Effective Recognition and Treatment of Generalized Anxiety Disorder in Primary Care

Home , Eptapirone, Flesinoxan, Suriclone

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Pretest and Objective

Articles are selected for CME credit designation on the basis of an assessment of the needs of readers of The Primary Care Companion, with the purpose of providing readers with a curriculum of CME articles on a variety of topics throughout each volume. There are no prerequisites for participation in this CME activity. To obtain credit, please study the designated article and complete the Posttest. Accreditation Pri-Med Institute is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Designation Pri-Med Institute certifies this educational activity for a maximum of 1.0 credit toward the American Medical Association Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

Date of Original Release/Review This educational activity is eligible for CME credit through April 30, 2006. The latest review of this material was February 2004.

Activity Learning Objective After participating in this activity, you should be able to diagnose generalized anxiety disorder (GAD) and identify at least 5 treatment options for patients with GAD.

This pretest is designed to facilitate your study of the material. 1. Benzodiazepines should be avoided in the treatment of patients with generalized anxiety disorder (GAD) due to their high potential for abuse: a. True b. False

Pretest answer and Posttest on page 42.

Disclosure of Off-Label Usage To the best of his knowledge, Dr. Culpepper has determined that trazodone, escitalopram, imipramine, sertraline, fluoxetine, flesinoxan, eptapirone, and suriclone are not approved by the U.S. Food and Drug Administration for the treatment of generalized anxiety disorder. Pregabalin and duloxetine are not approved for use in the United States.

ACADEMIC HIGHLIGHTS Effective Recognition and Treatment of Generalized Anxiety Disorder in Primary Care

This ACADEMIC HIGHLIGHTS section Anxiety Disorders in the Primary Care Setting T of The Primary Care Companion to The Journal of Clinical Psychiatry Larry Culpepper, M.D., M.P.H., tilation, gastrointestinal problems, or presents the highlights of the planning began the presentation by stating that other types of discomfort. Anxiety dis- roundtable “Effective Recognition and more than 26 million people aged 15 to orders usually emerge when patients Treatment of Generalized Anxiety Disorder 54 years in the United States suffer are in their 20s and early 30s; however, (GAD) in the Primary Care Setting,” held from anxiety disorders, either alone or anxiety disorders originate much ear- December 11, 2003, in Pittsburgh, Pa. comorbid with at least 1 other psychi- lier in life, with most anxiety develop- The planning roundtable and this ACADEMIC atric disorder.1 Anxiety disorders cost ing during childhood and adolescence. HIGHLIGHTS were supported by an billions of dollars in the United States Genetic background and early upbring- unrestricted educational grant from Pfizer. each year.2 This cost reflects not only ing are 2 predictors of anxiety dis- The planning roundtable was chaired the direct cost of treatment but also orders. Twenty percent to 30% of pa- by Larry Culpepper, M.D., M.P.H., Boston indirect costs such as missed days from tients with panic or GAD have relatives University School of Medicine, Boston, work.2 Patients with generalized anxi- with the same disorder, and thus pa- Mass. The faculty member was Kathryn M. ety disorder (GAD) and depression are tients with a family background of anx- Connor, M.D., Duke University Medical frequently described as high health iety are more likely to develop an anx- Center, Durham, N.C. care utilizers, with numerous visits to iety disorder than patients without a Continuing Medical Education their primary care physician.3 family background of anxiety.6,7 Early Faculty Disclosure Data1,4 indicate that the majority of adverse experiences can lead to an In the spirit of full disclosure and in psychiatric disorders in the United expression of a preexisting genetic vul- compliance with all ACCME Essential States are treated in the primary care nerability to stress and disease. Stud- Areas and Policies, the faculty for this setting. Dr. Culpepper discussed the ies8,9 indicate that children raised in un- CME activity were asked to complete need for awareness among primary predictable environments with neglect, a full disclosure statement. care physicians about the prevalence separation, or abuse are more likely to The information received is as follows: and types of anxiety disorders, focus- develop anxiety disorders than children Dr. Culpepper is a consultant for Forest, ing on GAD, as well as management raised in stable environments. Janssen, Eli Lilly, Pfizer, and Wyeth. strategies. Dr. Connor has received grant/research The Need for Recognition support from Eli Lilly, Pfizer, Pure World Origins of Worry and Anxiety of Anxiety Disorders in Botanicals, and Forest; is on the speakers Dr. Culpepper explained that anxi- the Primary Care Setting bureaus for Ortho-McNeil, Wyeth-Ayerst, ety expresses itself neurologically Anxiety is often a chronic condition Pfizer, Cephalon, Solvay, and Forest; is through higher cortical activity. For that can impair patients’ daily func- a consultant for Ancile Pharmaceuticals, example, this activity can be activated tioning and lead to secondary comor- Ortho-McNeil, Wyeth-Ayerst, and Pfizer; by sudden noises or memories. Higher bid conditions. The severity of physi- and has received other financial or cortical activity, in turn, stimulates cal and psychosocial impairment can material support from Dr. Wilmar other portions of the brain resulting in lead to decreased work productivity, Schwabe, Nutrition 21, and Cephalon. physiologic responses and consequent missed days from work, and even un- The opinions expressed herein are those somatic sensations (Figure 1).5 employment.10,11 Fifer et al.12 reported of the authors and do not necessarily reflect The somatic sensations are what that 10% of patients screened in clinic the views of the CME provider, publisher, drive many patients into primary care waiting rooms suffered from unrecog- or the commercial supporter. offices: heart palpitations, hyperven- nized or untreated anxiety. These pa-

