Once panic attacks have become more frequent and phobic avoidance has developed, general therapeutic guidelines should be followed: Pharmacologic treatment or cognitive behavioral therapy (CBT) have been shown in controlled trials to be equally effective in the treatment of panic disorder. A systematic review of 21 trials involving CBT and pharmacologic therapy found that combined therapy was somewhat more effective than pharmacotherapy with antidepressants alone (RR 1.24, 95% CI 1.02 to 1.52) or psychotherapy alone (1.17, 95% CI 1.05 to 1.31). 2009 treatment guidelines from the American Psychiatric Association recommend initiating treatment for most patients with medication or CBT, depending on patient preference and availability of adequately trained CBT therapists. Combined treatment is advised as an initial intervention for patients with more severe symptoms or those with comorbid PTSD or depression; it should also be offered to those with persistent symptoms after treatment with one modality. The basic behavioral and physiologic aspects of panic disorder should be discussed with the patient to help reframe a potentially frightening syndrome, and one that potentially carries some stigma, into a common treatable disorder in which the patient's "alarm system" trips indiscriminately. All side effects of treatment and the length of treatment should be discussed.
Once panic attacks are alleviated, the patient should be encouraged to reenter situations that have been avoided as a result of panic attacks, such as crowded places, parties, or driving on the freeway. A thorough psychosocial review should address personality traits, maladaptive coping styles, and current life stress, all of which can contribute to persistence of panic attacks. The patient may need referral to a marital or family therapist if the attacks develop in the context of marital or family strife. Similarly, referral for adjunctive psychodynamic or interpersonal therapy is indicated when chronic personality traits, low self-esteem, poor interpersonal relationships, and rejection sensitivity are prominent features. Psychiatric referral is indicated in patients with panic disorder who do not respond to adequate therapy within several months, who have serious comorbid psychiatric disorders, or who have serious suicidal ideation with suicidal intent or a plan.
Psychotherapy
Cognitive behavioral therapy — A number of well performed, randomized clinical trials have established the clinical efficacy of cognitive-behavioral treatments in patients with panic disorder. Cognitive behavioral psychotherapy focuses on correcting maladaptive cognitions that play a role in amplifying normal bodily sensations so that they are experienced as frightening and uncontrollable. As an example, increased heart rate after walking up a flight of stairs may provoke thoughts that one is having a cardiac arrhythmia or heart attack, which in turn provoke a greater increase in heart rate and respiratory rate.
A meta-analysis of 11 trials that compared cognitive behavioral therapy with antidepressants for panic disorder demonstrated similar outcomes (decrease in symptoms by 50 percent and decreased global anxiety and depression). The largest study evaluated was a double-blind, placebo-controlled trial of 312 patients who were randomly assigned to receive imipramine (up to 300 mg/day), cognitive behavioral therapy alone, placebo, cognitive behavioral therapy plus imipramine, or cognitive behavioral therapy plus placebo. In the acute phase of therapy (first three months), both cognitive behavioral therapy and imipramine were superior to placebo and were associated with a similar number of responders; combining therapy did not confer any significant additional benefit acutely. Among patients who responded, imipramine was associated with a higher quality response than cognitive behavioral therapy. Following another six months of maintenance therapy, there appeared to be an advantage for those who received combination therapy, although this advantage did not persist once treatment was stopped. Overall, patients who were treated initially with cognitive behavioral therapy alone did best in the follow-up phase after all therapy had stopped, emphasizing the point that panic disorder is a chronic illness that often requires indefinite therapy (see below), and that some of the skills learned in psychotherapy can be used once the therapy has stopped.
Short-term psychodynamic therapy — Although most studies of therapy for panic disorder have evaluated the role of CBT, one randomized trial investigated the short-term efficacy of panic-focused psychodynamic therapy (a form of psychotherapy based on a psychoanalytic model) in 49 adults with panic disorder. A biweekly 12 week program of this psychotherapy, compared to 12 weeks of relaxation training for the control intervention, resulted in a significant difference in response (73 versus 39 percent), as measured by a panic severity score rated by independent evaluators. Psychosocial functioning showed a similar improvement in the therapy group compared to controls. Unlike CBT, this therapy is less structured and does not involve exposure to fears, but focuses on the psychological significance to the individual of panic and avoidance. The findings of this trial need to be further replicated.
