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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.

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4. Why is it important to avoid long-term use of sedative-hypnotic medication?


Long-term use of hypnotics should be avoided for several reasons. First, many cases of insomnia are truly transient, and patients need to be informed clearly that brief treatment may be adequate. Some patients develop a habit of regular sedative usage; when they stop, the may be disturbed by brief rebound insomnia and believe that they must stay on medication. Tolerance, which tends to develop to most sedatives over time, decreases their efficacy and may promote escalation of dosage. All sedativekypnotics have side effects, including decreased dreaming and deep sleep and increased brief arousals at night, which make sleep less restful (see Question 8). Even more important is that long-term symptomatic treatment of insomnia may prevent the detection of an underlying medical or psychiatric condition that can be treated with better response. Although a number of conditions may benefit from long-term sedatives, it is important to diagnose and treat them adequately. In general, nonaddictive agents are preferred to treat chronic insomnia. Some studies have supported long-term use of nonbenzodiazepine hypnotics as a safe and effective treatment. An open trial in France of 180 consecutive days of 10-20 mg of zolpidem for insomnia showed little tolerance and virtually no withdrawal or rebound insomnia after discontinuation.

5. What factors should be considered in deciding which hypnotic is most appropriate for a specific patient? Assess the form of the patients insomnia. The four most common types of insomnia are: Sleep onset or initial insomnia Frequent short awakenings One or two long awakenings Early morning awakening (early awakening is a common symptom in major depressive disorder) Assess pertinent characteristics of the sedative-hypnotic: Rate of absorption Extent of distribution in body and CNS Affinity of CNS receptors Elimination half-life Route of metabolic biotransformation For the sake of simplification, rate of absorption and elimination half-life can be used to guide drug choice. GABAABenzodiazepine Receptor Agonist Hypnotics
HALF-LIFE (HRS) ABSORPTION TYPICAL DOSAGE

Zaleplon (Sonata) Zolpidem (Ambien) Triazolam (Halcion) Zopiclone Temazepam (Restoril) Estazolam (Prosom) Oxazepam (Serax) Alprazolam (Xanax) Lorazepam (Ativan) Clonazepam (Klonipin) Quazepam (Doral) Flurazepam (Dalmane)

1-1.2 1.54 2-5 5-6 8-12 12-20 5-15 12-20 10-22 22-38 50-200 50-200

Fast Fast Fast Fast Moderate Moderate Moderate Fast Moderate


Slow

Fast Fast

5-10 mg 2.5-10 mg 0.125-0.25 mg 3.75-7.5 mg 7.5-30 ing 1-2 mg 10-25 mg 0.25-1 .O mg 0.5-2 mg 0.5-2 mg 7.5-15 mg 15-30 mg

6. What drugs are most helpful for sleep onset or initial insomnia? If the patient has trouble falling asleep initially, zolpidem, triazolam, zaleplon, and temazepam are the best choices. Zolpidern is effective, rapidly absorbed, cleared quickly from the system, and there is minimal evidence of memory loss, motor incoordination, tolerance, or withdrawal symptoms.

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Zaleplon 10 mg has the same rapid onset of action and rapid clearing. Its short duration of action may convey even less risk of impairing coordination or cognition. A number of studies have suggested that triazolam is equivalent in efficacy and side effects (except perhaps rebound insomnia) if not used above 0.25 mg. It is a reasonable next choice atonethird the price. The fourth choice is temazepam, 15-30 mg, which is the least expensive of the four. Occasionally the three shorter-acting agents shift the patients sleep pattern from sleep-onset insomnia to early morning awakening after the drug is mostly cleared from the system. Temazepams longer duration of action may be helpful to combat this tendency. As temazepam is slowly absorbed, it may need to be taken I-1% hours before bedtime to aid getting to sleep. Elderly patients are generally given one-half the average adult dosage.
7. What drugs are most helpful for nocturnal and early morning awakening? Temazepam is the first choice for nocturnal and early morning awakenings. It is slowly absorbed, but its peak effect begins about 1-1 /2 hours after administration and persists for 6-10 hours. This duration of action may be ideal to maintain sleep until morning without leaving the patient groggy the next day. Depending on the patient, shorter-acting (triazolam, zolpidem) or longer-acting (estazolam, oxazepam, lorazepam, clonazepam) may be more suitable. The long-acting drugs, such as flurazepam, quazepam, and chlorazepate, are quite effective for nocturnal and early morning awakenings, but the patient may have daytime hangover, memory loss, or incoordination. These drugs are best for very anxious patients or for infrequent or intermittent usage. Zaleplon offers unique benefits. Three to four hours after ingestion, patients are nearly free of impaired cognition or coordination; thus, depending on arising time, the patient may take zaleplon as late as 2-3 AM to return to sleep without fear of hangover. This allows the patient to take medication only if he or she needs it, rather than prophylactically at bedtime in case nocturnal or early morning awakening occurs.
8. What are the likely side effects of benzodiazepine receptor agonists? The most common side effects of benzodiazepine receptor agonists are daytime sedation, motor incoordination, slow reaction times, anterograde and retrograde amnesia, confusional states, withdrawal states, rebound insomnia, respiratory depression, tolerance to drug effect, and potential for abuse. 9. With such side effects, why are benzodiazepine receptor agonists the drugs of choice? They are easily tolerated by most patients and highly effective in 75-90% of cases. Side effects can be minimized by drug choice, regulation of dosage, and dosing schedules. One of the major advantages is their safety in overdose. The lethal dose is so large for all benzodiazepine receptor agonists death is unlikely even from a whole months supply. A patient merely becomes highly sedated until the drug is cleared from the bloodstream.

