dosage range used for GAD (75–225 mg/day), but can occur with higher doses.

Long-term studies report remission of GAD during 6 months of continued treatment

with venlafaxine XR.

30 Duloxetine’s effectiveness has been demonstrated in shortand long-term trials, with the latter citing a decrease in relapse of GAD in patients

treated with 60 to 120 mg/day.

31–35

In a noninferiority comparison of duloxetine 60 to

120 mg/day and venlafaxine XR 75 to 225 mg/day, these agents achieved criteria for

noninferiority and demonstrated comparable tolerability.

36

Mirtazapine is a non-SSRI antidepressant with limited controlled data in the

treatment of GAD, though there is limited support in patients with comorbid major

depression.

37,38

It is unlikely to cause anxiety as a side effect, owing to its 5-HT

receptor type-2 blocking activity. (See Chapter 86, Depression for more information

regarding the clinical use of various antidepressant agents.) Finally, vortioxetine has

been studied in short- and long-term treatment of GAD with mixed results.

39–42 As

mentioned previously, lower initial doses of antidepressants are recommended to

avoid acute worsening of anxiety symptoms. Slow titration and patient education

regarding adverse reactions associated with antidepressants, including the black-box

warning for suicidality, are also recommended.

43 Although decreases in anxiety

symptoms during antidepressant treatment may appear within the first 2 weeks,

response is gradual and generally continues for 8 to 12 weeks or longer. Therefore,

optimal trials of antidepressants in GAD should allow at least 8 weeks of adequate

doses before a lack of response is determined. Continued improvements may occur

for 4 to 6 months in some GAD patients treated with antidepressants.

44,45

Overall, advantages of antidepressants compared with benzodiazepines in treating

GAD include their superior efficacy for both cognitive symptoms, such as excessive

worry, as well as for common comorbid disorders such as depression and other

anxiety disorders. Antidepressants also lack potential for abuse and dependence, a

safer withdrawal syndrome and no long-term cognitive impairments.

OTHER AGENTS USED TO TREAT GENERALIZED ANXIETY DISORDER

Buspirone was marketed in the United States as the first of a nonbenzodiazepine class

of anxiolytics, the azapirones, and is FDA-approved for the treatment of GAD.

Buspirone does not interact with GABA receptors and works as a partial agonist of

the 5-HT type 1A receptor, reducing 5-HT neurotransmission.

46

In addition,

buspirone enhances dopaminergic neurotransmission by blocking presynaptic

dopamine receptor-2 autoreceptors and also facilitates noradrenergic activity.

47

Buspirone is effective in treating cognitive anxiety symptoms and is not associated

with abuse or dependence; however, it has a delayed onset of anxiolytic effects and

is not appropriate for as-needed use.

Pregabalin, a schedule V controlled substance, may be recommended as a secondline agent following use of SSRIs or SNRIs.

20,24 Pregabalin appears to be efficacious

in managing somatic and psychic symptoms of GAD compared with active

comparators, including benzodiazepines and venlafaxine.

43,48 Further, it has been

studied as an adjunctive agent in combination with SSRIs or SNRIs.

49 Although there

is a paucity of comparison studies with SSRIs or SNRIs, some guidelines support use

of pregabalin as a first-line agent for GAD.

20,50 However, considerations need to

made for the potential for weight gain associated with long-term use, as well as

limitations with use in individuals with renal disease or those with a history of

substance abuse.

25 Pregabalin exhibits a dose–response effect that appears to plateau

at 300 mg/day, although one long-term continuation study of up to 24 weeks suggests

pregabalin 450 mg/day may be effective in preventing relapse compared with

placebo.

51 Further, an open-label study of doses up to 600 mg/day maintained

response for up to 1 year.

52

Finally, atypical antipsychotics are utilized off-label in patients with GAD, though

current guidelines highlight that use of these agents should not be initiated in primary

care and reserved after multiple antidepressant class failures.

24 Aripiprazole,

olanzapine, quetiapine, risperidone, and ziprasidone have been studied for treatmentresistant GAD, with the bulk of evidence and current guidelines supporting use of

quetiapine.

20,25,53 These agents may be useful in patients who fail to respond to firstline treatment options.