Medical therapy — There are five classes of medications that are equally useful and significantly more effective than placebo for panic disorder: serotonin reuptake inhibitors (SSRIs); serotonin-norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants (TCAs); benzodiazepines; and monoamine oxidase inhibitors.
Serotonin reuptake inhibitors — Selective SSRIs are the first-line treatment of choice for panic disorder in the primary care setting. Controlled studies have supported the efficacy of fluvoxamine, paroxetine, sertraline, citalopram, and fluoxetine. As an example, in a report of 75 patients with moderate to severe outpatient panic disorder, 13 of 23 (57 percent) receiving fluvoxamine were rated moderately improved or better at four weeks versus 8 of 20 (40 percent) given cognitive therapy and 5 of 23 (22 percent) receiving placebo. Freedom from panic attacks was reported in 43, 25, and 4 percent of patients, respectively.
In another report, 278 patients with a mean of 9.5 to 11.6 full panic attacks during the screening period were randomly assigned to double-blind treatment with a 10-week course of placebo or paroxetine at a dose of 10, 20, or 40 mg/day. During the last two weeks of the study, 67.4, 65.2, and 86 percent of the patients taking the various doses of paroxetine, respectively, were free of full panic attacks compared with 50 percent of the placebo-treated individuals.
Jitteriness, restlessness, agitation, headache, gastrointestinal symptoms (diarrhea and nausea), and insomnia are common side effects with SSRIs (show table 5). Thus, lower daily doses should initially be prescribed (eg, 5 to 10 mg of paroxetine; 12.5 to 25 mg of sertraline; 25 mg of fluvoxamine; 5 to 10 mg of fluoxetine; 10 mg of citalopram) for approximately one week, and then gradually titrated up to full doses. Therapeutic doses to completely alleviate panic attacks in most cases are 20 to 40 mg of paroxetine, 50 to 200 mg of sertraline, 100 to 300 mg of fluvoxamine, 20 to 40 mg of fluoxetine, and 20 to 40 mg of citalopram.
An initial therapeutic response typically occurs within four to six weeks of SSRI therapy. If there is no response by 8 to 12 weeks at a maximum therapeutic dose, the patient should be given a second trial of another antidepressant (eg, a different SSRI or TCA) or should be referred to a psychiatrist.
A significant percentage of men and women develop sexual side effects after several weeks or months of SSRI therapy; these adverse effects can lead to medication discontinuation. The management of SSRI-induced sexual dysfunction is discussed separately.
Serotonin norepinephrine reuptake inhibitors — Venlafaxine, in doses ranging from 75 to 225 mg daily, was found to reduce global severity of panic, and fear and avoidance of panic-triggers, but did not lead to significantly greater freedom from panic, in a randomized placebo-controlled trial. Because there are limited additional data on the efficacy of venlafaxine for panic disorder, SSRIs should be the first line of treatment.
Tricyclic antidepressants — Tricyclic antidepressants (TCAs) appear to be as effective as SSRIs for the treatment of panic disorder. Although less expensive, TCAs are not generally considered first line therapy because of associated adverse effects. Nevertheless, patients who have responded well to TCAs for depression or anxiety in the past and in whom side effects are not limiting can be treated with this class of medications. Clomipramine and imipramine have been shown to be effective in controlled studies; clinical experience suggests that other TCAs are also efficacious. Nortriptyline has fewer side effects than most tricyclic antidepressants.
As with SSRIs, TCAs should be started at low doses (eg, 10 to 25 mg of imipramine) with gradual increases every four to five days until panic attacks cease. Often patients will not tolerate the side effects of the TCAs (show table 5); switching to an SSRI, which usually has fewer side effects, is indicated in these circumstances.
