Treatment with Antianxiety and Sedative-Hypnotic Agents
From time immemorial, human beings have sought ways to achieve relief from subjectively distressing and disabling anxiety, as well as to counteract debilitating insomnia. Early recorded history documents that the anxiolytic and soporific effects of alcohol were discovered centuries ago, and ever since people have imbibed to ease anxiety, tension, and agitation and to lull themselves into a somnolent state. It was not until the nineteenth century, however, that chemists synthesized the bromides and the barbiturates, thereby inaugurating an era of relentless attempts to manufacture more effective and safer alternatives. Each of these, however, shares treatment-limiting and potentially life-threatening disadvantages, including
Rapid development of tolerance to their therapeutic effects
High risk of dependence
Significant withdrawal effects
Serious adverse effects
Lethality in overdose
Meprobamate (a bis-carbamate ester), first marketed in the early 1950s, was originally considered an improvement over the barbiturates, but soon it was recognized to have essentially the same liabilities as its predecessors (1).
The benzodiazepines (BZDs) were introduced 50 years ago. At the time, they were hailed as a breakthrough because of fewer drawbacks compared to earlier anxiolytics and sedative-hypnotics (SHs). They are also effective for a range of disorders; safe in combination with most drugs (except other sedatives), as well as alone in overdose; and generally mild in terms of adverse effects. For these reasons, BZDs quickly became and remain among the most widely prescribed drugs worldwide.
Subsequently, buspirone; the nonbarbiturate, non-BZD SHs (e.g., zolpidem, zaleplon, eszopiclone, ramelteon); antidepressants (e.g., selective serotonin reuptake inhibitors [SSRIs], venlafax-ine, duloxetine, and others); anticonvulsants (e.g., valproate, gabapentin, pregabalin, tiagabine); antipsychotics (e.g., quetiapine); antihistamines; and various investigational agents represent diverse attempts to achieve the same benefits seen with the BZDs while avoiding their unwanted properties (2,3,4; Table 12-1). Unfortunately, the use of these compounds has not entirely eliminated the hazards of adverse effects, tolerance, dependency, and withdrawal syndromes, although many of these compounds do have lower abuse potential than their predecessors.
The potential advantages over BZDs, however, do not justify dispensing these alternate agents which still must also be prescribed judiciously. Failure to monitor their use may endanger the patient, invite governmental restrictions, and possibly become the basis for a malpractice suit or the revocation of a medical license. For these reasons, it is imperative that clinicians become knowledgeable about the basic pharmacology of these drugs, as well as their dose and duration of usage. Most important, the appropriate clinical indications and limitations must receive as much attention as the benefits.
In this context, the BZDs continue to be the subject of a debate that centers on issues related to overuse, misuse, and abuse. Indeed, many
BZD-treated patients, their families, and their physicians now wonder whether a person should be considered an abuser after taking these drugs for longer than a few weeks. Several reviews, however, generally support the conclusion that even long-term therapeutic use is rarely accompanied by inappropriate drug-taking or drug-seeking behavior (e.g., high and sustained dose escalation; trying to obtain the drug from several physicians or illicitly; 5,6,7,8,9 and 10). A decade ago an international group of experts considered the therapeutic dose, potential for dependence, and abuse liability of BZDs in the long-term treatment of anxiety disorders. They concluded that although the BZDs pose a higher risk of dependence than most potential substitutes, they pose a lower risk of dependence than older sedatives and recognized drugs of abuse (11).
BZD-treated patients, their families, and their physicians now wonder whether a person should be considered an abuser after taking these drugs for longer than a few weeks. Several reviews, however, generally support the conclusion that even long-term therapeutic use is rarely accompanied by inappropriate drug-taking or drug-seeking behavior (e.g., high and sustained dose escalation; trying to obtain the drug from several physicians or illicitly; 5,6,7,8,9 and 10). A decade ago an international group of experts considered the therapeutic dose, potential for dependence, and abuse liability of BZDs in the long-term treatment of anxiety disorders. They concluded that although the BZDs pose a higher risk of dependence than most potential substitutes, they pose a lower risk of dependence than older sedatives and recognized drugs of abuse (11).
TABLE 12-1 ANTIANXIETY AGENTS Usual Daily Dosage (mg/d) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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In addition, there appears to be a clear distinction between BZD abusers and therapeutic-dose users. Almost exclusively, the former also abuse other prescription or street drugs or alcohol; take BZDs in large doses for euphoriant effects or to potentiate other (usually illicit street) drugs; and prefer other drugs when available. By contrast, patients who take a BZD continuously for more than 4 to 6 weeks may become dependent, but the vast majority
Do not drink more than social amounts of alcohol
Do not have a history of dependence on other drugs
Do not abuse BZDs
Do not take more than the prescribed dose
Usually attempt to reduce dose to avoid addiction
Are able to successfully withdraw from BZDs without resorting to another dependenceinducing drug (Table 12-2)
These distinctions are important because the advantages and the disadvantages of the therapeutic use of BZDs should not be confused with their abuse.
Pharmacodynamics
Table 12-3 lists the purported mechanism of action of the major classes of drugs presently used to treat anxiety disorders.
PHARMACOLOGY OF BENZODIAZEPINES
In 1977, BZD receptors were identified when it became possible to map their location within the central nervous system (CNS). The binding site for BZDs occurs at the interface of the α and γ subunits of the γ-aminobutyric acid (GABA) receptor. Thus, they were found to be intimately related to GABA, the most prevalent inhibitory
neurotransmitter system in the brain, which acts in the following locations:
neurotransmitter system in the brain, which acts in the following locations:
Stellate inhibitory interneurons in the cortex
Striatal afferents to globus pallidus and substantia nigra
Purkinje cells in the cerebellum
TABLE 12-2 MEDICAL VERSUS NONMEDICAL USERS AND/OR ABUSERS OF BENZODIAZEPINES | ||||||||||||||||||||||||
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TABLE 12-3 PHARMACODYNAMICS OF ANXIOLYTICS | |||||||||||||||||||||||||||||||||||||||
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GABA usually acts to balance the effects of glutamate, the primary excitatory neurotransmitter. Together they modulate CNS activity and arousal. Further, the recognition sites for GABA receptors were found to be coupled to chloride ion channels. When GABA binds to its receptors, these channels open and allow chloride ions to flow into the neuron making it more resistant to excitation. GABA exerts its actions at three physiologically and pharmacologically distinct classes of receptors, GABAA, GABAB, and GABAC (12). The BZDs, barbiturates, and alcohol bind to sites on GABAA receptors which are linked to, but distinct from the GABA recognition site. BZDs enhance the affinity of the recognition site for GABA, ultimately potentiating its inhibitory action by increasing the frequency of channel openings (13). Thus, BZDs facilitate GABA-mediated transmission by acting as indirect GABAA agonists.