Figure 1. Origins of Worries and Anxiety: Fight or Flight Responsea

Hippocampus (Emotional Memory) Physiologic Responses Corticotropin-Releasing Higher Adrenal and and Somatic Sensations Factor and Norepinephrine Cortial Activity Autonomic Responses (Palpitations, Hyperventilation, Brain Systems GI Sensations) Amygdala (Fear Response)

aData from Chrousos and Gold.5 Abbreviation: GI = gastrointestinal. tients reported substantially worse ders tend to be highly comorbid, and ing disorder, and patients will often functioning on both physical and emo- patients frequently suffer from mul- have periods of moderate anxiety com- tional measures than patients who re- tiple anxiety disorders. For example, bined with periods of acute exacerba- ported that they were not anxious. in an ongoing longitudinal naturalistic tion that may last for days or weeks.19 Maki et al.11 found that primary care study15 of anxiety disorders in the pri- Physicians may see patients during patients with GAD demonstrated more mary care setting, 36% of patients with phases of acute exacerbation when severe to comparable physical and GAD had 1 other anxiety disorder, patients have exhausted their coping psychosocial impairment compared 14% had 2 others, and 4% had 3 skills. with subjects who were diagnosed with others. Forty-one percent of the sub- Patients with GAD often present severe medical conditions such as dia- jects with anxiety had comorbid major with somatic complaints, such as mo- betes, hypertension, and recent myo- depression. tor tension or hyperarousal. The hall- cardial infarction. Anxiety disorders are the most com- mark of GAD is that patients are hav- Dr. Culpepper emphasized that rec- mon disorder associated with major ing difficulty controlling pervasive ognizing an anxiety disorder can be depressive disorder. Results from the worry, i.e, their worry is out of propor- difficult for physicians. Patients with National Comorbidity Survey16 found tion to the likelihood or impact of the anxiety disorders, such as GAD, fre- that 58% of respondents who had a dreaded events. quently turn to their primary care phy- lifetime prevalence of major depres- One study20 examined the relation- sician when they have exhausted their sive disorder suffered from an anxiety ship between physical symptoms and coping skills and are suffering from disorder as well. In general, major de- psychiatric symptoms reported by concerns about potential illness, pain, pression comorbid with another disor- 1000 patients in the primary care set- or other physical maladies. Often, der is more persistent and severe than ting. Somatic symptoms were deter- patients are unaware that their physi- primary depression.16 mined to be potential markers for an cal maladies are associated with the Dr. Culpepper noted that patients anxiety disorder. Although insomnia, presence of an underlying anxiety with anxiety and comorbid depression chest pain, and abdominal pain were disorder.13 Patients usually attribute experience more impairment in quality the most common somatic symptoms anxiety-like symptoms to 1 of 3 of life than those with either disorder.17 reported, followed closely by headache causes: somatic complaints, psy- The combination of anxiety and de- and fatigue, researchers determined chological complaints, or normalizing pression not only is more difficult that the number of symptoms, rather complaints. Patients who present their to treat but also places the patient at than the type of symptom, was the symptoms as psychological com- risk for more serious complications. strongest indicator of a mood or anxi- plaints, e.g., emotional exhaustion, Patients often attempt to self-medicate; ety disorder. have been found to be more likely to alcohol dependence and substance Dr. Culpepper stated that it is im- receive a psychiatric diagnosis than abuse are commonly seen in patients portant to realize that patients with patients whose symptom attribution with anxiety disorders. Comorbid de- GAD often have a range of somatic is normalizing (e.g., my problems pression may also place patients with complaints, but they frequently see are caused by work-related stress) or anxiety disorders at a higher risk for their physician about one particular somatizing.14 suicide attempts.11 symptom that is bothering them at the time. Usually patients are most con- Anxiety Comorbid Recognizing Patients With GAD cerned with this one symptom and fre- With Other Disorders The DSM-IV18 classifies GAD as quently view other symptoms as a nor- Physicians need to be aware of the excessive worry and anxiety, occur- mal part of their overall functioning. risk of comorbid conditions in patients ring for more days than not for at least Physicians need to ask patients about with anxiety disorders. Anxiety disor- 6 months. GAD is a waxing and wan- other potential symptoms in order to