Benzodiazepines — High potency benzodiazepines offer an alternative treatment for patients who are unable to tolerate or who do not benefit from an adequate trial of SSRI agents or TCAs. Alprazolam, lorazepam, and clonazepam have all been found to be more effective than placebo for the treatment of panic disorder. Starting doses of clonazepam 0.25 to 0.5 mg three times a day, alprazolam 0.25 mg four times a day, and lorazepam 0.5 mg three times a day can be increased gradually every one to three days until panic attacks cease. Between dose "rebound" is minimized by using longer half-life benzodiazepines such as clonazepam.
Patients with polydrug or alcohol abuse, chronic pain disorders, and severe personality disorders should not be prescribed benzodiazepines in light of potential problems with abuse.
Monoamine oxidase inhibitors — Monoamine oxidase inhibitors are at least as effective as tricyclic antidepressants for the treatment of panic disorder. However, their use in the primary care setting is limited because of significant side effects such as orthostatic dizziness, and the need for a tyramine-restricted diet and avoidance of specific medications (eg, ephedrine, SSRIs) to prevent possible hypertensive crises.
Combination therapy — Benzodiazepines can be prescribed in the severely symptomatic patient while concomitantly initiating treatment with an SSRI or TCA. A slow taper of the benzodiazepine is started (10 to 20 percent per week) once the antidepressant begins to take effect.
Support for a combination therapy approach in patients with severe symptoms was derived from a study of 34 patients with panic disorder who were randomly assigned to receive sertraline (target dose 100 mg/day) plus either clonazepam (0.5 mg three times a day) or placebo for four weeks, followed by clonazepam taper for three weeks and then discontinuation for the remaining five weeks of the trial. There were significantly more responders in the clonazepam than the placebo group after week one (41 versus 4 percent) and week three (63 versus 32 percent).
Collaborative care of panic disorder — Randomized, controlled trials of pharmacologic and psychotherapeutic treatments of panic disorder have largely been tested in tertiary care settings with selected populations (ie, efficacy trials). Randomized trials of health services approaches to more effectively deliver these treatments to primary care patients have been completed (ie, effectiveness trials). Despite highly effective medications and psychotherapy, few primary care patients who are accurately recognized as having panic disorder receive guideline levels of care.
"Collaborative care" strategies that seek to overcome patient, physician, and process-of-care barriers to mental health treatment, along with judicious use of specialty consultation and close and sustained follow-up of patients, have been evaluated. Several models of collaborative care, compared with usual care for panic disorder, have been shown to improve patient outcomes (symptom assessment, quality of life measures, and work status) in randomized controlled trials. Collaborative care strategies incorporate case management, stratification of patients by complexity, and access to psychiatric consultation. Care in these models has variably incorporated video and print educational materials, guideline-driven management, cognitive behavioral therapy, and direct or telephone contact with social workers or non-mental health professionals, often under the supervision of psychiatrists.
Treatment duration — Patients with panic disorder can usually be stabilized (eg, alleviation of panic attacks, avoidance, and agoraphobic behavior) within four months. Pharmacotherapy should be continued for at least one year and then reassessed. Relapse during or after a medication taper is less likely if comorbid psychiatric and medical conditions have been optimally treated and psychosocial stressors have been significantly reduced.
Antidepressants can be tapered over 4 to 8 weeks, while benzodiazepines may need to be tapered over 10 to 16 weeks to minimize withdrawal symptoms. If panic, anxiety, avoidance, or agoraphobic symptoms recur after tapering, indefinite maintenance therapy should be considered. In addition, a referral for cognitive-behavioral treatment may be added if this has not yet been tried.
Generalized anxiety disorder (GAD) is characterized by excessive worry and anxiety that are difficult to control and that cause significant distress and impairment. In addition, patients with GAD may present to their primary physicians with predominantly somatic symptoms, similar to those somatic symptoms experienced with panic disorder. Primary GAD is a rare presentation to nonpsychiatrists; more commonly, patients develop symptoms of GAD that are associated with other DSM-IV diagnoses such as panic disorder, major depression, alcohol abuse, or an axis II personality disorder.