10. What is anterograde amnesia? Discuss its cause and prevention. Anterograde amnesia is impaired consolidation of new memories of experiences or learning after administration of a drug. In contrast, retrograde amnesia is impaired recall of previously consolidated memory. Anterograde amnesia may occur when high doses of long-acting or short-acting drugs are used. It generally is prevented by using as low a dose of a hypnotic as possible and avoiding concurrent usage of other drugs or alcohol. High-potency hypnotics are more likely to cause anterograde amnesia. 11. What are the guidelines for prescribing to elderly patients or other groups that may suffer from impaired liver metabolism? For elderly patients or patients with liver impairment, very short-acting drugs such as triazolam, zaleplon, or zolpidem, or drugs that do not require hydroxylation by the liver, are preferred. Temazepam, lorazepam, and oxazepam are excreted by the kidneys without necessity of liver hydroxylation; therefore, their metabolism and excretion are not prolonged by age or liver dysfunction. Unexpected falls may be an unfortunate consequence of motor incoordination induced by hypnotics used in the elderly. The weakened and brittle nature of their bones makes them highly prone

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to hip fractures if they fall. The likelihood of hip fracture in the elderly may be correlated with the half-life of a regularly used hypnotic. One study showed that flurazepam is twice as likely as triazolam to cause a hip fracture with regular use in elderly patients. 12. What are the effects of sedativelhypnotic drugs on sleep quality? Benzodiazepine hypnotics generally increase total sleep time, tend to suppress and delay REM or dreaming sleep, increase the duration of stage 2 sleep, and decrease the amount of stage 3 and 4 or deep sleep. Most users feel more refreshed and alert in the daytime compared with periods ofinsomnia but less rested than in periods of normal, unmedicated sleep. Stopping such drugs after short or intermediate term usage may result in REM rebound (increase in REM sleep) and rebound insomnia for 0-3 days. Studies of zolpidem indicate that it increases total sleep time, increases deep sleep but does not suppress REM sleep or create REM rebound with discontinuation. Zaleplon decreases sleep latency, increases deep sleep, but may decrease REM sleep. Correct doses of most benzodiazepine receptor agonists enhance next day functioning.

13. What is the mechanism of action of benzodiazepineand nonbenzodiazepinehypnotics? Both benzodiazepine and the newer nonbenzodiazepine hypnotics have an inhibitory effect on the central nervous system that is mediated through the stimulation of benzodiazepine receptors creating an agonist effect on the neurotransmitter, gamma-aminobutyric acid (GABA). The GABAAreceptor complex in the brain contains two benzodiazepine receptor subtypes: omega-1 (0,)and omega-2 (w2). Agonistic stimulation of these receptors causes hyperpolarization of associated neural membranes which decreases the cells excitability or response to stimulus. Omega- 1 receptors seem to mediate sedation, whereas omega-2 receptors mediate anxiety reduction, anticonvulsant activity and, unfortunately, memory loss and motor incoordination. Most benzodiazepines stimulate both omega-1 and omega-2 receptors; therefore, their sedative effect correlates with an adverse effect on coordination and memory. but these receptors are mostly loBenzodiazepines typically stimulate a third receptor, omega-3 (a3), cated in the spinal cord and have no relevance to sleep, memory, or coordination. It should be that patients will feel an improvement in well-being from use of a hypnotic without an objective response in total sleep time. Changes in perception of sleep duration may be part of the drugs mode of action.