Table 1. Features of Anxiety Secondary Table 3. Types of Educational Messages Table 4. General Recommendations to Organic Causes Physician May Use to Improve Patient for Patients With Anxiety Disordersa a Onset of anxiety symptoms after age Compliance Avoid coffee or other caffeinated 35 years 1. Take the medication daily beverages Lack of personal or family history of 2. Be aware that antidepressants must be Avoid excess alcohol and nicotine an anxiety disorder taken for 2 to 4 weeks for a noticeable Exercise moderately to relieve tension Lack of childhood history of significant effect and improve sleep anxiety 3. Continue to take medication even if Monitor over-the-counter medications Absence of significant life events feeling better Adhere to prescribed treatment regimen generating anxiety symptoms 4. Do not stop taking antidepressant aBased on Culpepper.23 Lack of avoidance behavior without checking with the physician Poor response to psychiatric treatment 5. Remember instructions that have been given to resolve any questions insight-oriented therapy, and family a 22 Based on Lin et al. or group therapy. CBT works through reeducating patients to correct mis- Table 2. Differential Diagnosis: Anxiety Secondary to Organic Factors Relapse and Recovery conceptions, to modify unconscious Medical Illness Although patients may recover from mental representations of events, and Brucellosis anxiety disorders without treatment, to modify self-regulation of thoughts, Carcinoid syndrome the risk of relapse has been found to feelings, and behaviors. Cerebral arteriosclerosis Chronic obstructive pulmonary disease be greater in untreated patients. In a Patients with anxiety tend to not as- Coronary insufficiency study21 of the probability of recovery, sociate their behavior with an increase Diabetes mellitus relapse, and recurrence in a 3-year in their stress and anxiety levels. Phy- Drug withdrawal: anxiolytic agents, caffeine, alcohol, sedatives, opiates course of anxiety disorders, 40% of pa- sicians should provide patients with Pancreatic tumor tients with GAD achieved remission of general recommendations (Table 4) Pheochromocytoma symptoms after a 3-year period, but the that may aid in managing anxiety. Psychomotor epilepsy, complex partial seizures probability of relapse or recurrence of Pulmonary emboli symptoms was found to be near 30% Conclusion Thyroid disease (hypo- and among those that did remit. Anxiety disorders are often persis- hyperthyroidism, thyroiditis) Medications Patients with anxiety disorders need tent conditions that impair patients’ Analgesics to receive treatment in order to alle- daily functioning. Anxiety disorders Anticholinergics viate and prevent the recurrence of are highly prevalent in primary care Antihistamines Antihypertensives symptoms. settings and are often reported in terms Antimicrobials of somatic complaints. Anxiety disor- Calcium channel blockers Management of Anxiety Disorders ders are also highly comorbid with each Estrogen Insulin Patients with anxiety disorders are other and depression, which leads to an Muscle relaxants often hesitant to try medication due increased medical utilization and worse Non-steroid anti-inflammatory drugs to the stigma and embarrassment they outcomes than patients with anxiety or Sedatives Sympathomimetics associate with treatment. Patients who depression alone. GAD often develops Theophylline appear unwilling to try medication early in life and proceeds into major should be reminded that anxiety disor- depression. ders involve their brain neurochemis- Recognizing an anxiety disorder try and that treatment may improve that may be difficult; however, physicians more effectively diagnose an anxiety condition. Patients should be encour- can make a diagnosis of an anxiety disorder. aged to view their disorder as a disease. disorder through an active search of Although a number of medical con- It is also important for physicians symptoms in their patients, keeping in ditions can mimic anxiety, these condi- to continuously encourage patients to mind that the patient may have comor- tions are usually self-evident. For ex- maintain treatment compliance. Lin et bid psychiatric and/or medical condi- ample, patients who have begun a new al.22 found that patients who received tions as well. Physicians can help pa- medication and begin to report anxi- specific educational messages (Table tients to manage their anxiety through ety-like symptoms may be suffering 3) were more likely to comply with education and encouragement to ad- from an idiosyncratic reaction to their treatment during the first month of an- here to prescribed treatments. medication. By knowing the features tidepressant therapy than patients who of anxiety secondary to organic causes, did not receive any instructions. REFERENCES physicians can rule out non-anxiety dis- Psychotherapy may be another 1. Kessler RC, McGonagle KA, Zhao S, et al. order problems (Table 1). Differential effective treatment for anxiety disor- Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the diagnosis involves ruling out medical ders. Types of psychotherapy include United States: results from the National illness and iatrogenic causes (Table 2). cognitive-behavioral therapy (CBT), Comorbidity Study. Arch Gen Psychiatry

