Sheila Botts, Anna Lockwood, and Timothy Allen
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Describe pathophysiologic findings in generalized anxiety, panic, and social anxiety disorder patients.
2. List common presenting symptoms of generalized anxiety, panic, and social anxiety disorders.
3. Identify the desired therapeutic outcomes for patients with generalized anxiety, panic, and social anxiety disorders.
4. Discuss appropriate lifestyle modifications and nonprescription medication use.
5. Recommend psychotherapy and pharmacotherapy interventions for patients with generalized anxiety, panic, and social anxiety disorders.
6. Develop a monitoring plan for anxiety patients placed on specific medications.
7. Educate patients about their disease state and appropriate lifestyle modifications, as well as psychotherapy and pharmacotherapy for effective treatment.
KEY CONCEPTS
The goals of therapy for generalized anxiety disorder (GAD) are to acutely reduce the severity and duration of anxiety symptoms and restore overall functioning. The long-term goal in GAD is to achieve and maintain remission.
Antidepressants are considered first-line agents in the management of chronic GAD.
Benzodiazepines are recommended for acute treatment of GAD when short-term relief is needed, as an adjunct during initiation of antidepressant therapy, or to improve sleep.
The acute phase of panic disorder (PD) treatment lasts about 12 weeks and should result in marked reduction in panic attacks (ideally total elimination) and minimal anticipatory anxiety and phobic avoidance. Treatment should be continued to prevent relapse for an additional 12 to 18 months before attempting discontinuation.
PD patients are more likely to experience stimulant-like side effects of antidepressants than patients with major depression. Antidepressants should be initiated at lower doses in PD patients than in depressed patients or those with other anxiety disorders.
Antidepressants should be tapered when treatment is discontinued to avoid withdrawal symptoms, which include dysphoric mood, irritability, and agitation.
The dose of benzodiazepine required for improvement in PD generally is higher than that used in other anxiety disorders.
Based on their tolerability and efficacy, selective serotonin reuptake inhibitors are considered the drugs of choice for social anxiety disorder.
The onset of response to antidepressants in social anxiety disorder is delayed and may be as long as 8 to 12 weeks. Patients responding to medication should be continued on treatment for at least 1 year.
Pharmacotherapy of social anxiety disorder should lead to improvement in physiologic symptoms of anxiety and fear, functionality, and overall well-being.
Anxiety is a normal response to stressful or fearful circumstances. Most people experience some degree of anxiety in reaction to stressful situations. This allows an individual to adapt to or manage the stressful/threatening situation. Anxiety symptoms generally are short-lived and do not necessarily impair function. Anxiety that becomes excessive, causes irrational thinking or behavior, and impairs a person’s functioning is considered an anxiety disorder.
The diagnosis is often missed or attributed incorrectly to medical illnesses, and most patients are treated inadequately.1 The burden of detection and diagnosis most often falls to primary care clinicians. Untreated anxiety disorders may result in increased health care utilization, morbidity and mortality, and poorer quality of life.
EPIDEMIOLOGY AND ETIOLOGY
Epidemiology
Prevalence
With a lifetime prevalence of 28.8%, anxiety disorders collectively represent the most prevalent psychiatric disorders,2 with specific phobia (12.5%) and social anxiety disorder (SAD) (12.1%) being the most common.3 Recent reports from the National Comorbidity Survey Revised (NCS-R) estimate the lifetime prevalence of generalized anxiety disorder (GAD) for those 18 years of age and older to be 5.7%.3,4Rates for panic disorder (PD) are slightly lower, with an estimated lifetime prevalence of 4.7%.
Most studies report higher rates of anxiety disorders among women (2:1, female:male) and older adults.5 Prevalence rates across the anxiety spectrum increase from the younger age group (18–29) to older age groups (30–44 and 45–59); however, rates are substantially lower for those older than 59 years of age.3
Course of Illness
PD and GAD have a median age of onset of 24 and 31 years, respectively, whereas specific phobia and SAD tend to develop much earlier (median age of onset 7 and 13 years, respectively).3 As many as half of adult anxiety patients report subthreshold symptoms during childhood.6
Anxiety disorders are chronic, and symptoms tend to wax and wane, with less than a third of patients experiencing spontaneous symptom remission.7 The risk for relapse and recurrence of symptoms is also high for anxiety disorders. In a 12-year follow-up study of anxiety disorder patients, recurrence rates ranged from 58% of PD and GAD patients to 39% of SAD patients.8 Remission, if achieved with treatment, is most likely to occur within the first 2 years of an index episode.9 Similarly, the highest rates of relapse are seen within the same timeframe; thus, many patients need ongoing maintenance treatment. Rates of remission and relapse do not appear to vary by gender;9however, one study reported that women with PD without agoraphobia were three times more likely than men to experience a relapse of symptoms. Patients with anxiety disorders spend a significant portion of time “being ill” during a particular episode, ranging from 41% to 80% of the time.8 Expectedly, anxiety disorders are associated with impaired psychosocial functioning and a compromised quality of life.10 Appropriate treatment improves the patient’s overall quality of life and psychosocial functioning.10
Comorbidity
More than 90% of individuals with an anxiety disorder have a lifetime history of one or more other psychiatric disorders.11 Depression is the most common lifetime comorbid illness, followed by alcohol or substance use disorders, and other co-occurring anxiety disorders, especially GAD and PD.11 Generally, the onset of SAD and GAD symptoms precedes major depressive disorder (MDD), whereas there is an equal chance of PD onset before, during, or after MDD. Comorbid psychiatric illness is associated with lower rates of remission and higher rates of relapse. It is essential that both disorders are treated appropriately.
