J Am Board Fam Pract: first published as 10.3122/jabfm.2.1.37 on 1 January 1989. Downloaded from Advances In Anxiety ManagelDent William R. Yates, M.D., and Robert B. Wesner, M.D.

Abstract: Recent developments in neurobiology, di­ lation, have reemphasized the importance of anxi­ agnostic classification, and drug/psychotherapy tri­ ety disorders in family practice. This review als have increased our ability to manage patients presents treatment recommendations, including with anxiety disorders. These recent develop­ dosage, products, guidelines for monitoring, and ments, along with epidemiologic surveys showing discontinuation. Advances in the neurobiology of the high frequency of anxiety disorders in the gen­ anxiety are also included. (J Am Bd Fam Pract eral population as well as in the primary care popu- 1989; 2:37-42.)

Advances in treatment, including medication and Adjustment Disorders psychotherapy, demand accurate classification of Adjustment disorders describe a stress syndrome anxiety disorders. An accurate diagnosis is impor­ of maladaptive anxiety to a specific psychosocial tant in predicting the natural course and prognosis stressor. Maladaptive anxiety is medically signifi­ for individual patients. Table 1 presents the classi­ cant when there is impairment in occupational or fication scheme for anxiety disorders as outlined social function or the symptoms exceed appropri­ in the revised version of the Diagnostic and Statisti­ ate reaction to the stressor. Adjustment disorders cal Manual of Mental Disorders (DSM III_R).1 Al­ are short-term reactions lasting no longer than 6 though epidemiologic surveys of anxiety SUbtypes months. Patients with acute medical illness, inter­ in family practice populations are sparse, general­ personal problems, or work difficulties commonly ized anxiety disorder, adjustment disorder with have adjustment disorders with prominent anxi­ anxious features, and simple phobias appear to be ety. For example, a person unable to sleep and 2 the most common. ,3 with poor concentration during a period of work layoffs may meet criteria for adjustment disorder. Although other persons may be undergoing simi­ Generalized Anxiety lar levels of stress, intensity of symptoms, func­ Generalized anxiety is a disorder of excessive tional impairment, and the request for help from a anxiety or worry related to two or more life cir­ physician will identify an adjustment disorder cumstances. Often patients with generalized anxi­ with anxiety. ety can be described as "worry warts" ruminating http://www.jabfm.org/ about finances, family problems, or job diffict:·· ties. Such anxiety is nonproductive and does not Simple Phobias lead to changes in behavior that would reduce Simple phobias appear to be quite common, but anxiery. An example is the anxious patient who often they are mild and infrequently treated by focuses on problems that cannot be changed. By primary care physicians. They include excessive definition, generalized anxiety disorder must also fear of a specific animal, blood, closed spaces, on 23 September 2021 by guest. Protected copyright. include somatic symptoms (muscle tension, auto­ heights, or air travel. Phobias related to health and nomic hyperactivity, and hypervigilance). Initial health care are more commonly encountered by insomnia is common because the patient is unable family physicians. They include fear of venipunc­ to modulate voluntarily worry at bedtime. Gener­ ture, injections, dental procedures, and irrational alized anxiety disorder is not diagnosed if it occurs fear of illness. concurrently with depression or is related to pri­ mary organic factors, such as hyperthyroidism or excessive caffeine use. Other Anxiety Disorders Two anxiety disorders, while less frequently seen by family physicians, are important because of From the Department of Psychiatry, University of Iowa Col­ their potential to be quite severe and occasionally lege of Medicine, Iowa City. Address reprint requests to Wil­ liam R. Yates, M.D., Psychiatric Hospital, 500 Newton Road, disabling. Panic disorder with or without agorapho­ Iowa City, IA 52242. bia may become severe but is highly responsive to

Anxiety Mana9ement 37

., J Am Board Fam Pract: first published as 10.3122/jabfm.2.1.37 on 1 January 1989. Downloaded from