1994;51:8Ð19 and Bacon; 2000:15Ð35 bidity Survey. Br J Psychiatry 2. Greenberg PE, Sisitsky T, Kessler RC, 10. Bruce S, Rodriguez BF, Weisberg RB, 1996;168(suppl 30):17Ð30 et al. The economic burden of anxiety et al. Occupational impairment of primary 17. Weisberg RR, Keller MB, Allsworth JE, disorders in the 1990s. J Clin Psychiatry care patients with social anxiety disorder. et al. Functioning and well-being of pri- 1999;60:427Ð435 In: New Abstracts of the 156th Annual mary care patients with anxiety disorders. 3. Katon W, Von Korff M, Lin E, et al. Meeting of the American Psychiatric Presented at the 154th Annual Meeting of Distressed high utilizers of medical care: Association; May 22, 2003; San Francisco, the American Psychiatric Association; DSM-III-R diagnosis and treatment needs. Calif. Abstract NR779:291 May 13Ð18, 2000; Chicago, Ill Gen Hosp Psychiatry 1990;12:355Ð362 11. Maki K, Weisberg RB, Keller MB, et al. 18. American Psychiatric Association. Diag- 4. Weisberg RB. Management of anxiety dis- Psychosocial and work impairment in pri- nostic and Statistical Manual of Mental orders in primary care: implications for mary care patients with GAD. In: New Disorders, Fourth Edition, Revised. psychiatrists. In: Syllabus and Proceedings Research Abstracts of the 156th Annual Washington, DC: American Psychiatric Summary of the 156th Annual Meeting of Meeting of the American Psychiatric Association; 1994 the American Psychiatric Association; Association; May 19, 2003; San Francisco, 19. Rickels K, Schweizer E. The clinical pre- May 17Ð22, 2003; San Francisco, Calif. Calif. Abstract NR9:4 sentation of generalized anxiety in primary Abstract 24C:278 12. Fifer SK, Mathias SD, Patrick BL, et al. care settings: practical concepts of classifi- 5. Chrousos GP, Gold PW. The concepts Untreated anxiety among adult primary cation and management. J Clin Psychiatry of stress and stress system disorders: over- care patients in a health maintenance 1997;58(suppl 11):4Ð10 view of physical and behavioral homeo- organization. Arch Gen Psychiatry 20. Kroenke K, Spitzer RL, Williams JBW, stasis. JAMA 1992;267:1244Ð1252 1994;51:740Ð750 et al. Physical symptoms in primary care: 6. Crowe RR. The genetics of panic disorder 13. Wittchen HU, Kessler RC, Beesdo K, et al. predictors of psychiatric disorders and and agoraphobia. Psychiatr Dev 1985;3: Generalized anxiety and depression in pri- functional impairment. Arch Fam Med 171Ð185 mary care: prevalence, recognition, and 1994;3:774Ð779 7. Genetics and Mental Disorders: Report of management. J Clin Psychiatry 2002; 21. Rodriguez BF. Characteristics and clinical the NIMH’s Genetics Workgroup. National 63(suppl 8):24Ð34 course of GAD in primary care patients Institute of Mental Health 1998. Available 14. Kessler D, Lloyd K, Lewis G, et al. Cross [poster]. Presented at the 23rd Annual at http://www.nimh.nih.gov/publist/ sectional study of symptoms attribution Meeting of the Anxiety Disorders Associa- 984268.htm. Accessed Jan 20, 2004 and recognition of depression and anxiety tion of America; March 2003; Toronto, 8. Heim C, Nemeroff CB. The role of child- in primary care. BMJ 1999;318:436Ð440 Canada hood trauma in the neurobiology of mood 15. Rodriguez BF, Weisberg RB, Pagano ME, 22. Lin EH, Von Korff M, Katon W, et al. and anxiety disorders: preclinical and et al. Frequency and patterns of psychiatric The role of the primary care physician in clinical studies. Biol Psychiatry comorbidity in a sample of primary care patients’ adherence to antidepressant 2001;49:12023Ð12039 patients with anxiety disorders. Compr therapy. Med Care 1995;33:67Ð74 9. Sullivan GM, Kent JM, Coplan JD, et al. Psychiatry. In press 23. Culpepper L. Worries and anxiety. In: The neurobiology of stress and anxiety. 16. Kessler RC, Nelson CB, McGongale KD, DeGruy FV, Dickinson WP, Staton AW, In: Mostofsky DI, Barlow DH, eds. The et al. Comorbidity of DSM-III-R major eds. 20 Common Problems in Behavioral Management of Stress and Anxiety in depressive disorder in the general popula- Health. New York, NY: McGraw-Hill Med- Medical Disorders. Boston, Mass: Allyn tion: results from the U S National Comor- ical Publishing Division; 2002:385Ð404

