50.

ANTIANXIETY AGENTS
Robert D. Davies, M.D., aud Leslie Wiutev, M.D.
1. What are antianxiety agents?
Antianxiety agents are medications that decrease the symptoms of anxiety and induce calm. The physical symptoms typically seen in anxiety include flushing, palpitations, hyperventilation or shortness of breath, tremulousness, sweating, nausea, diarrhea, urinary urgency, dizziness, and lightheadedness. This is not to say that antianxiety agents are medications whose only actions are to decrease anxiety. In fact, many drugs commonly used to treat anxiety also have other beneficial effects (such as inducing sleep, muscle relaxation, anticonvulsant effects, and antidepressant effects). The most widely used antianxiety agents are benzodiazepines. However, as new drugs are developed and the full ranges of their beneficial effects are understood, many unique compounds, as well as established classes of drugs, are being found to have significant anxiolytic effects.

2. How do benzodiazepines work? Benzodiazepines are believed to exert their anxiolytic effect by binding to the GABA-benzodiazepine receptors in the brain. GABA (gamma-aminobutyric acid) is the primary inhibitory neurotransmitter. Benzodiazepines and GABA enhance the binding of each other to this receptor complex. Benzodiazepines are presumed to have no direct effect on this complex other than to increase GABAs effect on chloride channels. The binding of GABA to the receptor complex opens these channels, causing a decrease in neuronal excitability and thereby decreasing anxiety.

3. How do I choose which benzodiazepine to use in a given situation?

The two most important factors in choosing a particular benzodiazepine for a given clinical situation are the onset of action and the half-life. Benzodiazepines with rapid onsets of action and short half-lives typically are useful for inducing sedation and/or sleep (and are therefore referred to as sedativehypnotics). Using benzodiazepines with long half-lives for sleep induction will likely result in early morning grogginess or a hang-over effect. When treating occasional panic attacks (regardless of the disorder in which they occur), benzodiazepines with rapid onsets of action afford the quickest relief of symptoms. For more persistent forms of anxiety (such as is seen in generalized anxiety disorder or panic disorder with frequent panic attacks and/or significant anticipatory anxiety), benzodiazepines with longer half-lives tend to be more beneficial. Benzodiazepines with longer half-lives also may allow an easier taper and discontinuation when they have been used in a more chronic fashion. Pharmacokinetic Properties of Commonly Used Benzodiazepines
DRUG

ONSET OF ACTION (HRS)

HALF-LIFE (HRS)

Alprazolam Chlordiazepoxide Clonazepam Clorazepate Diazepam Flurazepam Lorazepam Oxazepam Temazepam Triazolam
268

1-2
2

1-2 1-2 1-2 0.5-2 1-2 3

1-2

0.5-2

10-15 > 50 18-20 > 50 > 50 > 50 10-15 10-15 7-12 2 4

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4. List the effects that benzodiazepines have on the stages of sleep. Increase total sleep time Increase amount of time spent in Stage 2 Decrease amount of time spent in Stages 3 and 4 Increase REM latency Decrease amount of time spent in REM sleep 5. What side effects are commonly seen with benzodiazepines? As a rule, benzodiazepines have a more favorable side-effect profile than other medications used in the treatment of anxiety. The most obvious side-effect is sedation. Other side effects include weakness or fatigue, ataxia, dry mouth, clumsiness, slurred speech, confusion (particularly in the elderly), and depression.

6. What are the potential risks of chronic treatment with benzodiazepines?

The greatest concern about the chronic use of benzodiazepines is the development of dependence. Approximately 50% of people who have been on a regular benzodiazepine dose for 4-6 months develop dependence. Dependence becomes apparent when the drug is discontinued and withdrawal symptoms emerge. Symptoms of withdrawal include agitation, insomnia, moodiness, irritability, headaches, anorexia, sweating, tremulousness, nausea, and perceptual disturbances. Sudden discontinuation of a benzodiazepine is likely to precipitate a severe withdrawal reaction that may include seizures. A more gradual taper, however, might only elicit mild withdrawal symptoms. Withdrawal symptoms usually are time-limited-peaking shortly after they appear and then diminishing over the next several days. The onset of withdrawal symptoms varies depending on the length of action of the benzodiazepine being used. Withdrawal symptoms from short-acting drugs may begin within 24 hours. For intermediate-acting drugs, the onset is within 1-2 days, and for long-acting drugs the onset may not be until 3-7 days after discontinuation. Concerns about patients abusing benzodiazepines are probably exaggerated. For those patients with alcohol or drug abuse histories, this is a reasonable concern. But the majority of people who are prescribed benzodiazepines do not have drug abuse histories and do not tend to abuse their medication. The most common cause of a drug-seeking patient, who uses up the prescription earlier than planned, is inadequate treatment of anxiety. Other concerns about chronic treatment with benzodiazepines include the possibility of developing memory impairment and depression.In addition, as people age they become more sensitive to the effects of benzodiazepines (particularly to effects on cognition and balance), and the clearance of these agents is decreased. Dosage adjustments should be considered for aging patients on chronic benzodiazepine regimens.