Etiology
Both genetic and psychosocial factors appear to play a role in the initiation and expression of anxiety disorders.12 Moderate genetic risk has been documented for all anxiety disorders. Currently, no definitive gene or set of genes has been identified as being the causative factor for a specific anxiety disorder. It is unclear if anxiety disorders share common genetic risk factors. Genetic overlap may exist between GAD and PD and, to a lesser extent, SAD.12
Genetics may create a vulnerable phenotype for an anxiety disorder, and an individual’s life stressors and means of coping with the stress may also play a role in precipitation and continuation of the anxiety disorder.13 Some researchers believe that stressful life events may play a strong role in the onset of anxiety disorders, especially in GAD and PD.12 It has been reported that those experiencing one or more negative life events have a threefold increased chance of developing GAD.5 Similar findings have been reported with PD.13
PATHOPHYSIOLOGY
The thalamus and amygdala are important in the generation of a normal fear response and play a central role in most anxiety disorders. The thalamus provides the first real processing region to organize sensory data obtained from the environment. It passes information to higher cortical centers for finer processing and to the amygdala for rapid assessment of highly charged emotional information. The amygdala provides the emotional importance of the information. This helps the organism to act quickly on ambiguous but vital events. The cortex then performs a more detailed analysis, and sends updates to the amygdala for comparison and any needed course corrections, thus enabling a decision on a course of action.
Anxiety can become independent of stimuli as in PD, be associated with benign stimuli as in phobias, or continue beyond the stimulus duration as in GAD. The precise mechanism by which these changes occur is unknown, but much has been discovered regarding how this may be regulated by treatment (Fig. 40–1).
Direct and indirect connections to the reticular activating system (RAS), a region spanning the medulla, pons, and midbrain, help to regulate arousal, vigilance, and fear. These connections are modulated by serotonin and norepinephrine, which have their primary origins in the RAS.14 The amygdala sends projections to the hypothalamus, thus influencing the autonomic nervous system to affect heart rate, blood pressure, and stress-associated changes. It also influences the hypothalamic–pituitary–adrenal (HPA) axis, leading to a cascade of stress hormones.15 One such hormone is cortisol, which, if elevated for prolonged periods, can damage the brain and other organs. These are important targets in our understanding of how the amygdala regulates the fear response.
FIGURE 40–1. Neurocircuitry and key neurotransmitters involved in mediating anxiety disorders.
Noradrenergic System
Norepinephrine (NE)-producing cells reside primarily in a region of the brain called the locus ceruleus (LC). Increased activity in this region is associated with an increase in arousal, anxiety, and panic. Drugs such as yohimbine that increase activity in the LC can be anxiogenic, whereas drugs that decrease activity in the LC appear to improve anxiety symptoms. Furthermore, dysregulation of this region is implicated by elevated levels of NE or its metabolites in subjects with GAD, PD, and specific phobias.15
Serotonergic System
The raphe nuclei and the resident cell bodies of serotonin (5-HT)-producing neurons over time inhibit firing of noradrenergic cells in the LC. They also regulate cells in the prefrontal cortex and amygdala. Perhaps the strongest evidence for the involvement of the serotonergic system is the success of serotonin reuptake inhibitors in treatment of anxiety disorders.15
γ-Aminobutyric Acid
γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter. The effects of GABA are nonspecific, and its role is complex. GABAergic drugs are used for acute anxiety reduction, but the lack of a specific target for their effect leads to multiple undesirable effects. Current research is focused on defining receptor subtypes that may allow for greater specificity in targeting anxiety symptoms.16
Hypothalamic–Pituitary–Adrenal Axis
The HPA axis provides a critical mechanism for regulation of the stress response and its effects on the brain and other organ systems. Several important hormones, including corticotropin-releasing hormone and cortisol regulate the effects of anxiety on the body and provide positive feedback to the brain.15 A cycle of anxiety and sensitization by such feedback could, if unchecked, result in escalation of symptoms. Neuropeptides may provide one mechanism to balance positive and negative feedback, helping to minimize such escalation.
Neuropeptides
Several neuropeptides are under investigation for their role in anxiety disorders. Important neuropeptides include neuropeptide Y (NPY), substance P, and cholecystokinin. NPY appears to reduce the effect of stress hormones and inhibits activity of the LC. Both mechanisms may contribute to the anxiolytic properties seen experimentally. Substance P may have anxiolytic and antidepressant properties due in part to its effects on corticotropin-releasing hormone.17
GENERALIZED ANXIETY DISORDER
TREATMENT
Desired Outcomes
The goals of therapy for GAD are to acutely reduce the severity and duration of anxiety symptoms and restore overall functioning. The long-term goal in GAD is to achieve and maintain remission. With a positive response to treatment, patients with GAD and comorbid depression should have minimal depressive symptoms.
Clinical Presentation and Diagnosis of GAD
General
Onset is typically in early adulthood. Anxiety emerges and dissipates more gradually than in PD. Laboratory evaluation usually is reserved for later onset, atypical presentation, or poor response to treatment.
Symptoms2
Excessive anxiety or worry involving multiple events or activities occurring more days than not for at least 6 months and associated with at least three of the following:
• Restlessness
• Easily fatigued
• Poor concentration
• Irritability
• Muscle tension
• Insomnia or unsatisfying sleep
Differential Diagnosis
Rule out underlying medical or psychiatric disorders and medications that may cause anxiety (Tables 40–1 and 40–2)
Laboratory Evaluation
• Basic metabolic panel
• Thyroid-stimulating hormone (TSH)
• Polysomnogram
Table 40–1 Medical Conditions That Can Cause Anxiety
|
Psychiatric Disorders |
|
Mood disorders, hypochondriasis, personality disorders, alcohol/substance abuse, alcohol/substance withdrawal, other anxiety disorders |
|
Neurologic Disorders |
|
CVA, seizure disorders, dementia, stroke, migraine, encephalitis, vestibular dysfunction |
|
Cardiovascular Disorders |
|
Angina, arrhythmias, congestive heart failure, mitral valve prolapse, myocardial infarction |
|
Endocrine and Metabolic Disorders |
|
Hypo/hyperthyroidism, hypoglycemia, Cushing’s disease, Addison’s disease, pheochromocytoma, hyperadrenocorticism, hyponatremia, hyperkalemia, vitamin B12 deficiency |
|
Respiratory Disorders |
|
Asthma, COPD, pulmonary embolism, pneumonia, hyperventilation |
|
Other |
|
Carcinoid syndrome, anemias, systemic lupus erythematosus |
COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident.