Treatment of Generalized Anxiety Disorder: Current Options and Future Developments

Kathryn M. Connor, M.D., stated ing patients with anxiety disorders, Noncompliance and treatment costs that GAD is the most prevalent anxiety physicians need to consider treatment can hinder a patient’s recovery. By se- disorder seen in the primary care set- options that have a rapid onset of ac- lecting medications that require once- ting.1 Since GAD patients are more tion, while minimizing adverse effects. a-day dosing, physicians may be able likely to see their primary care physi- Side effects can be particularly chal- to improve compliance. Many medica- cian than a psychiatrist, primary care lenging in patients with GAD, since tions used in the treatment of GAD are physicians need to be aware of the ben- patients with anxiety tend to be more now available in generic formulations, efits and drawbacks of current GAD sensitive to medication side effects which may ease patients’ financial bur- treatments. Current medication options than other patient populations, said Dr. den associated with treatment. include benzodiazepines, buspirone, Connor. Also, since GAD is a chronic tricyclic antidepressants, selective se- condition, physicians should consider Benzodiazepines rotonin reuptake inhibitors (SSRIs), prescribing medications that have a Benzodiazepines were one of the and venlafaxine, among others. Re- limited potential for abuse and are suit- earliest approved treatments for anxi- search on other potential treatments for able for long-term treatment. ety disorders and have been prescribed GAD is also underway. Table 5. Goals of Treatment in Generalized Anxiety Disordera Treatment Goals for GAD Response Response to treatment is a good ≥ 50% decrease from baseline in Hamilton Rating Scale for Anxiety (HAM-A) score start, but remission is the ultimate treat- or Clinical Global Impressions-Improvement Scale score of 1 or 2 b ment goal for GAD (Table 5). For pa- Remission HAM-A score ≤ 7 tients to achieve remission, physicians Asymptomatic patient must find treatments that are effective Psychosocial/occupational functioning restored in treating both the psychic and so- aData from Ballanger.3 b matic symptoms of GAD. When treat- Peer-reviewed published studies on remission in generalized anxiety disorder are not yet available.

Prim© C CareOPYRIGHT Companion 2004 J PClinHYSICIANS Psychiatry POSTGRADUATE 2004;6(1) PRESS, INC. © COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. 3839 ACADEMIC HIGHLIGHTS to patients steadily over the past 40 should slowly taper medication over part be due to buspirone’s lack of effi- years. In the 1960s, benzodiazepines several weeks to months in order to cacy for somatic symptoms. replaced barbiturates as the pharmaco- minimize potential risks. Buspirone does not work as quickly logic gold standard for anxiety treat- Alprazolam, a short-acting benzo- as benzodiazepines, and the half-life ment. Benzodiazepines potentiate diazepine, has recently been released is relatively short. Because of this the inhibitory effects of γ-aminobutyric in an extended-release formulation, short half-life, patients prescribed bu- acid (GABA) at the GABAA receptor, a while clonazepam is now available in spirone will often need a t.i.d. dosing major inhibitory neurotransmitter in the a quickly dissolving wafer formula- regimen. central nervous system. tion. Many benzodiazepine treatments Benzodiazepines have a rapid onset are also available in generic formula- Tricyclic Antidepressants of symptom relief; most improvement tions, which allows for low cost to Tricyclic antidepressants (TCAs) occurs within the first few weeks of patients. are one of the oldest classes of anti- treatment. In trials comparing benzo- depressants and the first class of anti- diazepines with placebo, 65% to Buspirone depressant medications to be studied 75% of patients achieved moderate- Buspirone was the first nonbenzo- in the treatment of GAD. TCAs work to-marked improvement with benzodiazepine anxiolytic approved for the through the inhibition of serotonin diazepines.2 treatment of GAD, in 1986. Buspirone and/or norepinephrine reuptake. TCAs