EPIDEMIOLOGY - GAD is a common anxiety disorder; twelve-month, and lifetime prevalence rates, based on DSM-IV criteria, are estimated at 2.1 and 4.1 percent, respectively. The prevalence is estimated to be between 5 and 8 percent in the primary care setting. Twice as many women as men have the disorder.
The number of office visits with a recorded anxiety disorder diagnosis increased from 9.5 million in 1985, to 11.2 million per year in 1993 to 1994 and 12.3 million per year in 1997 to 1998, accounting for 1.9, 1.6, and 1.5 percent of all office visits in those years, respectively.
The majority of patients with GAD have other comorbid psychiatric diagnoses. In the National Epidemiologic Survey of Alcohol and Related Conditions, a current comorbid disorder was reported in 90 percent of the 900 respondents who met 12-month criteria for GAD. In the National Comorbidity Survey, for example, patients with GAD had the following current (30-day) and lifetime frequencies of other psychiatric disorders: Social phobia - 23.2 and 34.4 percent Specific phobia - 24.5 and 35.1 percent Panic disorder - 22.6 and 23.5 percent Major depression - 38.6 and 62.4 percent.
GAD may also be associated with substance abuse, post-traumatic stress disorder, and obsessive compulsive disorder.
Between 35 and 50 percent of individuals with major depression meet criteria for GAD. Coexisting GAD in depressed patients may worsen the outcome by increasing the rates of suicide, worsening overall symptoms, conferring a poorer response to treatment, increasing the number of medically unexplained symptoms, and increasing functional disability.
In one study, 40 percent of patients sampled from primary care practices and identified in the study as having an anxiety disorder were not receiving treatment (either pharmacologic or counseling) for their anxiety. Untreated GAD is also associated with high rates of medical comorbidity and utilization of medical health care. This was evidenced in an evaluation of 119 high utilizers of health care who were identified by various means as being distressed; 21.8 percent suffered from GAD.
PATHOPHYSIOLOGY - GAD is characterized by a maladaptive response to stressful stimuli primarily involving the neurotransmitters norepinephrine, serotonin, and gamma-aminobutyric acid (GABA). Research has also focused upon possible hypothalamic-pituitary-adrenal axis abnormalities and the potential role of cholecystokinin.
Imaging studies in patients with GAD have shown differences in regional brain activity. As an example, one report using positron emission tomography measurements found high relative metabolic rates in parts of the occipital, temporal, and frontal lobes, and cerebellum, during a passive viewing task in patients with GAD relative to normal control subjects. Benzodiazepine treatment resulted in a significant decrease in glucose metabolism in the cortex compared with placebo, especially in the occipital cortex, limbic system, and basal ganglia.
Genetic factors appear to play only a modest role in the etiology of GAD. One study of over 1000 female twin pairs estimated that the heritability of GAD was approximately 30 percent, compared with 70 percent heritability in major depressive disorder.
Early environment is thought likely to be an important factor, interacting with genetic predisposition, and possibly more influential than inheritance on the development of GAD. One report which found that childhood adversity was associated with onset of GAD, as well as other DSM-III-R anxiety and depressive disorders. Specifically, witnessing trauma in childhood was strongly associated with the onset of GAD later in life.
CLINICAL MANIFESTATIONS AND DIAGNOSIS - Diagnostic criteria from the DSM-IV for GAD include excessive anxiety and worry about a number of events or activities, occurring more days than not for at least six months, that are out of proportion to the likelihood or impact of feared events. Affected patients also present with somatic symptoms, including fatigue, muscle tension, memory loss, and insomnia, and, as noted above, other psychiatric disorders. They often have little insight into the connection between reported worries, current life stress, and their physical symptoms.