The GABAA receptor contains five protein subunits. The binding site for GABA occurs at the interface of the α and β subunits. GABAA receptor subtypes are based on variations of the protein subunits (e.g., α1-5, β1-3, γ1-3 These subtypes in turn mediate specific effects of BZDs such as sedation and anxiety reduction (14). For example, the α1 subunit preferentially binds zolpidem and other similar agonists, mediating their sedative effects. In contrast, Low et al. (15) reported that the α2 subunit may mediate the anxiolytic effects of the BZDs. In a knock-in, point mutation mouse model for the α2 versus α3 subunits, they rendered diazepam ineffective for its anxiolytic effects only when the α2 subunit of the GABAA receptor was absent.
Barbiturates apparently interact with sites directly related to the chloride ion channel, prolonging the duration of its opening by as much as four- to fivefold. Evidence indicates that the effects of alcohol are also due in part to enhancement of GABAA receptor function (16).
There are two BZD receptor subtypes in the brain: BZ1 (type 1 or ω1) and BZ2 (type 2 or ω2). A third BZD receptor (BZ3 or ω3) is very abundant in peripheral tissues. There are also three types of ligands:
Partial or full agonists (e.g., diazepam), which are anxiolytic and anticonvulsant
Partial or full inverse agonists (e.g., FG 7142), which are anxiogenic and proconvulsant
Antagonists (e.g., flumazenil), which are neutral
The high density of BZD receptors within the amygdala suggests it is an important site for the actions of anxiolytic drugs. This is supported by a functional magnetic resonance imaging (fMRI) study that found lorazepam attenuated activation of the amygdala and related structures during emotional processing (17).
When inverse agonists are administered to human subjects, they can produce anxiety, terror, cold sweats, tremor, agitation, fear of impending death, and “intense inner strain” (18). BZD antagonists apparently lack intrinsic activity, but they may have both agonist and inverse agonist effects (19). For example, they are reported to reverse the increased anxiety that may occur after withdrawal of chronic BZD or alcohol use and to reverse BZD-caused amnestic effects (20,21 and 22).
Major Benzodiazepine Subgroups
BZDs belong to one of three major subgroups:
1,4-BZDs—contain nitrogen atoms at positions 1 and 4 in the diazepine ring; this grouping accounts for most therapeutically important agents (e.g., bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, lormetazepam, midazolam, nitrazepam, oxazepam, prazepam, quazepam, temazepam)
1,5-BZDs—contain nitrogen atoms at positions 1 and 5 in the diazepine ring (e.g., clobazam)
Tricyclic BZDs—often consist of the 1,4-BZD nucleus with an additional ring fused at positions 1 and 2 (e.g., alprazolam, adinazolam, loprazolam, triazolam)
In addition, another group of diazepines features replacement of the fused benzene ring with other heteroaromatic systems such as thieno or pyrazolo. Most compounds of this type are under investigation (e.g., brotizolam, a thienodiazepine). Because the pharmacological effects of these molecules are comparable with those of the BZDs, both groups are considered BZDs from a clinical standpoint.
These and other findings related to manipulation of the BZD/GABA-receptor complex indicate it is an important substrate in the neurobiological regulation of anxiety.
PHARMACOLOGY OF OTHER AGENTS
Agents that act via the serotonin (e.g., SSRIs, buspirone) or noradrenergic (e.g., clonidine, propranolol) systems also demonstrate anxiolytic effects. Like GABAergic agents, 5-HT and NE regulate neurocircuits that mediate symptoms of anxiety (e.g., amygdala; 23). In this context, agents that act through two different mechanisms may enhance benefit (24).
Stress may produce anxiety, long-term disruption in CNS function, and perhaps even in CNS structure. The following two critical neurocircuits regulate the stress response:
Autonomic nervous system (ANS)
Hypothalamic-pituitary-adrenal (HPA) axis
For example, overactivity of the HPA axis can culminate in hypercortisolemia. In turn, this can produce acute and chronic pathological stress, fear, and anxiety. These observations also led to the exploration of corticotrophin-releasing factor (CRF) antagonists to reduce stress associated with anxiety and depression.
Agents that block the histamine1 receptor produce sedation and are commonly employed as anxiolytics.
Various anticonvulsants also demonstrate anxiolytic effects. Though their mechanisms of action differ, modulation of GABA and glutamate activity and membrane stabilization via ionophore channel actions (e.g., Ca++, Na++) are thought to be relevant.
Finally, certain natural remedies are frequently employed to reduce anxiety. For example, kavopyrones may reduce limbic system excitability.
Pharmacokinetics
BENZODIAZEPINES
It is sometimes said that all BZDs are essentially the same, with no major differences among them. This is misleading, however, because variations in chemical structure and pharmacokinetics profoundly influence
Potency
Onset and duration of clinical activity
Type and frequency of adverse effects after both single and multiple doses
Withdrawal phenomena
These differences often make it possible to select the specific drug most likely to benefit an individual patient, while minimizing the risk (Table 12-4).
TABLE 12-4 BENZODIAZEPINE DIFFERENCES | |||||||||||||||||||||||||||
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Lipid Solubility
The more lipid soluble the BZD, the more readily it passes from the plasma through the lipophilic blood-brain barrier and the more rapid its onset of action. BZDs can be subdivided on the basis of lipophilicity—a factor that plays an important role in absorption. Midazolam, quazepam, and diazepam are among the more lipophilic of the BZDs. Because increasing lipophilicity also increases the rate of redistribution from blood and brain into adipose tissue, BZDs that are less lipophilic may have more persistent brain concentrations due to reduced peripheral redistribution (25).
Absorption
BZDs with rapid absorption produce a quicker onset of clinical activity than those with
slower absorption. BZDs given orally differ in their speed of absorption from the gastrointestinal tract. For example, absorption time is 0.5 hours for clorazepate, 1 hour for diazepam, 1.3 hours for triazolam, 2 hours each for alprazolam and lorazepam, 2 to 3 hours for oxazepam, and 3.6 hours for flurazepam. Absorption, however, may be influenced by the presence or absence of food in the gastrointestinal tract. Thus, patients who take a BZD SH with a bedtime snack may experience a slower onset of hypnotic activity than if the same drug were taken several hours after a meal.
slower absorption. BZDs given orally differ in their speed of absorption from the gastrointestinal tract. For example, absorption time is 0.5 hours for clorazepate, 1 hour for diazepam, 1.3 hours for triazolam, 2 hours each for alprazolam and lorazepam, 2 to 3 hours for oxazepam, and 3.6 hours for flurazepam. Absorption, however, may be influenced by the presence or absence of food in the gastrointestinal tract. Thus, patients who take a BZD SH with a bedtime snack may experience a slower onset of hypnotic activity than if the same drug were taken several hours after a meal.
Protein Binding
BZDs also differ in their plasma protein-binding capacity. For example, the percent of unbound drug ranges from 0.2% to 0.3% for oxazepam; 0% to 2% for diazepam; 3% to 8% for chlordiazepoxide; and 7% to 12% for lorazepam.