Although response to benzodiaze- is a serotonin-1A (5-HT1A) partial ago- have been found to be effective not pine treatment is usually seen at the nist, which is mechanistically differ- only as antidepressant treatments but beginning of treatment, benzodiaze- ent from other anxiolytics. Studies4,5 also as antianxiety agents. pines may lose effectiveness during have found buspirone to be superior to Rickels and coworkers6 conducted long-term treatment. Therefore, physi- placebo in the treatment of GAD and an 8-week placebo-controlled study cians may need to increase dosage mild depressive symptoms. Buspirone comparing the benzodiazepine diaze- during long-term treatment to maintain has recently become available in ge- pam, the TCA imipramine, and the efficacy. neric formulations. heterocyclic antidepressant trazodone. One drawback of benzodiazepines Buspirone, unlike benzodiazepines, Patients treated with diazepam showed is that they do not prevent depression is not associated with physiologic de- an early response that plateaued after and in some cases may precipitate or pendance, tolerance issues, withdrawal week 2. The antidepressants demon- exacerbate it. Other potential side ef- symptoms, or alcohol interactions. Bu- strated a slower but steady rate of im- fects of benzodiazepines include seda- spirone tends to be better tolerated than provement, and all active treatments tion, fatigue, impaired psychomotor benzodiazepines because it lacks the were found to have similar efficacy at performance, decreased learning abil- same degree of psychomotor and cog- endpoint (Figure 2). ity, synergistic effects with alcohol, and nitive impairment. However, patients Dr. Connor cautioned that TCAs sleep disturbances. Many physicians who respond well to benzodiazepines can be associated with a number of and patients are concerned about the do not seem to respond as well to bu- side effects, such as anticholinergic potential for patients to become depen- spirone. This lack of response may in effects (dry mouth, urinary retention), dent on benzodiazepine treatment. However, while the potential to de- Figure 2. Antidepressants and Benzodiazepines in Generalized Anxiety Disordera velop physiologic and psychological dependence with benzodiazepine treat- 28 Placebo (N = 55) 26 Trazodone (N = 61) ment does exist, few patients actually Diazepam (N = 56) develop a dependence on benzodiaze- 24 Imipramine (N = 58) pines. 22 Dr. Connor noted that, when dis- 20 continuing benzodiazepine treatment, 18 patients are at risk for developing re- † † 16 * bound anxiety and withdrawal symp- Score HAM-A Total * 14 * toms. Rebound anxiety may develop † * 12 * † † after the first week of discontinuation † † 10 and may last for up to 6 weeks. Re- 0 12345678Endpoint bound or withdrawal symptoms may Time (wk) occur in patients who have been treated for as few as 3 weeks. However, pa- aReprinted with permission from Rickels et al.6 *p < .05 vs. placebo. tients can be safely discontinued from †p < .01 vs. placebo. benzodiazepine treatment. Physicians Abbreviation: HAM-A = Hamilton Rating Scale for Anxiety.