From Refs. 2, 18, 19.
Table 40–2 Medications Associated With Anxiety Symptoms
Patient Encounter 1, Part 1
AX, a 27-year-old African American woman, presents to your clinic with GI complaints (e.g., constipation, bloating, and cramping) and fatigue. She is a single mother of three (ages 2, 3, and 6 years) and is a full-time college student. She states that she worries about everything: her grades, finances, the 6-year-old riding the school bus, etc. She states that “even if it’s not important, I still worry.” She has difficulty sleeping and says that she often feels like she might jump out of her skin. On one occasion she felt like she might be having a “heart attack or something.”
What manifestations described above are suggestive of an anxiety disorder?
What additional information do you need to establish a diagnosis and develop a treatment plan?
General Approach to Treatment
Patients with GAD may be managed with psychotherapy, pharmacotherapy, or both. The treatment plan should be individualized based on symptom severity, comorbid illnesses, medical status, age, and patient preference. Patients with severe symptoms resulting in functional impairment should receive antianxiety medication.
Patient Encounter 1, Part 2
AX returns to your clinic 4 months later stating that despite meeting with the school psychologist a few times, she continues to have problems. In addition to worrying and feeling nervous, she feels down a lot. “I don’t have the energy to play with my children. I obsess over everything. My grades have really gone downhill. I cry a lot and feel hopeless.”
PMH: IBS, GAD
FH: Mother treated for depression; father, ethanol dependence
SH: Drinks ethanol occasionally; cigarettes one pack a day; lives independently with three children
Meds: Centrum multivitamin
Given this information, what is your assessment of this patient?
Develop a treatment plan, including nonpharmacologic and pharmacologic recommendations, duration of therapy, and monitoring plan.
Nonpharmacologic Therapy
Nonpharmacologic therapy includes psychoeducation, exercise, stress management, and psychotherapy. Psychoeducation should include instructing patients to avoid stimulating agents such as caffeine, decongestants, diet pills, and excessive alcohol use. Regular exercise is also recommended. Cognitive-behavioral therapy (CBT), the most effective psychological therapy for GAD patients, helps patients to recognize and alter patterns of distorted thinking and dysfunctional behavior. Some trials suggest that treatment gains with CBT may be maintained for up to 1 year.21 The combination of CBT and an antidepressant may be more effective than either treatment alone. In a recent study, 80.7% of children were much improved on the combination of CBT and an antidepressant, versus 54.9% with sertraline and 59.7% with CBT alone.22
Pharmacologic Therapy
Antidepressants, benzodiazepines, buspirone, hydroxyzine, pregabalin, and the second-generation antipsychotics (SGAs), olanzapine and risperidone, have controlled clinical trial data supporting their use in GAD. Antidepressants have replaced benzodiazepines as the drugs of choice for chronic GAD owing to a tolerable side-effect profile, no risk for dependency, and efficacy in common comorbid conditions including depression, panic, obsessive-compulsive disorder (OCD), and SAD. Benzodiazepines remain the most effective and commonly used treatment for short-term management of anxiety where immediate relief of symptoms is desired. They are also recommended for intermittent or adjunctive use during GAD exacerbation or for sleep disturbance during the initiation of antidepressant treatment.27Buspirone and pregabalin are alternative agents for patients with GAD without depression. Hydroxyzine is usually adjunctive and is less desirable for long-term treatment owing to side effects including sedation and anticholinergic effects.
Patients with GAD should be treated to remission of symptoms. Most guidelines recommend continuing treatment for an additional 3 to 10 months.21,23–25 An algorithm for the pharmacologic management of GAD is shown in Figure 40–2.
Antidepressants
Antidepressants (Table 40–3) are considered first-line agents in the management of chronic GAD. These agents reduce the psychic symptoms (e.g., worry and apprehension) of anxiety with a modest effect on autonomic or somatic symptoms (e.g., tremor, rapid heart rate, and/or sweating). All antidepressants evaluated provide a similar degree of anxiety reduction. The onset of antianxiety effect is delayed 2 to 4 weeks. Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are usually preferred over tricyclic antidepressants (TCAs) such as imipramine owing to improved safety and tolerability. Selection of a particular antidepressant agent generally is based on history of prior response, side-effect profile, drug interaction profile (discussed in Chap. 38), cost, or formulary availability.
FIGURE 40–2. Treatment algorithm for GAD. (BZ, benzodiazepine; SSRI, selective serotonin reuptake inhibitor); SNRI, serotonin-norepinephrine reuptake inhibitor. (Adapted, from Kirkwood CK, Melton ST. Anxiety disorders: I. Generalized anxiety, panic and social anxiety disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1163–1178.)