Metabolism and Elimination
BZDs biotransformed by hepatic oxidation have relatively long half-lives and usually have active metabolites (Table 12-5). Those biotransformed by glucuronide conjugation have relatively short half-lives and no active metabolites. Only a few BZDs (e.g., clonazepam) are biotransformed by nitro reduction. Although oxidized BZDs and their metabolites may be more likely to accumulate due to age, liver disease, or concomitant use of estrogens or cimetidine, clinical data substantiating this are incomplete.
Biotransformation
Based on metabolic profile, BZDs can be divided into three groups:
Those biotransformed by oxidative metabolism in the liver, primarily N-demethylation or hydrox ylation (e.g., adinazolam, chlordiazepoxide, clobazam, diazepam), often yield pharmacolog ically active metabolites that must undergo fur ther metabolic steps before excretion
Unlike oxidized BZDs, conjugated BZDs (e.g., lorazepam, lormetazepam, oxazepam) do not have active metabolites and only the parent compounds account for clinical activity
BZD SHs that undergo a high first-pass effect before reaching the systemic circulation (e.g., midazolam and triazolam) may have short-lived but active metabolites
TABLE 12-5 METABOLISM OF BENZODIAZEPINE ANXIOLYTICS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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The first category of BZDs is more likely to be influenced by such factors as old age, liver disease, and coadministration of other drugs that may stimulate or impair hepatic oxidizing capacity. Another difference is that these BZDs tend to have longer elimination half-lives than agents that are conjugated directly. Based on elimination half-life, BZDs can again be divided into three groups:
Ultrashort-acting (less than 5 hours), such as midazolam and triazolam
Short-to-intermediate acting (6 to 12 hours), such as oxazepam, bromazepam, lorazepam, loprazolam, temazepam, estazolam, lormetazepam, and alprazolam
Long-acting (more than 12 hours), such as flunitrazepam, clobazam, flurazepam, clo razepate, ketazolam, chlordiazepoxide, and diazepam
Onset and duration of BZD clinical activity are not necessarily related to elimination half-life. When given in single doses, BZDs with long half lives may have a shorter duration of action than BZDs with shorter half-lives because of extensive
distribution. During multiple dosing, however, BZDs with longer half-lives accumulate slowly and after termination of treatment disappear slowly, whereas BZDs with short half-lives have minimal accumulation and disappear rapidly when treatment stops.
distribution. During multiple dosing, however, BZDs with longer half-lives accumulate slowly and after termination of treatment disappear slowly, whereas BZDs with short half-lives have minimal accumulation and disappear rapidly when treatment stops.
Potency
BZDs differ considerably in potency, which refers to the milligram dose needed to produce a given clinical effect. This is due in part to differences in receptor site affinity. If given in the appropriate dose, any BZD may exert anxiolytic, hypnotic, or anticonvulsant effects. For example, anxiolytics such as lorazepam and diazepam are often used as SHs when anxiety is a prominent symptom associated with insomnia.
OTHER AGENTS
With buspirone, there are some important pharmacokinetic issues to consider. Its short elimination half-life (i.e., 2 to 3 hours) requires a more frequent dosing schedule. It is also a substrate for CYP 3A4, and coprescribed drugs that induce or inhibit this isoenzyme may require a dose adjustment of buspirone to compensate. This agent also has a slower onset of action, and like antidepressants takes weeks to realize its full effect.
The pharmacokinetics of antipsychotics, antidepressants, and anticonvulsants used to treat anxiety disorders are discussed in Chapters 5,7 and 10, respectively.
Treatment of Generalized Anxiety Disorder
BENZODIAZEPINES
Although other drugs exert anxiolytic effects, the BZDs are still commonly used for the treatment of generalized anxiety disorder (GAD). Alternative treatment strategies, as well as disorders in which BZDs demonstrate little or no efficacy, are also discussed here.
Acute Treatment
A meta-analysis of several well-controlled studies found BZDs and azapirones superior to placebo and comparable to each other in the short-term management of GAD (26). Almost all studies indicated that BZDs quickly reduce symptoms in many patients, with most improvement occurring in the first week of treatment. Overall, Rickels (27) reported that about 35% of patients show marked improvement, 40% show moderate improvement, and 25% remain unchanged with BZDs. Patients most likely to respond usually have the following characteristics:
Acute, severe anxiety
Precipitating stresses
Low level of depression or interpersonal problems
No previous treatment, or a good response to earlier treatment
Expectation of recovery
Desire to use medication
Awareness that symptoms are psychological
Some improvement in the first treatment week
Many of these patients derive benefit from short-term BZD therapy only. In one study, 50% of those treated with diazepam (15 to 40 mg/day) for 6 weeks maintained their improvement during subsequent placebo therapy for an additional 18 weeks (28). In another study, 70% treated for 4 weeks with either lorazepam or clorazepate maintained improvement during 2 weeks on placebo (29). Even the chronically anxious may benefit from brief (4 to 6 weeks) treatment (30). In many cases, although discontinuation of medication may eventually lead to a re-emergence of anxiety, symptoms may not always be continuous, functionally significant, or cause patients to seek further treatment (31).
Ideally, BZD treatment of acute anxiety, GAD, and other related disorders should involve the lowest possible dose for the shortest possible time (32). Doses should be flexible and taken intermittently at a time of increased symptoms rather than on a fixed daily schedule. In general, 1 to 7 days of treatment are recommended for a reaction to an acute situational stress, although 1 to 6 weeks may be needed for short-term anxiety due to specific life events. BZDs may also be combined with antidepressants to reduce symptoms and/or adverse effects initially, while waiting for the full effect of the primary antidepressant.
Long-Term Treatment
Anxiety disorders are often lifelong, biologically based, crippling disorders that cause moderate to
severe suffering and handicap an otherwise healthy person. Because these disorders are chronic, long-term treatment is often required to achieve optimal benefit. Even when long-term BZD therapy is appropriate, however, periodic reassessment of its efficacy, safety, and necessity is good medical practice. In this context, existing data indicate
severe suffering and handicap an otherwise healthy person. Because these disorders are chronic, long-term treatment is often required to achieve optimal benefit. Even when long-term BZD therapy is appropriate, however, periodic reassessment of its efficacy, safety, and necessity is good medical practice. In this context, existing data indicate
Long-term users account for the bulk of anxiolytic and hypnotic BZDs sold in the United States
About 80% of SHs sold are consumed by individuals reporting daily use of 4 months or longer
The number of long-term users of anxiolytic and hypnotic agents has increased, even though its benefit is not established (33)
Although frequently needed, effective and reasonably safe, long-term BZD therapy for anxiety disorders has various problems, especially in the elderly. These include
Excessive daytime drowsiness
Cognitive impairment and confusion
Psychomotor impairment and a risk of falls
Paradoxical reactions and depression
Intoxication, even on therapeutic dosages
Amnestic syndromes
Respiratory problems
Abuse and dependence
Breakthrough withdrawal reactions
Thus, clinical judgment plays a major role in the decision to continue treatment beyond 4 to 6 weeks. Although long-term administration may maintain initial improvement, further gains are unlikely (34). To lessen the likelihood of adverse effects and withdrawal phenomena, many U.S. investigators recommend limiting BZD use to 4 months or less.