20,24,25

Clinical Presentation and Assessment of Generalized

Anxiety Disorder

CASE 83-2

QUESTION 1: L.V., a 32-year-old man, has been employed as a teacher for the past 10 years. He has had

an excellent work record until 8 months ago, when excessive absences and a tendency to become easily upset

at students and coworkers became noticeable. On clinical assessment, L.V. complains of being “on edge,”

irritable, and tense, with frequent stomach upset and diarrhea. He has no history of mental illness; however, he

admits to being stressed and worrying too much about “insignificant things.” He cannot seem to control these

symptoms regardless of how hard he tries. L.V. denies any symptoms indicative of panic disorder or OCD.

L.V.’s physical examination is unremarkable, and his family history is only notable for his sister who is

described as a “nervous person.” L.V. denies past or present use of any illicit substances and drinks three to

four beers at social events, which he has not enjoyed recently. His mental status examination reveals the

following:

Appearance and behavior: L.V. is neatly groomed and dressed and speaks coherently, but he constantly

fidgets and taps his right foot.

Mood: L.V. is anxious and worried about the clinician’s evaluation and admits to occasionally feeling

depressed and hopeless because of his anxiety. He often has difficulty falling asleep but generally

remains asleep throughout the night.

Sensorium: L.V. is oriented to person, place, and time.

Thoughts: L.V. denies any auditory or visual hallucinations, or suicidal or homicidal ideation.

L.V. states, at times, that he is unable to relax, particularly in the classroom around his students. His work

has been difficult for him lately, and the principal has told him that his job is in immediate jeopardy unless he

improves his performance. L.V. states that he just wants to be able to perform his job like he used to and be

able to “chill out” and get back to his old life. His insight and judgment are good, and he is motivated to obtain

treatment. The physician’s provisional diagnosis is GAD.

What clinical features of GAD are present in L.V., and how can his symptoms be assessed objectively?

L.V. exhibits the following target symptoms associated with GAD: excessive

worry that is difficult to control, irritability, tension, and inability to relax. Other

typical symptoms of anxiety present in L.V. include gastrointestinal (GI) problems

(upset stomach and diarrhea), being startled easily, and fidgeting. These target

symptoms are not necessarily diagnostic of any particular disorder, but other factors

in association with these symptoms are consistent with GAD. The absence of

physical or other psychiatric illnesses, as well as use of any illicit substances and

lack

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of recent use of alcohol, excludes possible secondary causes of anxiety. The 8-

month duration of symptoms is consistent with a diagnosis of GAD, and L.V.’s age is

consistent with the usual onset of GAD. More importantly, the symptoms are causing

significant occupational impairment for L.V. and interfering with his quality of life;

therefore, a diagnosis of GAD is appropriate in L.V.

The Hamilton Anxiety Rating Scale (HAM-A) is a useful assessment tool to

evaluate clinical anxiety, and it is the standard instrument used in GAD clinical

trials. A HAM-A score of greater than 18 is generally correlated with significant

anxiety, and a reduction of score to 7 to 10 is associated with no symptoms, defined

as remission.

54 The HAM-A can be used to assess baseline anxiety symptoms in

patients such as L.V. and to monitor response throughout treatment. The Sheehan

Disability Scale is a patient-rated instrument, which is commonly used to assess

functional impairment caused by GAD and other anxiety disorders. It measures 3

domains from 1 to 10. A score of 1 reflects mild disability whereas a score of 10

suggests severe impairment.

54

Indications for and Selection of Treatment

CASE 83-2, QUESTION 2: Based on the information presented in L.V.’s case, how can it be determined

whether treatment is indicated? What factors should be considered in choosing the most appropriate treatment

for L.V.?

L.V. meets the diagnostic criteria for GAD and is suffering significant disability

from his anxiety disorder. He also has insight into his illness and desires treatment

that will enable him to improve his job performance and quality of life. Appropriate

treatment of GAD can help achieve these goals and is therefore indicated for patients

such as L.V.

Treatment options for GAD include both pharmacologic and nondrug therapies.

Psychosocial treatments such as CBT can be effective in treating GAD, but use of

these therapies alone is generally reserved for patients with mild-to-moderate

symptoms. In L.V.’s case, prompt treatment is needed because his job is in immediate

jeopardy owing to impairments associated with his anxiety. Therefore,

pharmacotherapy in combination with psychological therapy, if available, is

indicated in L.V.

Among potential drug therapies, short-term use of benzodiazepines, maintenance

with SSRIs, SNRIs (duloxetine and venlafaxine), and buspirone are all considered

first-line treatments for GAD.