3940 © COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2004Prim PCareHYSICIANS Companion POSTGRADUATE J Clin Psychiatry PRESS 2004;6(1), INC. ACADEMIC HIGHLIGHTS orthostatic hypotension, sedation, and can limit patient compliance. Two sig- ment, and physicians may want to weight gain. These side effects can be nificant side effects that physicians consider beginning these patients on a troublesome to patients and may lead to have begun to appreciate in recent years combination of a benzodiazepine and medication noncompliance. TCAs have are sexual dysfunction and weight gain. an antidepressant in order to relieve also been associated with cardiac con- Physicians should make patients aware anxiety quickly and to minimize the duction abnormalities, and patients pre- of the potential for these side effects lag effect often seen with antidepres- scribed long-term treatment with TCAs before prescribing an SSRI. Physicians sant treatment alone. As patients im- need to have regular electrocardiogram and patients do have options in manag- prove, physicians may then consider (ECG) and blood level monitoring to ing these side effects, and physicians discontinuing the benzodiazepine. avoid toxicity. Physicians should be need to encourage patients to stay com- Adding a benzodiazepine or other an- aware that TCAs have been found to be pliant with their medication and report xiolytic agent may also be effective lethal in overdose and should use cau- any problems. in treating patients who are not re- tion when prescribing TCAs to patients One strategy to minimize potential sponding well to antidepressant with suicidal tendencies. side effects is to begin patients at a monotherapy. lower-than-recommended dose and Many patients with anxiety often Heterocyclic Antidepressants slowly titrate upward. For example, have poor anxiety management skills. Heterocyclic antidepressants are physicians may want to begin paroxe- Adding adjunctive psychotherapy to similar in action on the brain to TCAs tine treatment at 5 or 10 mg/day for a their treatment may be beneficial. In a and have been found to be effective in week or more to minimize the risk of 6-month follow-up of patients with treating depression with less risk of side effects. While this dosage is lower GAD who received CBT, 51% of overdose than TCAs.7 Heterocyclic an- than what is generally prescribed to pa- patients demonstrated improved re- tidepressants have demonstrated effi- tients treated for depression, starting at covery rates, compared to only 4% cacy in the treatment of acute GAD,6 a lower dosage may increase patient receiving psychoanalytically oriented but these drugs have not received FDA compliance and limit the potential for therapy.13 approval for this indication. adverse effects. Once patients achieve remission, there is often a strong tendency to Selective Serotonin Serotonin-Norepinephrine discontinue treatment. However, pa- Reuptake Inhibitors Reuptake Inhibitors tients who discontinue treatment early SSRIs are currently the most widely Venlafaxine-XR is currently the are at great risk for relapse and recur- prescribed treatment for anxiety disor- only serotonin-norepinephrine reuptake rence of symptoms. Physicians should ders and are considered a first-line treat- inhibitor (SNRI) approved for the treat- discourage patients from discontinu- ment. SSRIs are known to be effective ment of GAD and major depression in ing their medication unadvised. In antidepressant agents and are also ap- the United States. SNRIs bind with high general, a patient who has responded proved for a variety of anxiety indica- affinity to serotonin and norepineph- to pharmacotherapy should be stable tions. For many patients, however, the rine transporters and inhibit the pre- for about a year before considering cost of these medications is prohibitive, synaptic reuptake of these neurotrans- medication taper and discontinuation. which limits their utility, but some are mitters. At that time, if the patient continues available in generic formulations. Venlafaxine has been found to be to do well and has a stable psycho- In anxiety disorders, one of the more effective in short- and long-term treat- social situation, the clinician could widely studied SSRIs is paroxetine. ment of GAD, with or without comor- gradually taper the patient’s dose of Paroxetine has shown efficacy in both bid major depression.11,12 A placebo- medication over the next several short-term and long-term treatment of controlled study11 showed significant months. GAD.8 Sertraline9 and escitalopram10 improvement with venlafaxine as early have also demonstrated efficacy in the as the first week of treatment; however, Future Treatments treatment of GAD. the most significant effects were seen While several pharmacologic op- SSRIs, like TCAs, have a slower at the end of an 8-week period, when tions are currently available for the time to onset compared with benzo- patients were treated with higher doses treatment of GAD, these treatments diazepines. Patients may become frus- of venlafaxine (150 to 225 mg/day). are not effective for every patient. Re- trated by the lack of immediate effi- search into new treatments for GAD cacy, and physicians may need to Treatment Strategies has focused on other neurochemicals encourage patients to stay compliant Dr. Connor noted that patients with with novel mechanisms of pharma- with their medication. comorbid depression and anxiety are cologic action, as well as new com- While SSRIs have a lower risk of often more difficult to treat than pa- pounds with mechanisms similar to cardiovascular side effects than TCAs, tients with anxiety alone. These patients current medication, but with enhanced bothersome side effects may occur that often benefit from antidepressant treat- efficacy and tolerability profiles.

