerning antidepressants, all seem to be fairly effective short term and produce side effects less harmful than BZDs. Research on the most effective drugs in each class of antidepressants leads one to conclude the following: that the most effective TCA is imiprazine, the most effective SSRI is paroxetine, and the most effective SNRI is venlafaxine XR.  Venlafaxine and paroxetine are generally preferred over imiprazine, owing to the improved long-term efficacy of the former two substances.  There has been made no significant distinction between the successfulness of paroxetine vs. venlafaxine XR in the treatment of GAD. However, it appears from available research that venlafaxine XR might be slightly more favorable to some patients, due to its high tolerability and the advantage (commonly associated with many types of extended release capsules) of taking medicine only once per day (European Psychiatry, 2004).  More evidence is needed to confirm a significant difference between these two types of antidepressant treatments. 

    

 

 

 

Bibliography    

 

Pary, Ray MD, Matushka, Paul R., Lewis, Susan PhD., Caso, William MD, Lippmann, Steven MD (2003).  Generalized Anxiety Disorder.  Southern Medical Journal, 96, 581-586. 

 

Rouillon, Frederic (2004).  Long-Term Therapy of Generalized Anxiety Disorder.  European Psychiatry, 19, 96-101.

 

Fricchione, Gregory MD (2004).  Generalized Anxiety Disorder.  The New England Journal of Medicine, 351, 675-682.

 

American Psychiatric Association (2000).  Diagnostic and Statistical Manual of Mental Disorders: DSM-IV.  Ed. 4 text review, 473-476.

 

Yonkers, K.A., Warshaw, M., Massion, A.O., Keller, M.B. (1996).  Phenomenology and the Course of Generalized Anxiety Disorder.  British Journal of Psychiatry, 168, 308-311.

 

Carter, R.M., Wittchen H.U., Phister, H., Kessler R.C. (2001).  Study on the One-Year Prevalence of Sub-Threshold and Threshold DSM-IV Generalized Anxiety Disorder in a Nationally Representative Sample.  Depress Anxiety, 13, 78-88.

 

Rocca, P., Fonzo, V., Scotta, M., Zanalda, E., Ranizza, L. (1997).  Paroxetine Efficacy in the Treatment of Generalized Anxiety Disorder.  Acta. Psychiatric Scand., 95, 444-450.

 

Rickels, K., Downing, R., Schweitzer, E., Hassman, H. (1993).  A Placebo-Controlled Comparison of Imipramine, Trazodone, and Diazepam.  Arch. Of General Psychiatry, 50, 884-895. 

 

Katz, R., Reynolds, C.F., Alexopoulos, G.S., Hackett, D. (2002).  Venlafaxine as a Treatment for Generalized Anxiety Disorder in Older Adults: A Pooled Analysis of 5 Randomized Placebo-Controlled Clinical Trials.  Journal of American Geriatric Society, 50, 18-25.

 

Gelenberg, A.J., Lydiard, R.B., Rudolph R.L., Aguiar, L., Haskins, J.T., Salinas, E. (2000).  Efficacy of Venlafaxine Extended-Release Capsules in Non-Depressed Outpatients With Generalized Anxiety Disorder.  JAMA, 283, 3082-3088.

 

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