20,24,25 A primary consideration when choosing among

these options is whether any comorbid psychiatric conditions are present.

Antidepressants are the recommended initial choice for patients with concurrent

depression, which is common in GAD patients. Other medical or psychiatric

disorders may also be present, which can guide selection toward a treatment that may

be dually effective.

Another important consideration when selecting treatment for GAD is how quickly

therapeutic effects are needed. Benzodiazepines reduce anxiety within a few hours,

whereas antidepressants and buspirone have delayed onsets of anxiolytic effects.

Medication cost is another potential factor, and generic benzodiazepines or SSRIs

are inexpensive options.

In L.V.’s case, a benzodiazepine may be a good initial choice because of the need

for quick symptom relief relating to his problems at work. L.V. is young and healthy

with no past or present history of substance abuse or alcohol use that might make

benzodiazepines unsuitable for him. Although L.V. drinks beer on occasion at social

gatherings, he has not participated in these events recently, and he should continue to

avoid alcohol if a benzodiazepine is initiated. GAD is often chronic, and

antidepressants or buspirone are recommended over benzodiazepines for long-term

treatment. Therefore, one of these agents would also be appropriate to use in this

case.

Benzodiazepine Treatment

FACTORS INFLUENCING BENZODIAZEPINE SELECTION

CASE 83-2, QUESTION 3: The physician decides to treat L.V.’s GAD with paroxetine for maintenance and

a benzodiazepine for quick control of his anxiety during the first several weeks until the onset of paroxetine’s

anxiolytic effects. What factors are important in the selection of a particular benzodiazepine agent for L.V.?

Of the available benzodiazepines, none have demonstrated clear superior efficacy

in the treatment of GAD. However, certain agents have been used more extensively

than others. Alprazolam, lorazepam, clonazepam, and diazepam have been

successfully used in the treatment of GAD.

Because of similar overall anxiolytic efficacies of benzodiazepines, other factors

must be considered when selecting one agent versus another. Benzodiazepines differ

in their pharmacokinetic properties, and these are generally the main factors

considered in drug selection (Table 83-6).

Benzodiazepines can be differentiated pharmacokinetically according to their

elimination half-lives and their metabolism to active or inactive compounds (Table

83-6). Diazepam (Valium) and chlordiazepoxide (Librium) have half-lives between

10 and 40 hours, and are metabolized by hepatic oxidative pathways to the active

metabolite desmethyldiazepam (DMDZ).

23 The metabolite DMDZ has a long halflife, and chronic dosing of benzodiazepines that get converted to DMDZ can result in

drug accumulation and prolonged clinical effects.

55 This can be especially

detrimental in the elderly, those with liver disease, persons taking other drugs

interfering with benzodiazepine metabolism, or those who are poor metabolizers.

Although long durations of action make once-daily dosing possible, small, divided

daily doses are often used clinically to minimize side effects.

As highlighted in Table 83-6, the elimination half-life of clonazepam ranges from

20 to 50 hours, making once-daily dosing feasible. Alprazolam (Xanax, Niravam)

and lorazepam (Ativan) have intermediate half-lives of 10 to 20 hours, and oxazepam

(Serax) has a short to intermediate half-life of 5 to 14 hours. Alprazolam, lorazepam,

and oxazepam usually need to be taken on a three times a day to four times a day

dosing schedule for sustained clinical effects, but an extended-release (XR)

preparation of alprazolam allows daily or twice-daily dosing. Alprazolam XR may

be associated with fewer CNS side effects than the immediate-release form because

peak alprazolam blood levels are lower.

56 Notably, lorazepam, temazepam, and

oxazepam are free of active metabolites and are unlikely to accumulate with chronic

administration; they are preferred over longer-acting agents in patients with liver

disease and in the elderly. Unlike phase 1 oxidative metabolism, phase 2

glucuronidation processes, the pathway for these three agents, do not appear to

decline with age.

57

Benzodiazepines are readily absorbed after oral administration.

23 Lipid solubility

varies among the agents, resulting in differences in rates of absorption and speed of

onset, as well as duration of clinical effects (Table 83-6). Diazepam and clorazepate

have the highest lipid solubilities and the quickest onset of action, which can be

desirable when rapid anxiolysis is needed; however, both can produce a “drugged”

or “high” feeling in some patients. Highly lipophilic benzodiazepines are also more

quickly redistributed out of the brain, which decreases their duration of action

acutely.