7. How fast can I withdraw someone from a benzodiazepine? It depends on which benzodiazepine is being tapered, the dose that the person has been taking, and how long he or she has been taking it. In those cases where the person has been taking a benzodiazepine for 2 weeks or less, it is safe to just stop the medication. When treatment has lasted 2 4 weeks, a fairly quick taper schedule can be employed, with doses reduced by 50% every 3 4 days. When tapering a benzodiazepine that has been used for more than 12 weeks, decreases in dose should not exceed 25% of the total daily dose. For intermediate-acting agents, this can occur in weekly increments. For long-acting benzodiazepines, however, changes should not occur sooner than every 2 weeks. In cases where someone has been taking a benzodiazepine for more than 6 months, extending the time between dosage reductions even more may improve the success of the taper. It is important to plan out the taper with the patient and educate them about the possibility of some mild, transient withdrawal symptoms occurring after each decrease in dose. Keep in mind the psychological aspects of dependence-many patients experience increased anxiety as they proceed with a taper because of their fear of not having the medication.

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8. What is the difference between withdrawal, rebound, and recurrence? Withdrawal is the time-limited development of unique symptoms (as described in Question 6) as the result of decreasing or discontinuing the use of a psychoactive drug. Rebound occurs when a drug is withdrawn and the individual experiences anxiety symptoms that are more severe than those experienced prior to treatment. Recurrence is when the person experiences the same symptoms and severity of symptoms that existed prior to treatment. All of these phenomena can occur with the discontinuation of benzodiazepines, but they also have been described with nonbenzodiazepine treatments for anxiety (particularly SSRIs). 9. What other medications can be used to treat anxiety? Beta-blockers, such as propranolol, can be used to treat the physiologic symptoms of anxiety experienced in specific phobic situations. Their direct effect is to decrease autonomic arousal, although this may have an indirect effect on the cognitive components of the phobic response by interrupting the physiological feed-back loop that fuels catastrophic, distorted thought processes. Most commonly, these agents are used on an as-needed basis 30 minutes prior to the anxiety-producing situation. The typical dose range for propranolol is 10-40 mg. Buspirone, a selective agonist of the 5HTIA receptor, is a safe and effective treatment for generalized anxiety disorder. It has not been shown, however, to be effective in treating panic disorder, specific phobias, or social phobia. Dependence does not occur with chronic buspirone treatment. The clinical response is often delayed for up to 2 weeks of regular, daily use, and it is not effective when used on an as-needed basis. Tricyclic antidepressants (TCAs) are effective treatments for panic disorder and generalized anxiety disorder-although they have not demonstrated efficacy in social phobia. Care must be taken when initiating treatment with a TCA, as many people experience palpitations which may trigger a worsening of anxiety symptoms. The side-effect profile of TCAs tends to limit their current use, as newer agents with more agreeable side-effect profiles (such as SSRls) have become available. Monoamine oxidase inhibitors are useful in the treatment of panic disorder and social phobia. Despite their clear efficacy, their use is limited now because of the risk of hypertensive crisis induced by tyramine-containing foods and interactions with other medications. Serotonin-specific reuptake inhibitors (SSRIs) are quickly becoming the mainstay treatment of most anxiety disorders. They are effective in treating panic disorder, social phobia, generalized anxiety disorder, and obsessive-compulsive disorder. Anecdotal reports also suggest their efficacy in post-traumatic stress disorder. For the most part, they have a favorable side-effect profile (although certain side effects, such as sexual dysfunction, become prohibitive to their use in some cases). SSRIs may cause an initial worsening of anxiety and therefore treatment often is started at very low doses. Venlafaxine, which inhibits the reuptake of serotonin and norepinephrine, has been shown to be effective in treating panic disorder, social phobia, and generalized anxiety disorder. Newer agents that act on the GABA receptor complex, such as gabapentin, are showing promise as being effective antianxiety agents as well. 10. What benefits over benzodiazepines do these other agents offer? Use of these agents does not lead to dependence, as is seen with chronic benzodiazepine use. Therefore, they tend to be considered safer for chronic treatment. They also are the better option for use in individuals with histories of drug abuse or dependence. The antidepressants have the added benefit of treating comorbid depression-a common occurrence in individuals with anxiety disorders.