The chronic nature of anxiety disorders and the frequency of eventual relapse after treatment discontinuation, however, suggest that some patients require long-term treatment (28,31). In this context, only limited controlled data exist on the efficacy of chronic BZD administration. In one double-blind study, the effectiveness of continuous treatment with diazepam (15 to 40 mg/day) for up to 22 weeks was assessed in chronically anxious subjects (35). Half of all patients switched to placebo experienced a slow return of their original symptoms, indicating that diazepam continues to be effective for at least 22 weeks. In addition, since long-term therapeutic use is rarely accompanied by dose escalation, this suggests anxiolytic efficacy is retained even after prolonged use. Evidence indicates, however, that an unknown number of patients are long-term BZD users not because of the therapeutic efficacy of the drug but because they have become dependent and take the drug to preclude the occurrence of subjectively distressing withdrawal symptoms.
As Griffiths (33) cogently observed: “While it is true that the majority of people who use BZDs do so for relatively short periods of time (1 month), the majority of the drug dispensed is consumed by chronic long-term users under conditions in which efficacy has not been established and there are no generally accepted medical recommendations for use.” In support of this position, Griffiths cites a rigorous 1990 survey of the general population in the United States showing that 25% of past-year users of anxiolytics (primarily BZDs) reported daily use of 12 months or greater (36). Further, many longterm users continue to report high levels of baseline anxiety or “psychic distress” (5,37,38,39 and 40). This may represent
Undertreatment
Partial responsiveness that would worsen without treatment
Presence of symptoms more responsive to a different class of drug (e.g., an antidepressant)
Development of some degree of tolerance to the anxiolytic effect
Development of a chronic state of withdrawal
In two studies, Rickels et al. (39) and Schweiser et al. (40) found that baseline measures taken before BZD discontinuation showed significant anxiety and depressive symptomatology despite long-term drug therapy. In addition, patients who successfully completed either abrupt or gradual drug withdrawal achieved lower anxiety and depression levels than they had while receiving medication. This finding is not unexpected because this process selects patients with a good prognosis.
In a study of 50 consecutive patients attempting withdrawal from BZDs taken for 1 to 22 years, Ashton (38) reported that all had a variety of anxiety and/or depressive symptoms, which gradually increased over several years despite continuous BZD use. Several (number not given) also received unsuccessful behavioral therapy, and 10 became agoraphobic. Twelve underwent extensive
gastroenterological or neurological investigations for which various treatments were ineffective. Ashton notes that it is arguable whether these patients would have developed their symptoms without BZD treatment; however, they
gastroenterological or neurological investigations for which various treatments were ineffective. Ashton notes that it is arguable whether these patients would have developed their symptoms without BZD treatment; however, they
Were not present prior to initiation of the BZD
Were not amenable to other treatments during BZD use
Largely disappeared when the BZD was discontinued
A subsequent study of the extent and appropriateness of BZD use in an elderly community confirmed that the prevalence and incidence of SH use are strongly associated with increasing age. This study showed a high proportion of long-term users (61% to 70%), as well as high continued use (52%) among new users. Many of the long-term users were concurrently depressed. The findings of this study led to the conclusion that many older people use BZDs contrary to official guidelines with regard to their mental health. These findings also add to the weight of opinion that persistent and long-term BZD use should be discouraged (41).
Conclusion
Acute, short-term management of GAD with BZDs is an effective and relatively safe strategy. The diagnosis of all patients on long-term BZD therapy should be reassessed on a regular, intermittent basis. The high rate of comorbidity for GAD with other psychiatric disorders suggests that an alternative approach (such as an antidepressant or BZD discontinuation) may be more appropriate in certain patients. In addition, the following offer the best means of avoiding the dependence or withdrawal symptoms associated with long-term BZD use:
Regular treatment monitoring
Use of the lowest possible doses compatible with achieving the desired therapeutic effect
Use of intermittent and flexible dosing schedules rather than a fixed regimen
Gradual dose reduction
Some patients’ quality of life, however, may depend on long-term, therapeutic use of a BZD (42). Although periodic attempts to discontinue medication should be made to determine whether return of anxiety represents a withdrawal reaction or re-emergence of the original disorder, categorical withholding of BZDs may do more harm than good. For example, some may turn to more dangerous drugs in an effort to obtain relief, whereas others may seek a more permanent solution through suicide.
ALTERNATIVE TREATMENT STRATEGIES
In some patients, careful listening, astute questioning, and appropriate advice may be the best form of intervention. This contributes immensely to the patient-physician relationship, which is a powerful treatment tool. Bereavement-induced acute anxiety and insomnia should not be considered a disorder requiring drug therapy, although some may benefit from grief counseling and/or very brief use of a BZD if the disturbance is severe. Various psychotherapies (e.g., cognitive behavioral therapy [CBT], integrated interpersonal/emotional processes therapy; short-term psychodynamic therapy) are also reported to be effective in teaching techniques for coping with and reducing anxiety (43,44,45 and 46). If drug therapy is indicated, non-BZDs (e.g., an antidepressant or buspirone) may be appropriate alternatives.
Antidepressants
The serotonin/norepinephrine reuptake inhibitors (SNRIs) and SSRIs are increasingly recommended as first-line treatments for GAD in lieu of BZDs (47,48) because they
Can alleviate both anxiety and depression, which commonly co-occur (49)
Pose minimal risks for dependence and withdrawal symptoms compared to BZDs, particularly with long-term treatment
Have a different adverse effect profile than BZDs, which may be more tolerable for certain patients
It should be noted, however, that there is a virtual absence of well-controlled trials comparing these newer antidepressants with BZDs to assess their relative effectiveness (50).
Serotonergic/Norepinephrine Reuptake Inhibitors
Venlafaxine XR. Beginning, in the 1990s, evidence accumulated indicating that the newer
generation of antidepressants was effective in a range of anxiety disorders, including GAD. For example, venlafaxine extended-release formulation (XR) was efficacious in GAD outpatients without associated major depression. These data came from clinical trials conducted by expert clinical psychopharmacologists with broad experience in the assessment of psychotropic medications for anxiety disorders. The first of these trials (51) compared the efficacy of venlafaxine XR with buspirone. The second trial (52) also supported the efficacy of venlafaxine XR in nondepressed outpatients with GAD, and a third trial replicated these findings in a primary care setting (53). Two more recent controlled trials also supported the effectiveness of this agent for the treatment of GAD in children and adolescents (54; see Chapter 14).
generation of antidepressants was effective in a range of anxiety disorders, including GAD. For example, venlafaxine extended-release formulation (XR) was efficacious in GAD outpatients without associated major depression. These data came from clinical trials conducted by expert clinical psychopharmacologists with broad experience in the assessment of psychotropic medications for anxiety disorders. The first of these trials (51) compared the efficacy of venlafaxine XR with buspirone. The second trial (52) also supported the efficacy of venlafaxine XR in nondepressed outpatients with GAD, and a third trial replicated these findings in a primary care setting (53). Two more recent controlled trials also supported the effectiveness of this agent for the treatment of GAD in children and adolescents (54; see Chapter 14).