Table 40–3 Antidepressants Used in the Treatment of GAD
Antidepressants modulate synaptic 5-HT, NE, and/or dopamine (DA) reuptake and receptor-activated neuronal signal transduction. These intracellular changes ultimately modify the expression of genes and proteins important in stress response (e.g., increase messenger RNA [mRNA] for glucocorticoid receptors and brain-derived neurotrophic factor and decrease mRNA expression for corticotropin-releasing factor).26 Activation of these “stress-adapting” pathways is thought to improve both somatic and psychic symptoms of anxiety.27
Serotonin-Norepinephrine Reuptake Inhibitors
Venlafaxine and duloxetine alleviate anxiety in GAD patients with and without depression. Venlafaxine was shown to reduce anxiety effectively at doses 75 to 225 mg/day, and response was maintained over an additional 6 months of treatment.28 Venlafaxine has more favorable safety and side-effect profiles than TCAs. The most common venlafaxine side effects reported by GAD patients are nausea, somnolence, dry mouth, dizziness, sweating, constipation, and anorexia.28
Duloxetine is effective for the treatment of GAD as well, but long-term efficacy has not yet been established. At 60 to 120 mg/day, its efficacy is noninferior to venlafaxine, and tolerability is similar.29 For patients with concurrent pain syndromes, duloxetine has been found to improve anxiety, pain, and functional impairment when compared to placebo.30
Selective Serotonin Reuptake Inhibitors
The SSRIs paroxetine, escitalopram, and sertraline have been shown to be significantly more effective than placebo in reducing anxiety symptoms. Paroxetine at doses of 20 and 40 mg/day achieved response in 62% and 68% of patients, respectively, over 8 weeks of treatment.31 Remission occurred in 30% and 36%, respectively. In a 24-week relapse-prevention study, paroxetine was more effective than placebo at maintaining response, and patients were more likely to achieve remission with continued treatment (42.5% at 8 weeks versus 73% at 24 weeks).32 In GAD trials, paroxetine was associated with a high rate of somnolence, nausea, abnormal ejaculation, dry mouth, decreased libido, and asthenia compared with placebo.31
Escitalopram, in a dose range of 10 to 20 mg/day, was more effective than placebo in patients with GAD without depression. Fifty-eight percent of patients on escitalopram achieved response versus 38% on placebo over the 8 weeks of treatment.30 Side effects included headache, nausea, somnolence, upper respiratory tract infection, decreased libido, ejaculation disorder, and anorgasmia.33
Sertraline was more efficacious than placebo in patients with GAD being treated for 12 weeks. Sertraline treatment resulted in 56% of patients achieving response, whereas 31% achieved remission.34 Side effects included increased rates of nausea, insomnia, sweating, decreased libido, diarrhea, fatigue, and ejaculation disorder.34 Citalopram has been shown to be efficacious in the treatment of GAD in the elderly.35 Limited comparative trial data suggest comparable outcomes between these SSRIs.36,37 SSRI therapy is better tolerated than TCAs, and tolerability is similar to that with venlafaxine.
Tricyclic Antidepressants
Imipramine provided a higher rate of remission of anxiety symptoms than trazodone, diazepam, or placebo (e.g., 73% versus 69% versus 66% versus 47%) in an 8-week controlled trial of GAD patients.38Antidepressants were more effective than diazepam or placebo in reducing psychic symptoms of anxiety. The use of TCAs generally is limited by bothersome adverse effects (e.g., sedation, orthostatic hypotension, anticholinergic effects, and weight gain). TCAs have a narrow therapeutic index and are lethal in overdose due to atrioventricular (AV) heart block.
Novel Antidepressants
Mirtazapine, an α-2 adrenergic antagonist and postsynaptic serotonin (5-HT2, 5-HT3) receptor antagonist, is an effective antidepressant but has not been extensively evaluated in anxiety disorders. One open-label study found treatment of GAD for 12 weeks with mirtazapine 30 mg to be efficacious and well tolerated.39 Mirtazapine is not associated with sexual dysfunction, a common antidepressant side effect, but does have a greater propensity to cause sedation and weight gain. Bupropion, a dopamine and norepinephrine reuptake inhibitor, lacks the common antidepressant side effects of weight gain and sexual dysfunction. Bupropion has not been studied or used extensively in anxiety disorders owing to its stimulating effects that would be expected to worsen anxiety symptoms. However, a pilot-controlled trial comparing bupropion XL to escitalopram found buproprion to have comparable anxiolytic efficacy and tolerability.40
Benzodiazepines
Benzodiazepines are recommended for acute treatment of GAD when short-term relief is needed, as an adjunct during initiation of antidepressant therapy, or to improve sleep.21,23 Benzodiazepine treatment results in a significant improvement in 65% to 75% of GAD patients, with most of the improvement occurring in the initial 2 weeks of therapy.38 They are more effective in reducing somatic symptoms of anxiety than psychic symptoms. The major disadvantages of benzodiazepines are their lack of effectiveness in treating depression, the risk for dependency and abuse, and potential interdose rebound anxiety especially with short-acting formulations. Benzodiazepines should be avoided in patients with chemical dependency.
Benzodiazepines exert their effects by enhancing transmission of the inhibitory neurotransmitter GABA through interaction with the GABAA receptor complex.41 Although all benzodiazepines possess anxiolytic properties, only 7 of the 13 currently marketed agents are approved by the FDA for the treatment of anxiety disorders (Table 40–4). All benzodiazepines are expected to provide equivalent benefit when given in comparable doses. Benzodiazpines differ substantially in their pharmacokinetic properties and potency for the GABAA receptor site.
Benzodiazepines are metabolized by hepatic oxidation (cytochrome P450 3A4) and glucuronide conjugation. Because lorazepam and oxazepam bypass hepatic oxidation and are conjugated only, they are preferred agents for patients with reduced hepatic function secondary to aging or disease (e.g., cirrhosis commonly seen in patients abusing alcohol or with Hepatitis B/C from IV drug use). Many benzodiazepines are metabolized to long-acting metabolites (Table 40–4) that provide long-lasting anxiety relief. Drugs that either inhibit or induce CYP450 isozymes or glucuronidation are the major source of drug interactions (Table 40–5).