14. Is it possible to create a drug with fewer side effects by stimulating only the benzodiazepine omega-1 receptors? Theoretically, yes. At least three drugs have shown a pharmacological profile of selective binding to omega- 1 receptors. These include quazepam, zolpidem, and zaleplon. Quazepam itself is w,-selective, but its two long-acting metabolites are approximately 150 times more potent and not w,-selective. Zolpidem is wl-selective and has no significant active metabolites. It has the theoretical advantage of w1selectivity but has not been shown to have a statistically significant advantage in reduction of motor incoordination or memory impairment over non-w, -selective, short-acting benzodiazepines (e.g., triazolam) at typical therapeutic dosages. Evidence does suggest that zolpidem may offer a more physiologically normal sleep, produce fewer withdrawal symptoms, and be less prone to induce tolerance. Zaleplon is another nonbenzodiazepine sedative hypnotic with w, receptor selectivity. It differs from other short-acting sedatives in that its elimination half-life is only one hour. Studies have shown very little effect on cognition or coordination at 3 A hours post ingestion. This implies the possibility of using zaleplon not only to treat sleep onset insomnia but also to treat nocturnal or early morning awakenings as long as there is still 4 hours till arising time.
15. In addition to transient insomnia, what other common diagnoses or conditions may benefit from the use of sedative-hypnotic agents? Chronic insomnia due to: Age. Ones ability to remain asleep decreases with age. In severe cases, after encouraging physical activity and sleep hygiene, the clinician may give a 2-week trial of zolpidem, 5 mg; triazolam, 0.125 mg, or temazepam, 7.5-15 mg. If the drug is clearly helpful and side effects are not severe, it may be continued with attempts to shift to intermittent dosing if tolerance begins to develop.

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Chronic pain. Many nocturnal arousals from sleep are caused by pain. Tricyclic antidepressants (e.g., amitriptyline, 10-50 mg, doxepin, 10-50 mg) are first choices in patients with chronic pain, because they reduce pain sensations as well as frequency or duration of awakenings. Chronic medical condition. Congestive heart failure i s an example of a chronic medical condition that induces severely fragmented sleep. Temazepam, 15 mg, has been shown to decrease nighttime awakening and arousals and to improve daytime alertness with no compromise of the medical condition. Medication side effects. For example, in a 38-year-old asthmatic woman taking long-acting theophylline (300 mg/day) and using a metaproterenol sulfate inhaler (2 puffs 4 timedday), the stimulating effects of medication may induce severe insomnia and occasional symptoms of anxiety. Flurazepam, 15 mg, can be used at bedtime 3-6 timedweek to inhibit insomnia and daytime anxiety. Fibromyalgia, chronic fatigue syndrome. First choices are doxepin, 10-50 mg at bedtime; amitriptyline, 10-50 mg at bedtime; or nortriptyline, 10-50 mg at bedtime (if anticholinergic effect of doxepin or amitriptyline is too strong). Studies show that sleep improvement i s correlated with improvement in pain or fatigue in some patients. Patients who are intolerant of tricyclic antidepressants may consider trazodone, 25-1 00 mg, short-acting benzodiazepines, or mirtazapine, 15-60 mg qhs. Major depression Bipolar affective disorder Dysthymic disorder Panic disorder Generalized anxiety disorder Posttraumatic stress disorder Psychophysiologic insomnia. This is a conditioned negative response to ones sleep environment. Sleep hygiene, sleep restriction, stimulus control, and relaxation training often are effective. Short-acting benzodiazepine receptor agonists may aid psychological intervention as well as lowdose sedating tricyclics or trazodone. Restless leg syndrome. This crawling discomfort in the legs makes one feel a need to stretch or move the legs and causes sleep onset insomnia. It may be associated with iron or B 12 deficiency anemia, renal disease, or pregnancy after week 20. Periodic leg movements of sleep. Leg-jerking movements accompany restless leg syndrome but also may occur up to 2-3 timedminute during sleep in patients without restless leg symptoms. The arousals that they cause may make sleep nonrestorative. Recommended order of treatment for restless leg syndrome and periodic leg movements is Sinemet (the combination of carbidopa [15 mg] and levodopa [lo0 mg]), 1-2 tablets at bedtime. (This works about 50%of the time but may induce nightmares.) If it fails, try an alternative dopamine agonist like bromocriptine or pergolide. Other alternatives include: Temazepam, 15-30 mg at bedtime Clonazepam, 0.5-2 mg at bedtime Percocet (the combination of oxycodone HCL and acetaminophen), 1-2 tablets at bedtime. This may be the most effective treatment, but the addictive nature of the drug requires that the leg movements must be severe and documented by nocturnal polysomnogram. Studies have shown that Percocet and other opiates actually eliminate the leg-jerking movements rather than just allow the patient to sleep through the disturbance of the movement. Dosage can be held steady for many years without significant tolerance to benefits. Circadiadrhythm disturbances Melatonin is a hormone created by the pineal gland at night in concert with the calm phase of the bodys daily rhythm. Evidence suggests that 1-2 tablets of 2.5-mg Melatonin given in early afternoon help to maintain or reregulate an out-of-sync circadian rhythm. Triazolam, 0.125-0.25 mg, or zolpidem, 5-10 mg, also may be used to help reestablish a normal circadian sleep pattern. Bright light therapy can be used to reset circadian rhythm.