Following confirmation of acute benefit, investigators then ascertained the long-term efficacy of venlafaxine XR. For example, one 6-month, randomized controlled trial found this agent was safe and effective in a population of 251 GAD patients (55). This trial was conducted in 14 outpatient settings, with random assignment to either venlafaxine XR at 75 to 225 mg per day or placebo titrated clinically for 28 weeks. At the conclusion, 67% of the venlafaxine XR patients versus only 33% of the placebo patients were rated much or very much improved. Rating measures demonstrated statistically significant (p < 0.001) differences from week 1 or 2 through week 28 in favor of venlafaxine XR. Nausea, somnolence, and dry mouth were the most common patient-reported adverse events. This study was the first placebo-controlled demonstration of the long-term efficacy of any drug class in treating outpatients with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)—diagnosed GAD.
A second, long-term trial randomized 544 GAD patients to one of three fixed doses of venlafaxine XR (37.5, 75, or 150 mg/day) or placebo (56). In a last observation carried forward (LOCF) analysis, all three doses of venlafaxine XR were statistically superior to placebo in reducing Hamilton Rating Scale for Anxiety (HAM-A) scores, the HAM-A psychic anxiety factor score, and the Clinical Global Impression (CGI) score. Adverse effects with active drug that commonly led to discontinuation were nausea, headache, dizziness, sweating, and insomnia.
A third trial also involved doses of 37.5, 75, or 150 mg per day over 24 weeks. Again, all three doses separated from placebo to a significant degree (57).
These results supported venlafaxine XR as an effective, rapidly acting, and safe once daily agent for long-term treatment of GAD and led to its approval by the U.S. Food and Drug Administration (FDA) for this indication.
Duloxetine. Controlled short- and long-term trials also considered duloxetine for the treatment of GAD in adult and elderly patients (58,59 and 60). While effective in both age groups, there was a higher discontinuation rate in older patients due to adverse effects (61). Based on the results of these studies, this agent became the second SNRI approved by the FDA for treatment of GAD. Pain is often a debilitating comorbid symptom in anxiety disorders. Of interest, a post hoc analysis of two double-blind, controlled trials assessed the benefit of duloxetine (60 or 120 mg/day) compared with placebo for the management of painful physical symptoms and functioning in 840 patients with GAD (62). Both doses significantly separated from placebo in reducing ratings on several pain items as well as improvement in functioning and quality of life. Finally, comparison trials with venlafaxine XR demonstrated comparable efficacy and tolerability with duloxetine (63,64).
Selective Serotonin Reuptake Inhibitors
Paroxetine. Pollack et al. (65) reported the results of a placebo-controlled trial of paroxetine (flexible dosed) for GAD. Intent-to-treat outpatients (n = 324) were studied over an 8-week period, with 163 receiving placebo and 161 paroxetine (20 to 50 mg/day). All subjects had a baseline HAM-A score of at least 20. By week 8, the paroxetine-treated group had a significantly greater reduction in their scores versus those on placebo (p < 0.01). Further, by week 4, the active drug group also demonstrated a significantly greater improvement in the “social life” domain of the Sheehan Disability Scale (SDS; p < 0.001).
In a second trial, Rickels et al. (66) presented their data on an 8-week, double-blind, placebocontrolled trial of paroxetine (20 or 40 mg/day) in 566 subjects. At week 8, both doses of the SSRI produced significantly greater reduction in the HAM-A and SDS baseline scores in comparison to placebo.
In a third trial, Stocchi et al. (67) assessed the long-term efficacy and tolerability of paroxetine for GAD. After 8 weeks of treatment with paroxetine (20 to 50 mg/day), those whose CGI-Severity of Illness (CGI-S) scores had decreased by at least 2 points to ≤3 were then randomized to continue on active drug (n = 278) or switch to placebo (n = 288) under doubleblind conditions. Significantly fewer subjects on paroxetine relapsed (based on CGI-S score of ≥4) in comparison with placebo (i.e., 10.9% vs. 39.9%; p < 0.001) over a 24-week period. Further, during this period twice as many subjects on paroxetine achieved remission compared with those on placebo.
In all three trials, paroxetine was generally well tolerated, with an adverse effect profile similar to that seen in other studies involving depression or other anxiety-related disorders. Based on these results, the immediate-release formulation of paroxetine received FDA approval for GAD.
Sertraline. A 12-week, randomized, doubleblind study included 188 subjects (51% female) who received placebo and 182 subjects (59% female) who received flexible doses of sertraline (50 to 150 mg/day; 68). Outcome measures included the HAM-A and the Clinical Global Impression-Improvement (CGI-I). Clinical presentation of GAD was similar in men and women. The sertraline-treated patients had higher CGI-I response rates compared with patients on placebo from week 4 (males 39% vs. 18%, p < 0.003; females 33% vs. 21%, p = 0.054) through LOCF endpoint at week 12 (males 64% vs. 40%, p < 0.003; females 62% vs. 34%, p < 0.001). The authors concluded that sertraline was an effective and well-tolerated treatment for GAD. Brawman-Mintzer et al. subsequently reported efficacy for sertraline in a second placebo-controlled trial (69).
Escitalopram. Several double-blind, placebo-controlled trials of escitalopram (10 to 20 mg/day) report superiority to placebo in reducing symptoms of GAD for up to 24 weeks (70,71 and 72). One of these trials included paroxetine as an active comparator and found both were superior to placebo and equivalent in efficacy to each other (73). In a subsequent double-blind, 10-week trial of escitalopram, the addition of eszopiclone was superior to placebo in improving sleep and daytime functioning (74). A primary care practice setting, 10-week, placebo-controlled trial assessed the role of escitalopram (10 to 20 mg/day) in 177 patients with GAD who were 60 years or older (75). The results generally favored this SSRI over placebo, but a conservative ITT analysis was nonsignificant. The authors suggested that adherence issues were a contributor to the overall modest efficacy demonstrated. Generally, this agent was well tolerated.
Finally, Ball et al. (76) reported the results of a double-blind, flexible-dose comparison between paroxetine and sertraline in 53 GAD subjects. Both agents produced significant decreases in baseline HAM-A scores (paroxetine 57% [±28] and sertraline 56% [±28]). Further, there were no differences between these two SSRIs in terms of response rates, remission rates, or tolerability.
Other Antidepressants. Two studies indicate that imipramine may be as effective as BZDs in the treatment of GAD (77,78). No studies longer than 8 weeks’ duration exist, however, and the onset of anxiolytic action of imipramine may be even slower than that of buspirone. Although adverse effects also limit the usefulness of imipramine, its lack of dependence liability make it a potential alternative in chronically anxious patients who also suffer from panic and depression. Amitriptyline is another tertiary tricyclic antidepressant (TCA) with dual serotonergic-noradrenergic effects, which may be effective in anxiety disorders (79).