The most common side effects associated with benzodiazepine therapy include CNS depressive effects (e.g., drowsiness, sedation, psychomotor impairment, and ataxia) and cognitive effects (e.g., poor recall and anterograde amnesia). Anterograde amnesia is more likely to occur with high-potency benzodiazepines, such as lorazepam or alprazolam.42 Some patients also may be disinhibited with benzodiazepine treatment and experience confusion, irritability, aggression, and excitement.42 Discontinuation of benzodiazepines may be associated with withdrawal, rebound anxiety, and a high rate of relapse. Higher doses of benzodiazepines and longer duration of therapy increase the severity of withdrawal and risk of seizures after abrupt or rapid discontinuation. Patients should be tapered rather than discontinued abruptly from benzodiazepine therapy to avoid withdrawal symptoms. The duration of the taper should increase with extended duration of benzodiazepine therapy.24 For example, patients on benzodiazepine therapy over 2 to 6 months should be tapered over 2 to 8 weeks, whereas patients receiving 12 months of treatment should be tapered over 2 to 4 months. A general approach to the taper is to reduce the dose by 25% every 5 to 7 days until reaching half the original dose and then decreasing by 10% to 12% per week until discontinued. Patients should expect minor withdrawal symptoms and discomfort even when tapering. Rebound symptoms (e.g., return of original symptoms at increased intensity) are transient. The patient should be counseled so that rebound anxiety is not interpreted as a relapse. Relapse or recurrence of anxiety may occur in as many as 50% of patients discontinuing benzodiazepine treatment.38 It is unclear if this relapse rate represents an inferiority of benzodiazepines or supports the chronic nature of GAD.
Buspirone
Buspirone, a 5-HT1A partial agonist, is thought to exert its anxiolytic effects by reducing presynaptic 5-HT firing.43 Unlike benzodiazepines, it does not have abuse potential, cause withdrawal reactions, or potentiate alcohol and sedative-hypnotic effects. However, it has a gradual onset of action (i.e., 2 weeks) and does not provide immediate anxiety relief. Buspirone is considered a second-line agent for GAD owing to inconsistent data regarding its efficacy in chronic GAD or GAD with comorbid depression.21,23 Some research suggests that buspirone is less effective in patients who have been treated previously (4 weeks to 5 years) with benzodiazepines.44
Table 40–4 Benzodiazepine Comparison
Buspirone should be initiated at a dose of 7.5 mg twice daily and titrated in 5 mg/day increments (every 2–3 days) to a usual target dose of 20 to 30 mg/day.44 The maximum daily dose is considered to be 60 mg/day.
Buspirone generally is well tolerated and does not cause sedation. The most common side effects include dizziness, nausea, and headaches. Drugs that inhibit CYP3A4 (e.g., verapamil, diltiazem, itraconazole, fluvoxamine, nefazodone, and erythromycin) can increase buspirone levels. Likewise, enzyme inducers such as rifampin can reduce buspirone levels significantly. Bupirone may increase blood pressure when coadministered with a monoamine oxidase inhibitor (MAOI).
Alternative Agents
Hydroxyzine, pregabalin, and adjunctive SGAs are alternative agents. Hydroxyzine may be effective for acute reduction of somatic symptoms of anxiety.23 It does not improve psychic features of anxiety and does not treat depression or other common comorbid anxiety disorders.
Pregabalin is mechanistically unique for an anxiolytic. It is a presynaptic modulator of excessive excitatory neurotransmitter release. It accomplishes this by selectively binding to the α2-δ subunit of voltage-gated calcium channels. In a 4-week controlled trial versus alprazolam and placebo, pregabalin was effective for both somatic and psychic symptoms of anxiety with an onset of effect similar to that of alprazolam.45 Compared to venlafaxine and placebo, pregabalin was found to be safe, well-tolerated, and efficacious in GAD, and results were seen 1 week sooner than with venlafaxine.46 Pregabalin has an elimination half-life of approximately 6 hours and must be dosed two to three times daily. It is excreted renally and has a low risk of drug–drug interactions. Pregabalin is a schedule V controlled substance owing to a propensity to cause euphoria and risk of withdrawal symptoms when discontinued abruptly. Pregabalin should be used with caution in patients with a current or past history of substance abuse. It is not beneficial for depression or other anxiety disorders, and long-term effectiveness in GAD is not established.
Table 40–5 Pharmacokinetic Drug Interactions With Benzodiazepines
Atypical antipsychotics have recently been evaluated for anxiety. Both quetiapine and aripiprazole were effective in reducing anxiety symptoms when added to an antidepressant.47,48 However, several other studies of SGAs have failed to demonstrate a significant improvement in anxiety symptoms in poorly responsive patients. Given their risk for metabolic side effects including weight gain, increased triglycerides, and diabetes, compelling effectiveness data are needed to consider these agents as first- or second-line treatment options.
Outcome Evaluation
Assess patients for improvement of anxiety symptoms and for return to baseline occupational, social, and interpersonal functioning. With effective treatment, the patient should have no or minimal symptoms of anxiety or depression. While drug therapy is being initiated, evaluate patients more frequently to ensure tolerability and response. Increase the dose in patients exhibiting a partial response after 2 to 4 weeks on an antidepressant or 2 weeks on a benzodiazepine. Individualize the duration of treatment because some patients require up to 1 year of treatment.24
PANIC DISORDER
TREATMENT
Desired Outcomes
The main objectives of treatment are to reduce the severity and frequency of panic attacks, reduce anticipatory anxiety and agoraphobic behavior, and minimize symptoms of depression or other comorbid disorders.49 The long-term goal is to achieve and sustain remission.
General Approach to Treatment
Treatment options include medication, psychotherapy (e.g., CBT preferred), or a combination of both. In some cases, pharmacotherapy will follow psychotherapy treatments when full response is not realized. Patients with panic symptoms without agoraphobia may respond to pharmacotherapy alone. Agoraphobic symptoms generally take longer to respond than panic symptoms. The acute phase of PD treatment lasts about 12 weeks and should result in marked reduction in panic attacks (ideally total elimination), minimal anticipatory anxiety, and phobic avoidance. Treatment should be continued to prevent relapse for an additional 12 to 18 months before attempting discontinuation.49,50 Patients who relapse following discontinuation of medication should have therapy resumed.49,50
Clinical Presentation and Diagnosis of PD
General
Typically presents in late adolescence or early adulthood. Onset in older adults increases suspicion of relationship to medical disorders or substance use. Laboratory evaluation must be driven by history and physical examination.