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16. What changes in strategy can be used in prescribing hypnotics for chronic conditions? Use benzodiazepines on an intermittent basis 1 4 times/week to decrease tolerance and maintain potency. Strictly reinforce daily routine and relaxation techniques to enhance efficacy of medication. In appropriate populations for either primary or adjunctive treatment, consider alternatives, such as: Antidepressants (see Question 18) Mood stabilizers (see Question 19) Antihistamines (see Question 20) Antipsychotics (see Question 20)

17. How does one approach the evaluation of the patient who has chronically used benzodiazepines and/or alcohol for treatment of a chronic insomnia? Sedative-hypnotics and alcohol are estimated to be the cause of 10-15% of cases of insomnia
due to withdrawal symptoms and tendency to cause arousal and nonrestorative sleep. Alcohol has no place in chronic treatment of insomnia, and abstinence should be recommended. If this is difficult, formal detoxification and enrollment in substance abuse treatment may be needed. More compliant patients can stop alcohol and reduce their sedativelhypnotic by one therapeutic equivalent/week (e.g., 0.125 mg triazolam, 15 mg temazepam, or 5 mg zolpidem). During this period one should closely evaluate the patient for symptoms beyond the expected mild withdrawal symptoms (e.g., panic attacks, mood instability). The purpose of the taper and discontinuation is to allow better diagnosis of any underlying etiology of the insomnia and potentially to provide more effective treatment.

18. List antidepressantmedications that may be used for their sedative properties.
Antidepressant Medications with Sedative Properties *
DRUG DOSAGE USES

Mirtazapine (Remeron) Amitriptyline (Elavil) Doxepin (Sinequam)

18-60 mg
10-1 00 mg 10-200 mg

Fibromyalgia, adjunctive use with SSRI, can inhibit nausea, but often increases appetite Chronic pain, peripheral neuropathy, fibromyalgia Chronic fatigue syndrome, fibromyalgia, post alcohol withdrawal insomnia, as adjunct with nonsedating selective serotonin reuptake inhibitors (SSRIs) Adjunct to nonsedating SSRI; make sure to warn men about risk of priapism and potential need for immediate withdrawal from drug; also warn of orthostatic hypotension Often helpful for mild-to-moderateanxiety disorder and insomnia Less sedation thaii trazodone without risk of orthostatic changes or priapism; no REM sleep suppression Most sedating of serotonin reuptake inhibitors

Trazodone (Desyrel)

25-200 mg

Nortriptyline (Pamelor) Nefadazone (Serzone) Fluvoxamine

25-200 mg 100-500 mg

25-300 mg

* From most sedative to least sedative


19. How are mood stabilizers used as hypnotics? Adequate sleep is essential to stabilize a bipolar affective disorder. Carbamazepine is moderately to highly sedating and a typical sedating dose is 1 0 0 4 0 0 mg at bedtime. Bedtime doses of 1 0 0 4 0 0 mg may be used adjunctively with other primary mood stabilizers like lithium or valproate. Valproate is mildly to moderately sedating and may be used at doses of 125-1500 mg at bedtime. Both often may be used as adjunctive medicine for sedation or mood stabilization in patients still suffering from insomnia while treated with lithium carbonate or another mood stabilizer. In addition, they may be desired as primary agents in mixed or rapid cycling bipolar disorders with severe insomnia. These show some utility in patients with posttraumatic stress disorder, insomnia, nightmares, night terrors,

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and agitated drug withdrawal states. Although responses can be varied, Neurontest (gabapentin 100-200 mg) or Lomictal (lamotrigine 235-100 mg) can show distinctly sedative properties which may improve sleep and stabilization of bipolar disorder.