Buspirone
Buspirone is an azapirone anxiolytic that acts as a partial 5-HT1A agonist. In contrast to the BZDs, this agent has no immediate effect on the anxiety seen in patients undergoing medical procedures (e.g., endoscopy, cardioversion). Further, it is not available in a parenteral formulation. In contrast to BZDs, buspirone may be more effective in relieving cognitive symptoms; does not produce disinhibition euphoria; and, even in high doses, does not cause dependency.
The absence of adverse effects of the BZD type and its lack of abuse potential are major advantages. The lack of sedative properties may be very important because many dislike this
feeling and find that it interferes with various activities, such as problem solving, driving, and overall work function.
feeling and find that it interferes with various activities, such as problem solving, driving, and overall work function.
TABLE 12-6 BUSPIRONE VERSUS PLACEBO OR BENZODIAZEPINE FOR GENERALIZED ANXIETY DISORDER | ||||||||||||||||
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Though buspirone does not interact with CNS BZD receptors, studies indicate it is superior to placebo and as effective as BZDs for GAD (83,84,85 and 86; Table 12-6). In a long-term follow-up study of chronic GAD patients who participated in a 6-month trial comparing clorazepate and buspirone, Rickels and Schweizer (35) found a nonsignificant trend for former buspirone-treated patients to report less anxiety than former clorazepate-treated patients. In addition, whereas 65% of the former clorazepate-treated group were still taking anxiolytic medication at 40-month follow-up, no former buspirone patient was taking a psychotropic.
Buspirone differs clinically from the BZDs in several important ways (Table 12-7):
It is only useful when taken regularly for several weeks because it has no immediate effect after a single tablet and is not helpful in treating an acute episode; many patients who have taken BZDs expect relief after a single tablet, but buspirone cannot be used on an as needed basis
It may have diminished efficacy in the long-term treatment of anxiety
It was not effective for panic attacks in several small studies
It does not block BZD withdrawal symptoms; often a critical consideration because many patients previously have been on or are presently taking a BZD
Clinical studies also found that anxious patients treated for up to 12 months are able to stop buspirone treatment abruptly without withdrawal symptoms (87,88).
Buspirone has a slower onset of anxiolytic action (1 to 2 weeks) than the BZDs and requires multiple daily dosing. Increased antianxiety effects have been observed in some patients treated concurrently with low doses of buspirone and a BZD (89). Although this agent may not be as effective in patients who have previously used a BZD, some patients can be successfully switched (90). For example, an assessment of the impact of prior BZD use on response to bus-pirone showed that patient attrition was significantly higher in the recent BZD treatment group than in the remote and no prior BZD groups. Lack of efficacy was given as the primary reason for dropping out by patients who were receiving buspirone. Also in the buspirone group, adverse events occurred more commonly in the recent BZD treatment group than in the remote BZD and no prior BZD treatment groups (91). In such cases, a 2- to 4-week period of concurrent use before BZD tapering may help preclude the return of anxiety.
Buspirone may be an appropriate alternate choice for many patients with GAD who have not taken BZDs previously (92). Buspirone may also have an advantage in patients who experience
problems with BZD withdrawal symptoms. Increased antianxiety effects are observed in some patients treated concurrently with low doses of buspirone and a BZD. Further, buspirone may be indicated in individuals with GAD and a history of chemical dependency who have failed or who could not tolerate antidepressants (93).
problems with BZD withdrawal symptoms. Increased antianxiety effects are observed in some patients treated concurrently with low doses of buspirone and a BZD. Further, buspirone may be indicated in individuals with GAD and a history of chemical dependency who have failed or who could not tolerate antidepressants (93).
TABLE 12-7 CLINICAL DIFFERENCES BETWEEN BUSPIRONE AND THE BENZODIAZEPINES | ||||||||||||||||||||||||||||||||||||||||||||||||
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Antihistamines
Antihistamines are sedating, have little dependence potential, and are generally safe in terms of other complications, with the exception of their anticholinergic effects.
Numerous clinical trials attest to the anxi-olytic efficacy of hydroxyzine. Controlled trials confirmed its efficacy and safety at a fixed dose of 50 mg in GAD (94). In a double-blind, parallel-group, multicenter study in France and Great Britain, a total of 244 patients with GAD were allocated randomly to treatment with hydroxyzine (12.5 mg 3 times/day), buspirone (5 mg morning and midday and 10 mg in the evening), or placebo. Both hydroxyzine and bus-pirone were more efficacious than placebo, indicating that hydroxyzine is a useful treatment for GAD (95). One 3-month study also found hydroxyzine superior to placebo (96).
We would note that reports of diphenhy-dramine abuse should lead to judicious prescribing of this antihistamine with close monitoring for signs of misuse.
Noradrenergic Agents
Despite very limited efficacy data, noradrenergic β-blockers may be useful for highly somatic individuals, such as those with performance anxiety (97).
Anticonvulsants
Pregabalin. This agent is an α2 delta CA++ channel modulator which impacts several excitatory neurotransmitters presynaptically. It is presently approved by the FDA for the treatment of seizure disorders and neuropathic pain. Several double-blind, placebo-controlled trials also found this agent superior to placebo for the treatment of GAD (98,99,100,101,102 and 103). The first trial randomized 276 GAD subjects to pregabalin (150 mg or 600 mg/day), lorazepam (6 mg/day), or placebo (98). At the end of 4 weeks, all three active treatments were superior to placebo in mean change total scores on the HAM-A Scale (-9.2, -10.3, -12.0, and -6.8, respectively). No serious adverse events were reported, and no withdrawal syndrome was noted with pregabalin.
The second trial randomized 271 GAD subjects to pregabalin (50 mg, 3 times/day, n = 70), pregabalin (200 mg, 3 times/day, n = 66), lorazepam (2 mg, 3 times/day, n = 68), or placebo (n = 67; 99). Adjusted mean change scores on the HAM-A total score were significantly better for the 600 mg dose of pregabalin (p = 0.001) and the 6 mg dose of lorazepam (p = 0.048) than for placebo after 4 weeks. The most common adverse effects with pregabalin were sedation and dizziness, but in general it was well tolerated.
The third trial randomized 341 GAD subjects to pregabalin (200 mg, 2 times/day, n = 78), pregabalin (400 mg, 2 times/day n = 89), pregabalin (450 mg, 3 times/day, n = 88), or placebo (n = 86; 100). The mean change in HAM-A total score, LOCF, was superior for all three active drug groups versus placebo (p = 0.006, p = 0.001, p = 0.005, respectively). In general, pregabalin was well tolerated. Of note, the twice daily and thrice daily dosing schedules were comparable in efficacy and tolerability
The fourth trial found that three different doses of pregabalin (i.e., 300, 450, and 600 mg/day) as well as alprazolam (1.5 mg/day) were superior to placebo in reducing HAM-A total scores (LOCF) (101).
A fifth trial compared pregabalin to placebo and included venlafaxine XR as an active comparator (102). Four hundred twenty-one patients with GAD were assigned to pregabalin (400 or 600 mg/day), venlafaxine (75 mg/day) or placebo in a 6-week, double-blind trial. Both active treatments were superior to placebo based on HAM-A total score changes. Discontinuation due to adverse effects were 20.4% for venlafaxine; 6.2% and 13.6% for pregabalin (400 and 600 mg, respectively); and 9.9% for placebo.