A seven-item anxiety questionnaire (GAD-7) has been developed and validated in a primary care setting. This patient self-assessment tool may facilitate screening, but positive screens (a score of 8 or higher) should be followed by clinician interview to establish the diagnosis of GAD. The GAD-7 tool has been validated to screen for generalized anxiety, as well as for other types of anxiety (panic disorder, social anxiety disorder, and posttraumatic stress disorder). Additionally, the first two items of the GAD-7 tool (referred to as the GAD-2), with a cutoff score of 3 or more leading to further evaluation, may be equally sensitive to the GAD-7.
Many patients have the full constellation of symptoms that meet the DSM-IV criteria, but have had symptoms for a shorter period than the required six months. These individuals often have symptoms of anxiety as a result of a specific stressor, or symptoms that occur within three months of the onset of a stressor; they fulfill the DSM-IV diagnostic criteria for "adjustment disorder with anxious mood" rather than GAD. Patients with adjustment disorder may have considerable impairment in social relationships and occupational functioning.
Patients should be screened for comorbid psychiatric disorders and an organic etiology for anxiety by careful history taking, a complete physical examination, and appropriate laboratory studies: The initial interview should be open-ended and unhurried; family members should be involved when appropriate. The medical history should focus upon possible contributory factors relating to current medical disorders, medication side effects, or substance abuse. The psychosocial history should screen for comorbid psychiatric disorders such as major depression and agoraphobia, stressful life events, family psychiatric history, current social history, substance abuse history (including caffeine, nicotine, and alcohol), and past sexual, physical and emotional abuse, or emotional neglect. Laboratory studies to consider include a complete blood count, chemistry panel, serum thyrotropin (TSH), urinalysis, electrocardiogram (in patients over 40 with chest pain or palpitations), and any other specific studies required to diagnose a suspected medical cause of anxiety. Urine or serum toxicology measurements or drug levels can be obtained for drugs or medications suspected in the etiology of anxiety.
ACUTE TREATMENT - Most patients with GAD will present initially to primary care physicians, and receive their treatment primarily or exclusively in primary care. Coexisting organic or psychiatric diagnoses should be treated aggressively. Treatment of GAD itself may consist of therapy (cognitive behavioral), medication, or both.
Supportive therapy and counseling - Cognitive behavioral therapy (CBT) is frequently recommended as first line psychological treatment for GAD. A meta-analysis found CBT to be more effective in reducing symptoms in patients with GAD than treatment as usual or waiting list, but outcomes were similar for CBT and supportive therapy. Cognitive behavioral therapy in primary care settings that have integrated mental health resources can be particularly effective.
Primary GAD or anxiety disorders of shorter duration in response to stressors (eg, adjustment disorder with anxious mood) also may respond to cognitive behavioral or supportive problem-focused therapy in the primary care setting. A brief series of primary care office visits can be effective in alleviating symptoms of anxiety. Many patients are more accepting of this mode of treatment than psychiatric referral, since psychosocial exploration and therapy can be linked to follow-up medical office visits for other organic problems, allowing patients to continue to focus on their somatic complaints. Family or marital counseling may be appropriate in some cases.
A controlled study of 91 patients with new episodes of GAD found that family physicians who used brief supportive psychotherapy had three-month and six-month follow-up results similar to those who prescribed benzodiazepines. Neither group of patients increased their consumption of alcohol, tobacco, or nonprescribed drugs, and the psychotherapy group did not make increased demands upon the physician's time.
A subgroup of patients in the previous study who were more distressed were compared in a second trial; control groups received benzodiazepines while intervention patients had problem-focused therapy with a psychiatrist over four to five sessions. The two groups again experienced similar outcomes.
Drug therapy - While benzodiazepines and tricyclic antidepressants (TCAs) traditionally were commonly used drug treatments for GAD, selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs, eg venlafaxine), and buspirone are also effective, and because of their lower side effect profiles and lower risk for tolerance have become first-line treatment.