Symptoms2
Recurrent, discrete episodes that typically develop rapidly and peak within 10 minutes involving at least four of the following symptoms:
• Palpitations or rapid heart rate
• Sweating
• Trembling or shaking
• Sensation of shortness of breath or smothering
• Feeling of choking
• Chest pain or discomfort
• Feeling dizzy or lightheaded
• Feelings of unreality or being detached from oneself
• Fear of dying
• Numbness or tingling sensation
• Chills or hot flushes
Differential Diagnosis
Rule out underlying medical or psychiatric disorders and medications that may cause anxiety (Tables 40–1 and 40–2).
Laboratory Evaluation
• Urine drug screen
• Basic metabolic panel
• TSH
• Electrocardiogram
• Holter monitor
• Electroencephalogram
• Urine vanillylmandelic acid (VMA)
Nonpharmacologic Therapy
Patients with PD should be counseled to avoid stimulant agents (e.g., decongestants, diet pills, and caffeine) that may precipitate a panic attack. CBT consists of psychoeducation, continuous panic monitoring, breathing retraining, cognitive restructuring, and exposure to fear cues.50 CBT may involve these features to varying degree. Panic-focused psychodynamic psychotherapy (PFPP) focuses on underlying meaning of panic symptoms (e.g., they have a specific emotional significance) and on current social and emotional functioning.50 PFPP may be used alone or with other modalities. Exposure therapy is useful for patients with phobic avoidance. CBT is considered a first-line treatment of PD, with efficacy similar to that of pharmacotherapy. In a large placebo-controlled trial comparing CBT with imipramine or combination (CBT + imipramine), CBT was as effective as the antidepressant after 12 weeks. Patients receiving CBT were less likely to relapse during the 6 months after treatment discontinuation.51,52 In a recent trial of PD with or without agoraphobia, SSRI plus CBT therapy was more effective than SSRI or CBT monotherapy after 9 months of treatment.53
Pharmacologic Therapy
PD may be treated successfully with TCAs, SSRIs, SNRIs, or MAOIs, as well as benzodiazepines50,52 (Table 40–6). While all these agents are similarly effective, SSRIs have become the treatment of choice in PD. Benzodiazepines often are used concomitantly with antidepressants, especially early in treatment, or as monotherapy to acutely reduce panic symptoms. Benzodiazepines are not preferred for long-term treatment but may be used when patients fail several antidepressant trials.49,50 PD patients with comorbid depression should be treated with an antidepressant. An algorithm for pharmacologic management of PD appears in Figure 40–3.
Antidepressants
Antidepressants have a delayed onset of antipanic effect, typically 4 weeks, with optimal response at 6 to 12 weeks. Reduction of anticipatory anxiety and phobic avoidance generally follows improvement in panic symptoms. PD patients are more likely to experience stimulant-like side effects of antidepressants than patients with major depression. Antidepressants should be initiated at lower doses (Table 40–6) in PD patients than in depressed patients or those with other anxiety disorders. Target doses are similar to those used in depression. Antidepressants should be tapered when treatment is discontinued to avoid withdrawal symptoms including irritability, agitation, and dysphoria.
Tricyclic Antidepressants
Treatment with imipramine, the most studied TCA, leaves 45% to 70% of patients panic-free. Both desipramine and clomipramine have demonstrated effectiveness in PD as well. Despite their efficacy, TCAs are rendered second-line pharmacotherapy due to poorer tolerability, patient acceptance, and toxicity on overdose.49,50 TCAs are associated with a greater rate of discontinuation from treatment than SSRIs.54PD patients taking TCAs may experience anticholinergic effects, orthostatic hypotension, sweating, sleep disturbances, dizziness, fatigue, sexual dysfunction, and weight gain. Stimulant-like side effects occur in up to 40% of patients.49,50
Table 40–6 Antidepressants Used in the Treatment of PD
Selective Serotonin Reuptake Inhibitors
SSRIs are the drugs of choice for PD. All SSRIs have demonstrated effectiveness in controlled trials, with 60% to 80% of patients achieving a panic-free state.25,49,50 With similar efficacy reported and no trials comparing different SSRIs, selection generally is based on pharmacokinetics, drug interactions, side effects, and cost differences (see Chap. 38). The most common side effects of SSRIs include headaches, irritability, nausea and other GI complaints, insomnia, sexual dysfunction, increased anxiety, drowsiness, and tremor.49,50
Serotonin-Norepinephrine Reuptake Inhibitors
Venlafaxine is FDA approved for the treatment of PD. In doses of 75 to 225 mg/day, it reduced panic and anticipatory anxiety in short-term controlled trials, and it prevents relapse with extended treatment over 6 months.55,56 The most common side effects include anorexia, dry mouth, constipation, somnolence, tremor, abnormal ejaculation, and sweating.
Monoamine Oxidase Inhibitors
MAOIs have not been evaluated systematically for treatment of PD under the current diagnostic classification and generally are reserved for patients who are refractory to other treatments.49,50 They have significant side effects that limit adherence. Additionally, patients must adhere to dietary restriction of tyramine and avoid sympathomimetic drugs to avoid hypertensive crisis (see Chap. 38).
The reversible inhibitors of monoamine oxidase A (RIMAs) (brofaromine and meclobemide) have been studied with mixed results.49 Neither is approved for use in the United States, but they are available in Canada.
Other Drugs
Bupropion, trazodone, and nefazodone are not recommended for treatment of PD.50
Benzodiazepines
Benzodiazepines are effective antipanic agents with significant effects on anticipatory anxiety and phobic behaviors. Alprazolam, the one studied most extensively, is associated with significant panic reduction after 1 week of therapy (e.g., 55–75% panic-free).49,50 Benzodiazepines achieve similar outcomes to antidepressants over extended treatment, but benzodiazepine-treated patients are more likely to relapse when the drug is discontinued.49,50 The risk for dependence and withdrawal and lack of efficacy for depression are significant concerns for long-term treatment of PD. There is no evidence that tolerance to therapeutic effect does occur. In fact, patients do not require dose escalation during extended treatment. Patients with PD do experience greater rebound anxiety and relapse when discontinuing benzodiazepines than do GAD patients. Tapering should be done at a slower rate and over a more extended period of time than with other anxiety disorders.25,49,50
FIGURE 40–3. Algorithm for the pharmacotherapy of panic disorder. BZ, benzodiazepines; SSRIs, selective serotonin reuptake inhibitors (Adapted from Kirkwood CK, Melton ST. Anxiety disorders: I. Generalized anxiety, panic and social anxiety disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1163-1178.)