Table 1. Relative Prevalence and Severity of Anxiety needed to assess their importance to family prac­ Disorders. tice. Additionally, a discrete anxiety disorder, per­ formance anxiety, has been described in which pa­ Diagnosis Prevalence Severity tients are symptomatic when they are required to function in front of a large group of people. This ++ Panic disorder with or +++ disorder may be especially devastating for musi­ without agoraphobia cians, actors, and public speakers. Generalized anxiety disorder +++ + Adjustment disorder with +++ + anxious mood Social phobia + ++ Drug Treatment Simple phobia +++ + Tricyclic Antidepressants Posttraumatic stress disorder + ++ Although best studied for depression, tricyclics Obsessive-compulsive disorder + +++ playa key role in drug management of primary 6 8 anxiety disorders. - Imipramine and desipra­ + = low, ++ = intermediate, +++ = high. mine (100 to 300 mg daily) are the tricyclic agents of choice for panic disorder. They have the advantage of requiring no special dietary re­ medical treatment. Recurrent and spontaneous strictions as do monoamine oxidase inhibitors, panic attacks are discrete periods of acute anxiety and they can be taken safely for a long time. usually accompanied by physical symptoms, such Disadvantages include anticholinergic side ef­ as palpitations, chest pain, dizziness, and short­ fects and cardiovascular toxicity in overdose. ness of breath. These attacks are the hallmark of Tricyclics may be helpful for some patients with panic disorder. DSM III-R requires at least four generalized anxiety disorder, although their use panic attacks in a 4-week period to make a panic for patients with this condition is less well stud­ disorder diagnosis. Patients often are young wom­ ied. Adjustment disorder patients with promi­ en who commonly present with concerns that nent anxious features, including insomnia, may they are having heart attacks. Agoraphobia is a be­ benefit from more sedative antidepressants such havioral syndrome that can complicate this dis­ as amitriptyline, doxepin, or trazodone. Trazo­ order. It is characterized by phobic avoidance of done has the advantage of a low anticholinergic crowds, shopping malls, churches, or other places profile but also the disadvantage of reports of where patients perceive they are separated from priapism. Preliminary studies of post-traumatic

sources of security. stress disorder have suggested benefits from the http://www.jabfm.org/ Obsessive-compulsive disorder (OeD) is another same medications that are effective against panic, potentially severe and disabling anxiety condi­ primarily desipramine and monoamine oxidase 9 lo tion.4 In OeD, patients may be tormented by inhibitors. • Although some patients with ob­ such intrusive thoughts as fear of killing their sessive-compulsive disorder are benefited by children, blasphemy, contamination with dis­ currently available antidepressants, clomipra­ eases such as AIDS, or fear of forgetting to turn mine appears to be the drug of choice and is

off appliances and sources of gas or electricity in currently in FDA trials for release in the United on 23 September 2021 by guest. Protected copyright. their homes. These obsessions are often paired States. with compulsive rituals, e.g., frequent hand­ washing, counting, touching, and checking be­ haviors. Obsessive-compulsive disorder often Monoamine Oxidase (MAO) Inhibitors produces clinical depression that can be severe MAO inhibitors are excellent drugs for anxiety and precipitate contact with a physician. Recent disorders and for mixed anxiety-depression con­ developments in the understanding of oeD have ditions. Phenelzine (45 to 90 mg daily) and tran­ produced more drug research, and several drugs ylcypromine (30 to 60 mg daily) are two com­ may soon be available to treat this disorder ef­ monly used agents of this class. Some efficacy in fectively. social phobias has also been shown. Patients con­ Three other anxiety disorders are also recog­ sidered for MAO inhibitors need to be assessed for nized. Social phobia 5-an intense fear of em­ their ability to comply with a tyramine-free diet, barrassment-and post-traumatic stress disorder especially avoiding beer, wines, and cheese. Alco­ (PTSD) are less well-defined, and more research is hol abusers should not receive these drugs.

38 The Journal of the American Board of Family Practice-Vol. 2 No.1 / January - March 1989 J Am Board Fam Pract: first published as 10.3122/jabfm.2.1.37 on 1 January 1989. Downloaded from Benzodiazepines (BZD) of alcohol or drug problems, a family history Benzodiazepines are effective drugs for a variety of alcohol or drug abuse, or patients with anti­ of anxiety conditions and, when used properly, social personality disorder. Nonbenzodiaze­ will provide additional help for the anxious pa­ pines should be preferred in patients with any tient. ll, 12 Diazepam (5 to 30 mg daily) and al­ risk factor for substance abuse. prazolam (0.75 to 3.0 mg daily) are examples of long- and short-acting benzodiazepines, each having specific indications. A primary advantage Other Drugs of benzodiazepines is their rapid onset of anxi­ Buspirone (15 to 60 mg daily) represents the first olytic effect, which can be quite helpful in acutely novel class of anxiolytic agents released in the last anxious patients such as those with adjustment 25 years. This drug has been targeted for patients disorders. Side effects tend to be minor, and the with generalized anxiety disorder. 13 It requires drugs are usually well tolerated. They probably several weeks to reduce anxiety and therefore has are best suited for short-term use. less to offer for adjustment disorder. This drug Short-acting benzodiazepines (alprazolam and may be especially helpful for the generalized anxi­ lorazepam) have been used to manage panic dis­ ety disorder patient with no previous benzodiaze­ order effectively. Their potency offers an advan­ pine experience. Little is known about the long­ tage because high doses produce less sedation term efficacy of buspirone. than longer-acting agents, making them useful Propranolol, atenolol, and other beta-block­ to control panic attacks. Clonazepam is a high­ ing agents appear to have some effect in social potency BZD that is also long acting and may phobia and performance anxiety. 5 Patients with be effective for panic disorder. The relative disad­ disabling anxiety during performances such as vantage of the short-acting agents is their ability public speaking, recitals, or test taking may be to produce withdrawal syndromes. This requires helped with beta-blockers. Beta-blockers appear patients to taper the dosage slowly (for example, to work by blocking peripheral anxiety symp­ 0.5 mg per week of alprazolam or lorazepam) in toms, e.g., tachycardia and tremulousness, order to discontinue their medication without symptoms that can escalate subjective anxiety withdrawal symptoms or rebound anxiety. Al­ and impair performance. When using beta­ ternatively, an equipotent switch to a longer­ blocker$ specifically for performance anxiety, acting agent with a more rapid taper can be used the patient should have several practice experi­ to discontinue a benzodiazepine. For patients ences with the drug before undergoing the per­ who require long-term use of benzodiazepines, formance or test itself. Test doses of propranolol