Antidepressants - Several randomized, placebo-controlled trials have demonstrated the efficacy of antidepressants in patients with generalized anxiety disorder, including trials of paroxetine, sertraline, citalopram, venlafaxine, duloxetine, imipramine, and trazodone. A systematic review concluded that five patients with GAD would need to be treated with antidepressants versus placebo in order for one more patient to meet criteria for a clinical response (ie, NNT=5).
Most trials have not included older adults in the study population. A post hoc analysis of five randomized, controlled trials of venlafaxine for GAD found similar efficacy and tolerability in younger and older patients. A 12-week randomized trial in adults with GAD aged 60 and older found evidence of greater symptom improvement for the group who took escitalopram compared to placebo, although there was no significant difference between treatment and placebo groups in the intention-to-treat analysis, with an 18.5 percent dropout rate in both groups.
While only certain SSRIs have been approved by the US FDA for the treatment of GAD, the efficacy of SSRIs for GAD is most likely a class effect. As such, the choice among SSRIs can be based upon side effects and cost.
There are fewer data in children and adolescents with GAD, but a nine-week double-blind, placebo-controlled study (n = 22) found that sertraline, at a maximum dose of 50 mg daily, was a safe and effective treatment for GAD, with positive results manifesting by week 4.
Tricyclic antidepressants, SSRIs, or SNRIs may be associated with side effects such as restlessness and insomnia, symptoms which can be similar to the symptoms of GAD and which may jeopardize medication adherence. These adverse effects can be minimized by starting at lower doses and gradually titrating to full doses as tolerated. As examples, lower daily doses of SSRIs (5 to 10 mg of paroxetine, 12.5 to 25 mg of sertraline, 25 mg of fluvoxamine, 5 mg of fluoxetine, or 10 mg of citalopram) can initially be prescribed for approximately one week to minimize agitation, headache, gastrointestinal symptoms (diarrhea and nausea), and insomnia. Availability of liquid forms of several SSRIs (fluoxetine, paroxetine, citalopram and sertraline) can make dose titration more convenient.
Another strategy to minimize side effects when initiating SSRIs for patients with panic disorder is to add a low dosage of a benzodiazepine in the first few weeks of treatment. The benzodiazepine should be tapered as the SSRI dosage is raised to therapeutic levels. It is important at the outset to be clear with patients about the intention to prescribe a benzodiazepine for several weeks only.
In most cases, titrating to therapeutic doses of 20 to 40 mg of paroxetine, 50 to 200 mg of sertraline, 100 to 300 mg of fluvoxamine, 20 to 40 mg of fluoxetine, or 20 to 40 mg of citalopram is required. For imipramine, a starting dose of 10 to 20 mg by mouth at night can be gradually titrated up to 75 to 300 mg each night. Venlafaxine may be best tolerated in the sustained release form and can be started as venlafaxine XR 37.5 mg daily, with dose increases in increments of 37.5 mg every one to two weeks until a dose of 150 mg to 300 mg is attained.
A significant percentage of patients (20 to 35 percent) develop sexual side effects after several weeks or months of SSRI therapy, especially a decreased ability to have an orgasm. These adverse effects can lead to medication discontinuation. Addition of bupropion (75 to 150 mg/day in divided doses) or buspirone (15 to 30 mg twice daily) may alleviate decreased libido, diminished sexual arousal, or impaired orgasm.
Benzodiazepines - Several controlled studies have demonstrated the efficacy of benzodiazepines (eg, chlordiazepoxide, diazepam, alprazolam) in the treatment of GAD. Physicians are often reluctant to prescribe these medications because of the potential for abuse. However, abuse is quite rare in practice. Most abusers of benzodiazepines have a history of polydrug or alcohol abuse; these patients should not be prescribed benzodiazepines, especially on a long-term basis.