Diazepam, lorazepam, chlordiazepoxide, and midazolam are also available for

parenteral (intravenous [IV] and intramuscular [IM]) administration

23

for treatment of

severe agitation or seizures, or for induction of preoperative sedation and anxiolysis.

IM injection of both chlordiazepoxide and diazepam can be very painful. Lorazepam

is the preferred agent when IM dosing is needed for quick control of anxiety or

agitation.

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Table 83-6

Pharmacokinetic Comparison of Benzodiazepine Agents

Drug

Elimination

Half-Life

(hours)

a Active Metabolites

Protein

Binding (%)

Pathway of

Metabolism

Rate of Onset

After Oral

Administration

Chlordiazepoxide >100 Desmethyldiazepam 96 Oxidation Intermediate

Diazepam >100 Desmethyldiazepam 98 Oxidation

(CYP3A4,

CYP2C19)

Very fast

Oxazepam 5–14 None 87 Conjugation Slow

Flurazepam >100 Desalkylflurazepam,

hydroxyethylflurazepam

97 Oxidation Fast

Clorazepate >100 Desmethyldiazepam 98 Oxidation Fast

Lorazepam 10–20 None 85–90 Conjugation Intermediate

Alprazolam 12–15 Insignificant 80 Oxidation

(CYP3A4)

Fast

Temazepam 10–20 Insignificant 98 Conjugation Intermediate

Triazolam 1.5–5 Insignificant 90 Oxidation

(CYP3A4)

Intermediate

Quazepam 47–100 2-Oxoquazepam, Ndesalkyl-2-

oxoquazepam

>95 Oxidation Fast

Estazolam 24 Insignificant 93 Oxidation Intermediate

Clonazepam 20–50 Insignificant 85 Oxidation,

reduction

(CYP3A4)

Intermediate

Midazolam 1–4 None 97 Oxidation

(CYP3A4)

NA

aParent drug + active metabolite.

CYP, cytochrome P-450; NA, not applicable.

Cost is another important factor in benzodiazepine selection. Brand-name

benzodiazepines can be relatively expensive, but all are available in less costly

generic versions. Potential drug interactions should also be considered in the

selection of an agent because they can alter pharmacokinetics and clinical effects

(see Case 83-4, Question 1).

Because L.V. is young and healthy and is not taking any other medications, the

clinician could choose any benzodiazepine. A shorter-acting high-potency agent, such

as lorazepam or alprazolam, would be a reasonable option for L.V. Appropriate

starting doses would be lorazepam 0.5 to 1 mg TID or alprazolam 0.25 to 0.5 mg

TID. Dosages can be increased every 3 to 4 days, if needed, within the dosage ranges

indicated in Table 83-4. L.V. should notice a decrease in his anxiety symptoms

within the first few days of treatment. Prescription of a generic formulation is

recommended to reduce treatment costs.

ADVERSE EFFECTS AND PATIENT COUNSELING

CASE 83-2, QUESTION 4: Alprazolam 0.25 mg TID is prescribed for L.V. in addition to paroxetine. What

side effects may occur with benzodiazepine treatment, and how should L.V. be counseled regarding

benzodiazepine therapy?

Overall, benzodiazepines are very safe and well tolerated. Sedation and feelings

of tiredness are the most common side effects of benzodiazepines, but sedation can

also be beneficial in alleviating insomnia that often accompanies anxiety. Tolerance

usually develops to the sedative effects of benzodiazepines within 1 to 2 weeks of

continued treatment; consequently, benzodiazepine sedative-hypnotics are

recommended for only short-term use.

20,23,25 Tolerance does not appear to develop to

the anxiolytic or muscle relaxant effects of benzodiazepines.

Benzodiazepines can cause cognitive impairment and anterograde amnesia

(decreased memory for new information after taking the drug), which is dose-related

and reversible on medication discontinuation. Tolerance often develops to the

cognitive adverse effects, but they can also persist throughout therapy in some

patients.

58 Newer studies have demonstrated a possible association with long-term

benzodiazepine use and dementia.

59,60 Use of alcohol during benzodiazepine therapy

greatly increases the risks for memory problems and sedation, as well as for other

more dangerous effects, including respiratory depression. Elderly individuals are

more sensitive to sedative, cognitive, and psychomotor effects of benzodiazepines,

and tolerance to these effects may occur more slowly than in the nonelderly.

61