longer-acting agents may have a slight advan­ (20 to 40 mg) or atenolol (50 mg) are reasonable http://www.jabfm.org/ tage for disorders such as generalized anxiety starting points. disorder. They can be used less frequently and will produce fewer withdrawal symptoms on a day-to-day basis. Some panic patients appear to Duration of Treatment and Discontinuation benefit from a combination of benzodiazepine The duration of treatment, including decisions to and tricyclic at the beginning of their treatment, discontinue antianxiety medications, will be pa­ with tapering of the benzodiazepine as the tricy­ tient specific. For patients who experience good­ on 23 September 2021 by guest. Protected copyright. clic becomes effective. to-excellent improvement in target anxiety symp­ The following guidelines may help the clinician toms, 4 to 12 months of drug treatment is use benzodiazepines effectively: reasonable. Patients with severe anxiety syn­ dromes receiving nonbenzodiazepines may need 1. Consider nonbenzodiazepine drugs first for longer continuous treatment. When a decision is the drug-naive patient if possible. made to begin a medication taper, a slow gradual 2. Target benzodiazepine use for specific short­ reduction (one-fourth dose reduction every I to 2 term symptoms. A total duration of 2 to 8 weeks) can be started. During the taper phase, weeks' treatment should be agreed upon with patients will need closer monitoring than during the patient before initiation ofbenzodiazepine maintenance. Recurrence of symptoms with im­ treatment. pairment may necessitate returning to a full 3. Patients should be screened for potential sub­ dosage or beginning a nondrug intervention stance abuse, which includes personal history program.