The dose of benzodiazepine required for improvement generally is higher than that used in other anxiety disorders, and this may explain why high-potency agents such as alprazolam and clonazepam generally are preferred. Lorazepam and diazepam, when given in equivalent doses, produce similar treatment benefits.49 Doses should be titrated to response (Table 40–4). The use of extended-release alprazolam or clonazepam will minimize breakthrough panic symptoms that are sometimes observed with immediate-release alprazolam.57
Side effects associated with benzodiazepines in PD patients are similar to those observed in other disorders. Sedation, fatigue, and cognitive impairment are the most commonly reported side effects.49Benzodiazepines should be avoided in patients with current or past substance abuse/dependence or sleep apnea. Additionally, caution should be used in older adults because they have more pronounced psychomotor and cognitive effects.
β-Blockers
Pindolol 25 mg three times a day has been shown effective as an adjunctive treatment for PD when used with an SSRI.58 Propranolol 120 to 240 mg/day has been found equivalent to alprazolam in reduction of panic attacks.59 β-Blockers are not expected to reduce psychic anxiety or avoidance behavior. Additionally, heart rate and blood pressure reduction are dose-related adverse events that may limit use.
Outcome Evaluation
Evaluate patients for symptom improvement frequently (e.g., weekly) during the first 4 weeks of therapy. The goal is to alleviate panic attacks and reduce anticipatory anxiety and phobic avoidance with resumption of normal activities. Alter the therapy of patients who do not achieve a significant reduction in panic symptoms after 6 to 8 weeks of an adequate dose of antidepressant or 3 weeks of a benzodiazepine. Strategies may include augmentation (e.g., add CBT if already on medication) or switch to another medication or treatment modality. Regularly evaluate patients for adverse effects, and educate them about appropriate expectations of drug therapy.
Once the patient has achieved a significant response, continue therapy for at least 1 year. Evaluate for symptom relapse as well as adverse effects that may emerge with continued treatment (e.g., weight gain and sexual dysfunction). During drug discontinuation, monitor frequently for withdrawal, rebound anxiety, and relapse.
SOCIAL ANXIETY DISORDER
TREATMENT
Desired Outcomes
SAD is a chronic disorder that begins in adolescence and occurs with significant functional impairment and high rates of comorbidity. The goal of acute treatment is to reduce physiologic symptoms of anxiety, fear of social situations, and phobic behaviors. Patients with comordid depression should have a significant reduction in depressive symptoms. The long-term goal is to restore social functioning and improve the patient’s quality of life.
General Approach to Treatment
Patients with SAD may be managed with pharmacotherapy or psychotherapy. There is insufficient evidence to recommend one treatment over the other, and data are lacking on the benefits of combining treatment modalities. Pharmacotherapy often is the first choice of treatment owing to relative greater access and reduced cost compared with psychotherapy.60 Patients with SAD generally respond slowly to treatment, and many will not achieve a full response. Relapse is common when patients are discontinued after effective short-term treatment. Patients generally are continued on treatment for at least 1 year before attempting discontinuation.
Clinical Presentation and Diagnosis of SAD
General
Often occurs in context of other anxiety disorders. The feared social or performance situation can be limited to a specific social interaction (e.g., public speaking) or generalized to most any social interaction. Differs from specific phobia, in which the fear and anxiety are limited to a particular object or situation (e.g., insects, heights, public transportation).
Symptoms2
• Persistent fear of social interactions, during which time the individual is concerned about being embarrassed or being under scrutiny.
• Engaging in the feared activities can lead to extreme anxiety and panic.
• The fear leads to distress or avoidance of the situation sufficient enough to cause trouble in the patient’s life.
Differential Diagnosis
Rule out underlying medical or psychiatric disorders and medications that may cause anxiety (Tables 40–1 and 40–2).
Laboratory Evaluation
Laboratory investigation is of limited value and should be pursued only in context of other history or physical examination findings.
Nonpharmacologic Therapy
Patient education on disease course, treatment options, and expectations is essential given the chronic nature and functional impairment of SAD. Support groups may be beneficial for some patients. CBT targets avoidance-learning and negative-thinking patterns associated with social anxiety by exposing the patient to a feared situation. CBT is effective for reducing anxiety and phobic avoidance and leads to a greater likelihood of maintaining response after treatment discontinuation than does pharmacotherapy.60
Pharmacologic Therapy
Several pharmacologic agents have demonstrated effectiveness in SAD, including SSRIs, venlafaxine, phenelzine, RIMAs, benzodiazepines, gabapentin, and pregabalin. SSRIs are considered the drugs of choice based on their tolerability and efficacy for SAD and comorbid depression if present. The onset of response for antidepressants may be as long as 8 to 12 weeks.25,61 Patients responding to medication should be continued on treatment for at least 1 year. Many will relapse when medication is discontinued, and there are no clear predictive factors for who will maintain response.61 Some patients may elect more long-term treatment owing to fear of relapse. A suggested treatment algorithm is shown in Figure 40–4.
Patient Encounter 2
BB, a 34-year-old white woman with generalized SAD is transferring her care to your clinic. She has been maintained on diazepam 10 mg twice daily for the past 4 years for her SAD. She states that her current therapy has her anxiety under control, and she is performing her duties as an office manager without problems. She has joined a gym recently and is attending a church social for single women once monthly. She has noticed she has difficulty thinking “sharply” and is more forgetful. She occasionally feels sad and becomes tearful but is usually able to “pick herself up.” She is moderately overweight (BMI 29) with no other current medical problems. Denies ethanol or other substance use.