A sixth trial assessed the effectiveness of pregabalin in 273 elderly patients with GAD (103). Doses of pregabalin ranging from 150 to 600 mg were effective and superior to placebo, while discontinuation rates due to adverse effects were similar (i.e., 10.7% for pregabalin; 9.4% for placebo).
Other Anticonvulsants. Tiagabine, a selective GABA reuptake inhibitor (SGRI), may also be effective in treating GAD. In a 10-week, randomized, open-label study, 20 patients with GAD
received 2 mg twice daily of tiagabine to a maximum of 8mg twice daily, and 20 subjects received paroxetine (20 to 60 mg/day), which served as a positive control (104). Subjects were assessed using the Hamilton Depression Rating Scale (HDRS), the Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index (PSQI), and the SDS. The mean tiagabine dose was approximately 10 mg per day (range, 4to 16 mg/day), and the mean paroxetine dose was 27 mg per day (range, 20 to 40 mg/day). Significant improvement in both anxiety and comorbid depressive symptoms was observed with both agents. Sleep quality and daytime functioning also improved.
received 2 mg twice daily of tiagabine to a maximum of 8mg twice daily, and 20 subjects received paroxetine (20 to 60 mg/day), which served as a positive control (104). Subjects were assessed using the Hamilton Depression Rating Scale (HDRS), the Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index (PSQI), and the SDS. The mean tiagabine dose was approximately 10 mg per day (range, 4to 16 mg/day), and the mean paroxetine dose was 27 mg per day (range, 20 to 40 mg/day). Significant improvement in both anxiety and comorbid depressive symptoms was observed with both agents. Sleep quality and daytime functioning also improved.
Second-Generation Antipsychotics
Quetiapine XR, risperidone, olanzapine, arip-iprazole, and ziprasidone have been considered in controlled or open-label designs as either monotherapy or adjunctive strategies for GAD (105,105a,106,107,108,109,110 and 111). The results generally demonstrate superior efficacy for these SGAs versus placebo. Within this group, quetiapine XR is the best studied with doses of 50 to 150 mg/day found effective. A major concern, however, is the potential safety and tolerability issues associated with antipsychotic agents (e.g., weight gain; metabolic changes) and whether the risk/benefit ratio is acceptable in this population. As yet, no agent in this class presently has FDA approval for GAD.
Natural Remedies
Kava (Piper methysticum) is a member of the pepper tree family and for centuries has been a part of cultural traditions in the South Pacific islands, where it is used to induce a sense of tranquility and to enhance sociability. Kava is also a popular herb in Europe, where it is used medicinally as a treatment for mild stress and anxiety and recreationally in kava bars. Findings from extensive animal testing suggest that kava has the following characteristics (112):
It may be an anxiolytic
The development of tolerance and withdrawal would be unlikely at therapeutic doses
It may work through inhibition of sodium or calcium channels, having an antiglutaminergic effect
Kava may also potentiate 5-HT1A agonists, thereby suggesting either a direct or indirect serotonergic mechanism f action. Effects on GABAA and N-methyl-D-aspartate (NMDA) receptors are unclear.
Controlled trials of kava support the likelihood that it benefits anxiety disorders (113,114,115,116,117 and 118). Early onset of action was noted in two of three placebo-controlled trials, and efficacy has been noted on several scales. A pooled analysis of three small trials, however, found this agent did not separate from placebo (119). Kava is generally well tolerated at doses of 210 to 240 mg/kL (kavalactones) daily, without the accompaniment of sedation or other adverse effects. Treatment for up to 6 months was examined in one study with the finding that the drug did not lose its effectiveness over time relative to placebo; however, studies of the safety and efficacy of long-term use of kava are needed.
Given the recreational use of this herb, clinicians should be aware that consumption might result in an alcohol intoxication-like state in doses higher than those recommended. As with other medications and herbs, use in pregnancy and while nursing is not recommended. Several cases of severe liver toxicity (e.g., hepatitis, cirrhosis, and liver failure) are reported with kava. Although the exact role of this agent has yet to be determined, these reports led to restrictions of its use worldwide.
Investigational Treatments
Agomelatine. This agent has a novel mechanism impacting both elatonin receptors (MT1, MT2) and the 5-HT2c serotonin receptor. Based on anxiolytic effects in preclinical models and in major depression, a large (n = 121) placebo-controlled trial assessed agomelatine (25 to 50 mg/day) for treatment of GAD (122). The positive results regarding efficacy, tolerability, and absence of discontinuation symptoms prompted the authors to recommend further study.
Abecarnil. Controlled trials also indicate that this partial BZD agonist may be a safe, effective, short-term treatment for GAD (123,124 and 125).
Riluzole. In an open, pilot trial, this presynaptic glutamate release inhibitor benefited 12 out of 18 GAD patients (126).
RELAPSE AND REMISSION
Once acute symptoms are adequately controlled, focus shifts to prevention of relapse and maintenance of remission. Factors that may contribute to a more difficult long-term course include psychosocial issues, particularly dissatisfaction with life and poor family relationships (127). Comorbidity, particularly with major depression, is a frequent complication which can substantially compromise attaining and maintaining remission. Further, abrupt discontinuation of drug therapy typically increases the risk of withdrawal phenomenon (e.g., BZDs; ADs) and relapse or recurrence.
While there is far less evidence to guide treatment strategies, the existing clinical trials support the continuation of effective acute treatments for 6 to 12 months to reduce the risk of relapse. In patients with a clear history of relapse upon medication discontinuation, indefinite maintenance treatment may be warranted. In this context, paroxetine has FDA approval for maintenance treatment of GAD. Long-term exposure must be balanced, however, by the potential for adverse effects such as dependency with BZDs and metabolic and neurological issues with SGAs. Alternative to pharmacotherapy for long-term management may include psychotherapeutic approaches such as CBT, well-being therapy, or their combination (128,129 and 130). In this context, the judicious use of short-term (e.g., 3 to 4 weeks), intermittent BZDs in combination with psychotherapy may preclude relapse and/or preserve remission.
CONCLUSION
While there is ample support for acute pharmacotherapy, it is not clear how useful or how detrimental chronic medication exposure may be for patients with GAD. Whenever possible, discontinuation (using agradual tapering schedule) should be attempted to clarify persistence of anxiety or the existence of masked drug-induced adverse effects. Alternative strategies to BZDs include
Nonpharmacological interventions (i.e., various psychotherapies)
Antidepressants
Azapirones (e.g., buspirone)
β-Blockers or antihistamines in selected cases
Anticonvulsants (e.g., pregabalin)
Second-generation antipsychotics (e.g., queti-apine XR)
Nutraceuticals (e.g., kava)
Figure 12-1 summarizes the strategy we would recommend for the management of acute and chronic generalized anxiety.