Duloxetine. Duloxetine, an SNRI, effective in rapidly treating both the Psychiatry 1993;50: 884Ð895 7. Cyr M, Brown CS. Nefazodone: its place is a more potent serotonin reuptake in- somatic and psychic symptoms of GAD among antidepressants. Ann Pharmacother hibitor than fluoxetine.14 It has antide- and was better tolerated than venlafax- 1996;30:1006Ð1012 8. Pollack MH, Zanielli R, Goddard A, et al. pressant effects as well as antianxiety ine. Common side effects included diz- Paroxetine in the treatment of generalized effects. FDA approval for the treat- ziness and somnolence. anxiety disorders: results from a placebo- ment of depression with duloxetine is controlled, flexible dose trial. J Clin Psychi- atry 2001;62: 350Ð357 pending. Conclusion 9. Dahl AA. Sertraline in GAD: HAM-A item 5-HT Agonists. Since the introduc- Patients with GAD and a variety of factor analysis. In: New Research Abstracts 1 of the 156th Annual Meeting of the Ameri- tion of buspirone, research has been anxiety disorders often present to pri- can Psychiatric Association; May 22, 2003; directed toward developing other mary care physicians before they San Francisco, Calif. Abstract NR823:307 10. Davidson JRT, Bose A, Zheng H. Escitalo- 5-HT1A partial agonists with greater ef- present to mental health specialists. Pri- pram treatment of generalized anxiety disor- ficacy than buspirone, a faster onset of mary care physicians, therefore, play a der: a double-blind, placebo-controlled, flex- action, and fewer side effects. key role in making the diagnosis and ible dose study. In: New Research Abstracts of the 156th Annual Meeting of the Ameri- GABAA receptor modulators. instituting proper treatment. Physicians can Psychiatric Association; May 22, 2003; GABA receptor modulators have neu- should begin treatment immediately San Francisco, Calif. Abstract NR821:307 A 11. Rickels K, Pollack MH, Sheehan DV, et al. rochemical properties similar to ben- and should be aggressive in reaching a Efficacy of extended-release venlafaxine in zodiazepines. Suriclone has been goal of symptom remission. Early treat- nondepressed outpatients with generalized anxiety disorder. Am J Psychiatry 2000;157: evaluated in patients treated with GAD ment may offset and even prevent the 968Ð974 and has shown significant improve- development of comorbid conditions 12. Montgomery SA, Sheehan DV, Meoni P, et ment over placebo on the Hamilton and improve a patient’s overall func- al. Characterization of the longitudinal course of improvement in GAD during long- Rating Scale for Anxiety and the Clin- tional level. Dr. Connor encouraged term treatment with venlafaxine. J Psychiatr ical Global Impressions-Improvement physicians to consider the possibility Res 2002;36:209Ð217 13. Fisher PL, Durham RC. Recovery rates in scale. Diazepam was found to have a of depressive symptoms in patients generalized anxiety disorder following psy- significantly higher number of adverse who have an anxiety disorder. A num- chological therapy: an analysis of clinically 15 significant change in the STAI-T across out- events than suriclone. ber of current treatments are effective come studies since 1990. Psychol Med 1999; Neuroactive peptides. Currently a in treating both anxiety and depressive 29:1425Ð1435 number of neuroactive peptides are be- symptoms, and future treatments have 14. Karpa KD, Cavanough JE, Lakoski JM. Duloxetine pharmacology: profile of a dual ing studied in the treatment of GAD, the possibility of providing faster effi- monoamine modulator. CNS Drug Rev such as cholecystokinin (CCK) recep- cacy with relatively few side effects. 2002;8:361Ð376 15. Ansseau M, Olie JP, von Frenckell R, et al. tor antagonists. CCK is an important Controlled comparison of the efficacy and neurotransmitter found in the gut and REFERENCES safety of 4 doses of suriclone, diazepam, brain and is thought to interact with and placebo in GAD. Psychopharmacology 1. Maier W, Gansicke M, Freyberger HJ, et al. 1991;104:439Ð443 other neuronal systems to cause anxi- Generalized anxiety disorder (ICD-10) 16. Pande AC, Greiner M, Adams JB, et al. ety. Research has focused on the activ- in primary care from a cross-cultural per- Placebo-controlled trial of the CCK-B spective: a valid diagnostic entity? Acta antagonist, CI-988, in panic disorder. ity at the CCKA and CCKB receptor Psychiatr Scand 2000;10:29Ð36 Biol Psychiatry 1999;46:860Ð862 17. Rickels K, Pollack MH, Lydiard RB, et al. subtypes. CI-988, a CCKB receptor an- 2. Greenblatt DJ, Shader RI, Abernathy DR. Drug therapy: current status of benzodiaze- Efficacy and safety of pregabalin and alpra- tagonist, has been found to be well- pines. 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Valium, and others), escitalopram (Lexapro), 17,18 Antidepressants for the treatment of gener- fluoxetine (Prozac and others), imipramine Studies comparing pregabalin alized anxiety disorder: a placebo- (Tofranil and others), paroxetine (Paxil and with alprazolam and venlafaxine have controlled comparison of imipramine, others), sertraline (Zoloft), trazodone (Desyrel), demonstrated rapid onset of effect with trazodone, and diazepam. Arch Gen venlafaxine (Effexor). pregabalin. Time to response was within 1 week with pregabalin treat- To cite a section from this ACADEMIC HIGHLIGHTS, follow the format below: Conner KM. Treatment of generalized anxiety disorder: current options and future developments, pp 38Ð41. ment, faster than onset seen with alpra- In: Culpepper L, chair. Effective Recognition and Treatment of Generalized Anxiety Disorder in Primary zolam and venlafaxine. Pregabalin was Care [ACADEMIC HIGHLIGHTS]. Prim Care Companion J Clin Psychiatry 2004;6:35Ð41