Many anxious patients who start on benzodiazepines have difficulty stopping them, particularly since rebound anxiety and withdrawal symptoms can be moderate to severe. Benzodiazepines with short elimination half-lives (eg, alprazolam) are particularly apt to cause these problems. Methods of facilitating withdrawal and decreasing rebound symptoms include tapering the medication slowly, converting short-acting benzodiazepines to a long-acting preparation (eg, clonazepam) prior to tapering, and treating the patient with an antidepressant before attempting to taper. In a placebo-controlled study, the success of tapering was significantly enhanced by treatment with imipramine prior to and during the taper. Rebound and withdrawal can also be minimized by short-term cognitive behavioral therapy (eg, several weeks to six months).
Symptoms of anxiety can be alleviated in most cases of GAD with clonazepam 0.25 to 0.5 mg by mouth twice daily titrated up to 1 mg twice daily or three times daily, or lorazepam 0.5 to 1.0 mg by mouth three times daily titrated up to 1 mg by mouth three times daily or four times daily. It is important to gradually titrate these doses to limit unwanted side effects.
Most often an antidepressant is prescribed concomitantly with a benzodiazepine and also gradually titrated with respect to side effects. After six to eight weeks, when the antidepressant begins to have its optimal effects in treating anxiety (and possibly comorbid major depression or panic disorder), the benzodiazepine usually should be tapered.
Tapering typically takes months, achieving roughly a 10 percent dose reduction per week. If symptoms recur it may be difficult to differentiate between benzodiazepine withdrawal or recurrence of GAD symptoms; symptoms that wane within two weeks most likely represent benzodiazepine withdrawal and suggest that the taper rate should be decreased slightly.
Patients with polydrug or alcohol use, chronic pain disorders, and severe personality disorders probably should not be prescribed benzodiazepines in light of high potential in such patients for benzodiazepine dependence. Prolonged use of higher doses of benzodiazepines may warrant referral to a psychiatrist for consideration of alternate therapies.
Buspirone — Buspirone appears to be as effective as the benzodiazepines for the treatment of GAD. However, the onset of action can be several weeks, and there are occasional gastrointestinal side effects. Advantages of using buspirone instead of benzodiazepines include the lack of abuse potential, physical dependence, or withdrawal, and lack of potentiation of alcohol or other sedative-hypnotics. Most patients need to be titrated to doses of 30 to 60 mg per day given in two or three divided doses. One study suggested that recent benzodiazepine use negatively impacted the effect of subsequent buspirone therapy; it is not clear if this was due to benzodiazepine withdrawal symptoms or some other mechanism.
Herbal therapy — Multiple herbal products have been proposed and are being used for treatment of anxiety disorders, with variable evidence of efficacy. Two of the more commonly used are kava kava and valerian.
Providers should ask patients with anxiety if they are using herbal supplements or teas, and document their use. There are concerns about potential drug/herb interactions through cytochrome P450 mechanisms. A discussion of side effects and resources for information about herbal products is presented separately.
Kava kava — Studies on the effectiveness of kava kava for the treatment of generalized anxiety disorder have important methodologic flaws and placebo effects are significant. Kava kava has been associated with fatal hepatotoxicity and the FDA has issued a safety alert. We advise against the use of kava kava for treatment of anxiety.
Valerian — The herbal preparation valerian is principally marketed for treatment of insomnia but has also been used as a mild sedative for anxiety disorders. Clinical studies are inconclusive about its effectiveness for treatment of insomnia. It has been shown to have mild sedative effects in animals, although human studies are not available. Few adverse effects are reported, but there are no data on long-term safety.
LONGTERM TREATMENT — Generalized anxiety disorder, for many patients, is either a chronic disorder that is part of an anxious temperament, or a relapsing-remitting disorder that is provoked by stressful life events. For panic disorder, relapses are less frequent after successful treatment with cognitive behavioral therapy, compared to medication. Patients with the most severe initial symptoms of GAD are less likely to respond to acute treatment; relapse is most likely in patients with residual symptoms.
Longterm recovery in GAD is achieved in only about one third of patients. Many patients will need chronic treatment with medication to prevent relapse; other patients may be treated with intermittent courses of acute treatment. Randomized studies of SSRIs versus placebo have shown longterm benefits of maintenance SSRI treatment after acute treatment response.