Anxiety Management 39 J Am Board Fam Pract: first published as 10.3122/jabfm.2.1.37 on 1 January 1989. Downloaded from Nondrug Treatment Practically speaking, physicians can use the fol­ Nondrug interventions provide opportunity for lowing guidelines in managing the anxiety dis­ extending improvement in patients who received order patient: medication, as well as providing an alternative to those who do not need medication or refuse to 1. For most severely ill patients, combination consider medication as an option. Using nondrug therapy using medication and psychotherapy interventions for milder cases of generalized anxi­ of the cognitive-behavioral type is the treat­ ety or social phobias may be appropriate. Family ment of choice. physicians can often provide office counseling for 2. When cognitive-behavioral therapies are un­ anxiety disorders. 14 available, drug therapy alone may be tried. If An exercise prescription is an appropriate non­ improvement plateaus despite control of anxi­ drug intervention for many anxiety patients. The ety symptoms, consideration should be given focus on exercise helps restructure any feelings of to adding a psychotherapy modality such as increasing disability related toward the anxiety. cognitive-behavioral therapy. Aerobic exercise at 60 to 70 percent of maximum 3. Patients best suited for nondrug therapies heart rate 4 to 5 times per week can increase self­ alone are those with relatively mild symp­ esteem, lower resting pUlse, and reduce auto­ toms and no impairment. Also, chronic dis­ nomic activity. Some panic patients have reported orders requiring long-term therapy may increased anxiety during aerobic exercise, but benefit by a nondrug therapy. If the patient generalized anxiety disorder patients tolerate ex­ should experience exacerbation of anxiety ercise well. Several weeks to months may be re­ symptoms during times of exceptional stress, quired for the effects to occur for patients who are then short-term medication use can be added not in good physical condition. to psychotherapy for effective long-term Relaxation training also can be helpful for some management. anxiety disorder patients. The techniques include progressive muscle relaxation, visual imagery, biofeedback, and hypnosis. Because the effects of Neurobiology focused relaxation can occur quickly, adjustment Along with importance of stress as a precipitating disorders with specific muscle tension symptoms and causative factor for anxiety disorders, we are may be appropriate. becoming more aware of the brain biochemistry Cognitive-behavioral therapy has more re­ involved with the patient's vulnerability to anxi­ search support than all other psychotherapies for ety. Gamma aminobutryic acid (GABA) appears treatment of anxiety disorders}5.)6 These ther­ to be an especially important neurotransmitter in http://www.jabfm.org/ apies usually require weekly visits for 12 to 16 modulating the symptoms of anxiety.2o Current weeks. Simple phobias respond to in-vivo expo­ research supports the role of GAB A and a GABA sure therapy. Social phobia. performance anxiety, receptor in opening the chloride channels across and generalized anxiety disorder have received lit­ cell membranes, resulting in a general inhibition tle psychotherapy research attention but theoreti­ of neuronal function. Inhibition appears to reduce cally are candidates for cognitive-behavioral ther­ subjective anxiety, to facilitate muscle relaxation, apy. Panic disorder appears to be best treated by a and to modify seizure thresholds. on 23 September 2021 by guest. Protected copyright. cognitive-behavioral strategy in conjunction with A benzodiazepine receptor has been demon­ drug therapy. Other therapies besides cognitive­ strated in the brain using positron emission to­ behavior therapy are occasionally indicated. For mography (PET). GABA and benzodiazepines ap­ adjustment disorder patients having prominent pear to work as a complex at this receptor site symptoms from marital or family problems, focus­ with GABA's effects potentiated by the presence ing on marital or family relations can be important of benzodiazepines. It has been suggested that a in reducing the symptoms. naturally occurring endogenous benzodiazepine­ Increasing attention has focussed on specific like substance having antianxiety properties is treatment options for specific anxiety disorders. )7-19 produced by the central nervous system. Benzo­ Table 2 presents a diagnosis-specific treatment diazepines may mimic the effects of this endoge­ scheme for drug and nondrug interventions. This nous substance. table is based on clinical experience and the lim­ It has been postulated that changes in receptor ited research on diagnosis-specific treatment. function as well as levels of GABA or endogenous 40 The Journal of the American Board of Family Practice-Vol. 2 No. 1 / January - March 1989 I 1 J Am Board Fam Pract: first published as 10.3122/jabfm.2.1.37 on 1 January 1989. Downloaded from benzodiazepine may alter a person's vulnerability for Huntington's chorea and Duchenne muscu­ to the psychological and somatic symptoms of lar dystrophy. anxiety. For example, a relative deficiency of Advances in the neurobiology of anxiety have GAB A or endogenous benzodiazepine may medi­ implications for practicing physicians. These in­ ate an increase in subjective anxiety. clude: Along with progress in brain biochemistry supporting a neurochemical contribution to 1. The biological model of anxiety can be used as anxiety, advances in psychiatric genetics have supportive evidence that pharmacologic treat­ highlighted the familial nature of panic disorder, ment is an appropriate alternative. Explaining generalized anxiety disorder, and obsessive­ this model to patients may encourage some to compulsive disorder. 21.22 Family studies of consider appropriate medication trials. anxiety disorders support the notion of a sub­ 2. Anxious patients should be viewed as persons stantial genetic contribution. Further investiga­ with a biological vulnerability that is ex­ tion at the molecular level, using restriction pressed at a certain level of psychosocial fragment length polymorphisms, is now under­ stress. way to identify specific chromosomal markers 3. Obtaining an accurate family history of all for these disorders. These laboratory techniques, psychiatric illnesses is now essential for evalu­ borrowed from molecular genetics, are the same ating all patients with a chief complaint of that were used to find the chromosomal markers anxiety.

Table 1. Ratings for Anxiety Modalities by DSM Ill-R SUbtype.