Treatment of Phobic Disorders
All of these disorders are characterized by disabling anxiety (which at times is also associated with panic attacks) and avoidance behavior resulting from fear of exposure to
Places or situations from which one cannot readily escape
A specific feared object or situation (e.g., heights)
Certain types of social or performance situations
AGORAPHOBIA
Inasmuch as most drug treatment studies involved agoraphobic patients with panic disorder, there is relatively little evidence to suggest any agent is more than minimally effective for agoraphobia alone. In vivo exposure therapy, however, may be very useful in those willing to tolerate the distress associated with confronting the feared situation (131).
SOCIAL ANXIETY DISORDER
This disorder (also referred to a social phobia) usually begins in adolescence and runs a persistent course throughout adulthood (132). Two subgroups are recognized:
Generalized (i.e., fear of most social situations) which represents about 67% of those affected and is associated with greater impairment, chronicity, and comorbidity
Nongeneralized (i.e., fear of a limited number of specific situations, such as dating)
The core characteristics as outlined in the DSM-IV-TR include
Marked and persistent fear of one or more social or performance situations
Fear of being embarrassed or humiliated
Such situations are avoided or endured with distress or anxiety
Symptoms interfere with social, occupational, and/or academic activities
Recognition that fear is excessive or unreasonable
 Figure 12-1 Management of acute and chronic generalized anxiety. |
Epidemiological studies indicate that the lifetime prevalence of this disorder in the United States ranges from 12% to 13% (133). Further, this condition causes substantial impairment and reduction in quality of life (134). Comorbid conditions such as depression and alcoholism often complicate social anxiety disorder (SAD) (135). Biological correlates may include
Amygdala overactivity (136)
A decreased left hemispheric advantage for word or syllable processing (138)
While behavioral treatments for SAD are well studied, the existing data also supports various pharmacological approaches.
Antidepressants
Selective Serotonin Reuptake Inhibitors (SSRIs). Several placebo-controlled trials found sertraline effective and generally well tolerated (139,140,141,142 and 143). In one study, 80% of patients responded with all measures of social anxiety and avoidance, depression, and social functioning showing a statistically significant change from baseline to treatment endpoint (143).
Subsequently, the results of four short-term, placebo-controlled, randomized trials led to the FDA approval of paroxetine for the treatment of SAD (144,145,146 and 147). Further, a double-blind, placebo-controlled, relapse prevention trial in 257 subjects found paroxetine superior to placebo in terms of number relapsed (14% vs. 39%; OR = 0.24; p < 0.001; 148). In another controlled trial, however, pindolol augmentation of paroxetine did not enhance the overall efficacy of this SSRI (149).
Other SSRIs also demonstrate benefit. For example, fluoxetine (10 to 60 mg/day), comprehensive cognitive group behavioral therapy (CCBT), or their combination were superior to placebo, but the combination strategy was no more effective than either active treatment alone (150). Results from trials of the extended-release formulation of fluvoxamine also warranted FDA approval for treatment of generalized SAD (151).
In summary, two meta-analyses affirmed the efficacy of SSRIs for SAD without detecting any significant differences among them (152,153).
Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs). Several placebo-controlled trials report that venlafaxine XR is superior to placebo in adult and pediatric populations (154,155,156,157,158 and 159). In two of these trials, venalfaxine XR was also similar to paroxetine in terms of efficacy and tolerability
Monoamine Oxidase Inhibitors. Several controlled and open trials have considered monoamine oxidase inhibitors (MAOIs). In general, they demonstrated benefit over placebo but are relegated to a later option given their potential for serious drug-food and drug-drug interactions (see Chapter 7) (160,161,162,163 and 164).
Given the chronic, recurrent course associated with SAD, maintenance of acute benefit, as well as prevention of recurrence are important questions to consider. Limited data support the continued use of effective acute treatment with agents such as paroxetine and citalopram (148). Further, since SAD typically begins earlier in life, the role of antidepressant treatment in this age group is an important question. While trials demonstrate benefit for paroxetine and venlafaxine XR, the issue of suicidality warrants a more conservative approach to prescribing and, when used, monitoring carefully for this potential complication (159,165) (see Chapters 7 and 14).
Other Approaches
The potential role of gabapentin for SAD was also supported in the meta-analysis of pharmacological treatments by Blanco et al. (153). For example, in one trial gabapentin (flexibly dosed between 900 and 3,600 mg/day) was superior to placebo (p < 0.05) in reducing symptoms of SAD in 69 subjects. Dizziness, dry mouth, somnolence, flatulence, and decreased libido occurred more often in the active treatment group (166). The authors concluded that, given gabapentin’s favorable safety and tolerability profile, this agent should be compared to other known effective therapies (e.g., SSRIs, clonazepam) to assess its relative benefit.
Preliminary positive results from open and controlled trials exist for other anticonvulsants, including pregabalin, tiagabine, levit-eracitam, topiramate, valproate, and clonazepam (167,168,169,170,171 and 172).
Preliminary small, controlled trials also demonstrated benefit for quetiapine and D-cycloserine (173,174).
While reports describe efficacy with alprazolam and clonidine, systematic data are lacking (175,176). Further, even though BZDs may produce rapid relief of certain symptoms, their use in a population with high comorbidity for substance abuse should be minimized.
While β-blockers (e.g., propranolol, atenolol) are often prescribed, the available evidence limits their use to performance anxiety (177). Similarly, a small, placebo-controlled trial failed to find benefit with St. John’s Wort (178).
Cognitive behavioral therapy (CBT) demonstrated substantially greater benefit than various “placebo” conditions in two metanalyses (179,180). In addition, while it appears to be comparable to SSRIs in effectiveness, larger appropriately designed trials are needed to resolve this question. Results thus far do not demonstrate a benefit for combined CBT plus medication (181).
SPECIFIC PHOBIAS
Systematic desensitization and in vivo exposure are the most effective treatment methods available for specific phobias. Pharmacological treatment is not well investigated, but studies involving antidepressants suggest that TCAs and MAOIs are ineffective (182,183). In addition, studies suggest that SH anxiolytics may undermine the behavioral treatment of specific phobias (184,185 and 186). In one study, volunteers with animal phobias were exposed to their phobic object 1.5 hours after administration of either tolamolol, diazepam, or placebo in a double-blind crossover design. Though tolamolol abolished the stress-induced tachycardia, it had no beneficial behavioral or subjective effects (187). An open study found gabapentin (400 or 800 mg/day) helpful for physiological and subjective symptoms associated with public speaking (188).
CONCLUSION
SSRIs, venlafaxine XR, MAOIs, certain anticon-vulsants (e.g., gabapentin), and CBT or exposure therapy appear to benefit generalized SAD. Limited data exist to support drug management in specific phobic disorders for which behavioral techniques are currently the treatment of choice. Figure 12-2 summarizes the management strategy we would recommend.
Treatment of Sleep Disorders
The DSM-IV-TR (189) defines insomnia as “difficulty in initiating or maintaining sleep or nonrestorative sleep, which causes distress or impairment in functioning.” It divides insomnia into three categories:
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