Develop a treatment plan for this patient. Include (a) goals of therapy, (b) a detailed therapeutic plan, and (c) a monitoring plan for recommended therapy.
Selective Serotonin Reuptake Inhibitors and Venlafaxine
The efficacy of paroxetine, sertraline, and escitalopram was established in large controlled trials.60–63 SSRIs improve social anxiety and phobic avoidance and reduce overall disability. Approximately 50% of patients achieve response during acute treatment. Limited data suggest that both fluvoxamine and citalopram are effective in SAD. Fluoxetine is not effective.60,61
The initial dose of SSRI is similar to that used in depression. Patients should be titrated as tolerated to response. Many patients will require maximum recommended daily doses. Patients with comorbid PD should be started on lower doses (Table 40–6). When discontinuing SSRIs, the dose should be tapered slowly to avoid withdrawal symptoms. Relapse rates may be as high as 50%, and patients should be monitored closely for several weeks.60,61 Side effects of SSRIs in SAD patients are similar to those seen in depression and most commonly include nausea, sexual dysfunction, somnolence, and sweating.
FIGURE 40–4. Algorithm for the pharmacotherapy of SAD. BZ, benzodiazepines; SSRI, selective serotonin reuptake inhibitor (Adapted from Kirkwood CK, Melton ST. Anxiety disorders: I. Generalized anxiety, panic and social anxiety disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1163–1178.)
Venlafaxine extended release, in doses of 75 to 225 mg/day, improves social anxiety, performance, and avoidance behavior with a reduction in disability.64 Treatment with venlafaxine results in response rates similar to those seen with paroxetine.64 Venlafaxine may be effective in SSRI nonresponders.65 As with SSRIs, doses should be tapered slowly when discontinuing therapy. Tolerability is similar to that observed in depression trials with venlafaxine extended release. Common side effects are anorexia, dry mouth, nausea, insomnia, and sexual dysfunction.
MAOIs/Reversible Inhibitors of MAO-A
Phenelzine is effective in 64% to 69% of SAD patients.61 It is generally reserved for treatment-refractory patients owing to dietary restrictions,66 drug interactions, and side effects. The RIMAs brofaromine and meclobemide are effective in SAD. Neither is currently available in the United States, but they are available in Canada.
Alternative Agents
Benzodiazepines
Benzodiazepines are used commonly in SAD; however, there are limited data supporting their use. Clonazepam has been effective for social anxiety, fear, and phobic avoidance, and it reduced social and work disability during acute treatment.61 Long-term treatment is not desirable for many SAD patients owing to the risk of withdrawal and difficulty with discontinuation, cognitive side effects, and lack of effect on depressive symptoms. Benzodiazepines may be useful for acute relief of physiologic symptoms of anxiety when used concomitantly with antidepressants or psychotherapy. Benzodiazepines are contraindicated in SAD patients with alcohol or substance abuse or history of such.
Anticonvulsants (Gabapentin, Pregabalin)
Gabapentin, a nonbenzodiazapine GABA analog, was modestly effective in a 14-week controlled trial in SAD. Most patients were titrated to a maximal dose of 3,600 mg/day.61 Pregabalin 600 mg/day was effective for social anxiety, fear, and avoidance behavior in a 10-week controlled trial.67 Pregabalin was well tolerated, and the most common side effects were somnolence and dizziness.
β-Blocker
β-Blockers decrease physiologic symptoms of anxiety and are useful for reducing performance anxiety. Propranolol or atenolol should be administered 1 hour before a performance situation. β-Blockers are not useful in generalized SAD.61
Patient Care and Monitoring
1. Review medical and laboratory data to rule out contributing causes of anxiety.
2. Assess the patient’s symptoms and level of functional impairment to determine if pharmacotherapy is appropriate for the anxiety disorder.
3. Obtain a thorough history of prescription, nonprescription, and natural product use.
4. Determine what treatments have been tried or were useful in the past. Is the patient taking medication that may cause anxiety?
5. Educate the patient about lifestyle changes that will improve symptoms of anxiety. These include adequate sleep and exercise, stress management, meditation, and coping skills.
6. Inform patients of treatment options for anxiety disorders and the expected benefits of each (e.g., pharmacotherapy, psychotherapy, and combination treatment).
7. Develop a plan to assess the effectiveness of drug therapy during the first 12 weeks.
8. Determine an appropriate duration of treatment. Is long-term maintenance treatment needed?
9. Assess improvement in academic, social, interpersonal, and occupational functioning; quality of life, and well-being.
10. Evaluate the patient for the presence of adverse drug effects, drug-drug interactions, and drug allergies.
11. Stress the importance of adherence to medications to achieve and maintain response.
12. Provide patient education regarding disease state, lifestyle modifications, and pharmacotherapy:
• What differentiates anxiety from an anxiety disorder? How should it be treated?
• What are potential complications of an untreated anxiety disorder?
• What potential adverse effects may occur? Is there a risk of dependence?
• Which drugs may interact with therapy?
• How to record symptoms (e.g., fears, panic attacks, avoidance behaviors) and report back to their clinician.
Outcome Evaluation
Pharmacotherapy of SAD should lead to improvement in physiologic symptoms of anxiety and fear, functionality, and overall well-being.23 Many patients may not achieve full remission of symptoms, but they should have significant improvement. Monitor patients weekly during acute treatment (e.g., initiation and titration of pharmacotherapy). Once patients are stabilized, monitor monthly. Inquire about adverse effects and SAD symptoms at each visit. To aid in assessing improvement, ask patients to keep a diary to record fears, anxiety levels, and behaviors in social situations.23 You may administer the Leibowitz Social Anxiety Scale (LSAS) to rate SAD severity and change, and the Social Phobia Inventory can be used as a “self-assessment” tool for SAD patients. Lastly, counsel patients on appropriate expectations of pharmacotherapy in SAD, including the gradual onset of effect and the need for extended treatment of at least 1 year.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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