11. What drawbacks do the use of these drugs have?

Neither the antidepressants nor buspirone offer immediate relief from symptoms. Often there is at least a 2-week lag in response. Delay in symptom relief may play some role in the development of phobic avoidance behaviors. As mentioned previously, the TCAs and the SSRIs both may cause some initial worsening of anxiety symptoms. For these two reasons, it often is necessary to initially

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start a person on an antidepressant along with a benzodiazepine, and then later discontinue the benzodiazepine. BIBLIOGRAPHY
1. Keck PE, McElroy SL: New uses for antidepressants:Social phobia. J Clin Psychiatry 58(Suppl 14):32-36, 1997. 2. Pies RW: Handbook of Essential Psychophannacology.Washington DC, Ainerican Psychiatric Press, Inc., 1998. 3 . Schatzherg AF, Nemeroff CB: Textbook of Psychopharmacology, 2nd ed. Washington, DC, American

Psychiatric Press, Iuc., 1998.

4. Schnabel T: Evaluation of the safety and side effects of antianxiety agents. Am J Med 82:7-13, 1987. 5. Schweizer E: Generalized anxiety disorder: Longitudinal course and pharmacoiogic treatment. Psychiatr Clin North Am 18(4):843-857, 1995. 6. Uhlenhuth EH, Baiter MB, Ban TA, Yang K: International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: V. Treatment strategies in panic disorder, 1992-1997. J Clin Psychopharm 18(6 Suppl2):27S-31S, 1998.

5 1. SEDATIVE-HYPNOTIC DRUGS
Kim Nagel, M.D.
1. What clinical situations provide clearcut indications for sedative-hypnotic drugs?
Transient insomnia and recurrent transient insomnia are the only clearcut indications for sedative-hypnotic drugs. Additional indications and longer-term use require careful clinical assessment and weighing other treatment options.

2. How is transient insomnia defined?

Transient insomnia is a period of insomnia usually 1-14 days in length and often in response to a specific stressor (e.g., loss, illness, hospitalization, long-distance travel). After a duration of 3 months, insomnia is considered to be subacute or chronic and requires further work-up to define underlying etiology. Case study: A 34-year-old woman presents 7 days after the unexpected death of her father. She reports trouble getting to sleep before 2-2:30 AM, difficulty arising for work in the morning, and daytime fatigue. Although sad, she reports few vegetative signs of depression. She is given 20 tablets of zolpidem, 10 mg, to use as needed over the next 3-4 weeks. At follow-up she says that she took the medication nightly with good response and ran out 3 days before her appointment. She has slept only approximately 5 hours for the last 3 nights off medication and feels that continuing it would be helpful. A few times in the last week she woke up early and was unable to return to sleep, but overall she feels that her mood is good. Two additional refills of zolpidem, 10 mg, are given with follow-up as needed. Her next visit occurs in 8 weeks, and she reports that early morning awakening has become more frequent. Occasionally she takes an additional one-half pill to get back to sleep at 3:OO AM. When she ran out of pills, sleep became much more difficult and impairment of concentration at work became more noticeable. She says that she has lost weight and feels less enthusiasm. Major depression is diagnosed, and sertraline is started at 50 mg and increased to 100 mg the next week. Four weeks after starting sertraline, her sleep returns to normal, and she stops zolpidem on her own. At this point she agrees that weekly psychotherapy would be beneficial to deal with issues arising from her fathers death and that continuing sertraline is appropriate at this time.

3. What is the recommended treatment for transient insomnia? A consensus paper published by the National Institute of Mental Health (NIMH) in 1984 stated
that benzodiazepines (and closely related compounds) are the first choice of medication for transient insomnia because of safety, efficacy, and side-effect profiles. The consensus recommended use of the lowest possible dose for the shortest period of time until insomnia improves, with a maximum of 20 dosedmonth for 3 months.