DSM III-R Subtype

Generalized Panic Anxiety Adjustment Social Simple Performance Obsessive Modality Disorder Disorder Disorder Phobia Phobia PTSD Anxiety Compulsive

Antidepressants Imipramine +++ 0 0 0 ++ 0 + Desipramine } + Amitriptyline + 0 0 + 0 + Nortriptyline } + + http://www.jabfm.org/ Doxepin + ++ + 0 0 + 0 + Trazodone 0 + + 0 0 + 0 + Clomipramine 0 0 0 0 0 0 0 +++ Phenelzine +++ 0 ++ + ++ 0 + Tranylcypromine } + Benzodiazepines Diazepam Chlordiazepoxide + ++ +++ 0 0 + 0 + on 23 September 2021 by guest. Protected copyright. Clonazepam I Alprazolam ++ +++ 0 0 + 0 + Lorazepam } + Other drugs Buspirone 0 ++ 0 0 0 0 0 0 Propranolol 0 0 + 0 0 ++ 0 Atenolol } + Nondrug therapy Exercise + ++ 0 0 0 + 0 0 Relaxation + ++ + + 0 0 + 0 Cognitive-behav- ior ++ ++ + + +++ + ++ +

0= ineffective or no treatment, + = effective in some patients, ++ = effective in many, +++ = modality (ies) of choice.

Anxiety Management 41 J Am Board Fam Pract: first published as 10.3122/jabfm.2.1.37 on 1 January 1989. Downloaded from References 12. Charney DS, Woods SW, Goodman WK, et al. 1. American Psychiatric Association. Diagnostic and Drug treatment of panic disorder: the comparative statistical manual of mental disorders. 3rd ed. efficacy of imipramine, alprazolam, and trazo­ Washington, D.C.: American Psychiatric Associ­ done. J Clin Psychiatry 1986; 47:580-6. ation, 1987. 13. Wheatley D. Buspirone: multicenter efficacy 2. Von Kroft'M, Shapiro S, Burke JD, et al. Anxiety study. J Clin Psychiatry 1982; 43:92-4. and depression in a primary care clinic. Arch Gen 14. Williamson PS. Psychotherapy by family physicians. Psychiatry 1987; 44:152-6. In: Yates W, ed. Primary care: psychiatric illness. 3. Reich J. The epidemiology of anxiety. J Nerv Ment Philadelphia: W.B. Saunders, 1987; 14: Dis 1985; 136:267-71. 803-16. 4. Zohar J, lnsel TR. Obsessive-compulsive disorder: 15. Beck AT, Emery G, Greenberg RL. Anxiety dis­ psychobiological approaches to diagnosis, treat­ orders and phobias: a cognitive perspective. New ment, and pathophysiology. BioI Psychiatry 1987; York: Basic Books, 1985. 22:667-87. 16. Michelson L, Ascher LM, eds. Anxiety and stress 5. Liebowitz MR, Gorman JM, Fyer AJ, Klein DF. disorders. New York: Guilford Press, 1987. Social phobia. Review of a neglected anxiety 17. Noyes R Jr, Chaudry DR, Domingo DV. Pharma­ disorder. Arch Gen Psychiatry 1985; 42:729-36. cologic treatment of phobic disorders. J Clin Psy­ 6. Hollister LE. Pharmacotherapeutic considerations chiatry 1986; 47:445-52. in anxiety disorders. J Clin Psychiatry 1986; 18. Noyes R Jr. Drug treatment of anxiety disorders: 47(Suppl):33-6. update 1987. J Affective Disord 1987; 13:95-8. 7. Lydiard RB, Ballenger JC. Antidepressants in 19. Gorman JM, Gorman LK. Drug treatment of social panic disorder and agoraphobia. J Affective Disord phobia. J Affective Disord 1987; 13:183-92. 1987; 13:153-68. 20. Paul SM, Skolnick P. The biochemistry of anxiety: 8. Ballenger JC. Psychopharmacology of the anxiety from pharmacotherapy to pathophysiology. In: disorders. Psychiatr Clin North Am 1984; 7:757-71. Klein D, ed. Psychiatry update: the APA annual 9. Van der Kolk BA. The drug treatment ofpost-trau­ review, Vol 13. Washington, D.C.: American Psy­ matic stress disorder. J Affective Disord 1987; chiatric Association, 1984:482-90. 13:203-13. 21. Crowe RR, Noyes R Jr, Wilson AF, Elston RC, 10. Falcon S, Ryan C, Chamberlain K, Curtis G. Tricy­ Ward U. A linkage study of panic disorder. Arch elics: possible treatment for posttraumatic stress Gen Psychiatry 1987; 44:933-7. disorder. J Clin Psychiatry 1985; 46:385-8. 22. Noyes R Jr, Clarkson C, Crowe RR, Yates WR, 11. Sheehan DV. Benzodiazepines in panic disor­ McChesney CM. A family study of generalized der and agoraphobia. J Affective Disord 1987; anxiety disorder. Am J Psychiatry 1987; 144: 13:169-81. 1019-24. http://www.jabfm.org/ on 23 September 2021 by guest. Protected copyright.

41 The Journal of the American Board of Family Practice-Vol. 2 No. 1 / January - March 1989