20. What other drugs are of occasional usefulness as sedative-hypnotic agents? Other Drugs With Sedative-Hypnotic Properties
DRUG
DOSAGE USES

Antihistamines
Diphenhydramine 25-100 mg Allergies, mild insomnia, patients at risk to abuse medications, patients on antipsychotic medication with extrapyramidal symptoms such as muscle dystonia or parkinson-liketremor Posttraumatic stress disorder, cluster headaches with insomnia, nightmares

Cyproheptadine

4 4 0 mg

Atypical Neuroleptics
Quetapine (Seroquel) Olanzapine (Zyprexa) Risperidine (Risperdal) 25-600 mg 2.5-20 mg 0.9-10 mg First-line treatments for psychotic disorders; often useful in bipolar disorder or in borderline personality disorder; atyp ical neuroleptics commonly used for insomnia, agitation, or paranoia in elderly demented patients

Traditional Neuroleptics
Thioridazine (Mellenil) Penphenazine (Tailafon) Haloperidol (Haldol) Buspirone Clonidine Valerian 10-800 mg 2-66 mg 0 . 5 4 0 mg

Others
5 4 0 mg 0.1-1.2 mg 400-900 mg Shown to be effective occasionally for nocturnal agitation in elderly patients Opiate withdrawal insomnia, refractory posttraumatic stress disorder, and treatment-resistant bipolar disorder Limited evidence of mild hypnotic effect; little safety data and no comparisons to other drugs

21. Which agents should not be prescribed for sleep?


Ethchlorvynol, methaqualone, and barbiturates no longer have a place as sedative/hypnotic agents alone. They have greater risk of abuse, dependence, and lethal overdose and tend to lose effectiveness much more rapidly than benzodiazepines. Alcohol is sedating but promotes nocturnal awakenings, and severely impairs sleep quality; tolerance develops rapidly. Chloral hydrate is now felt to be of only brief, limited usefulness because of overdose potential, rapid tolerance, GI disturbance, and interactions with other drugs. A review of all evidence about melatonins efficacy found no evidence that it improves sleep. There are also concerns that melatonin may inhibit ovarian function, alter immune system, or cause vasoconstriction of cerebral and coronary arteries. Patients taking steroids, those with an immune disease, cancers of the immune system, and women of childbearing age should be counseled not to use it.

22. Are sedative-hypnoticsassociated with homicidal behavior, psychotic reactions, or agitation?


Short-acting hypnotics have been associated with agitated states, sleepwalking, psychotic reactions, and at least two cases of homicide. Triazolam has been associated with at least two cases of homicide. It is suspected that the underlying pathology that caused the insomnia may have been a major factor. A committee of the U.S. Institute of Medicine thoroughly reviewed all studies and literature related to triazolam and concluded they . . . do not support clearly the existence of a unique profile or syndrome of adverse events. Zolpidem has been associated with sleepwalking and pyschotic reactions that are unrecallable the next day. With the million of users of these drngs, it is unlikely that they represent a significant hazard. It is prudent to avoid short-acting sedatives in patients

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with history of severe agitation, highly anxious states, and impulsiveness and to keep sedative hypnotic dosages within accepted parameters.

BIBLIOGRAPHY
1. Bunney WE Jr, Azarnoff DL, et al: Report of the Institute of Medicine Committee on the Efficacy and Safety of Halcion. Arch Gen Psychiatry 56:349-352, 1999. 2. Greenblatt DI, Harmatz JS, von Moltke LL, et al: Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo. Clin Pha-macol Ther 64(5):553-561, 1998. 3. Kryger M, Roth T. Dement WD (eds): Principles and Practice of Sleep Medicine, 3rd ed. Philadelphia, W.B. Saunders, 1999. 4. Lob0 BL, Greene WL: Zolpidem: Distinct from triazolam? Ann Pharmacother 3 1(5):625-632, 1997. 5. Mendelson WB: Efficacy of melatonin as a hypnotic agent. J Biol Rhythms 12(6):651-656, 1997. 6. National Institute of Mental Health, National Institutes of Health: Drugs and Insomnia. Consensus Development Conference Summary, vol4, no 10. Bethesda, MD, U S . Department of Health and Human Services, 1984. 7. Nolen TM: Sedative effects of antihistamines: Safety, performance, learning, and quality of life. Clin Ther 19(1):39-55, 1997. 8. Poceta JS, Mitler MM: Sleep Disorders: Diagnosis and Treatment. Totowa, NJ, Humana Press, 1998. 9. Reite ML, Nagel KE, Ruddy JR: Concise Guide to the Evaluation and Management of Sleep Disorders. Washington, DC, American Psychiatric Press, 1997. 10. Wagner J , Wagner ML, Hening WA: Beyond benzodiazepines: Alternative pharmacologic agents for the treatment of insomnia. Ann Pharmacother 32(6):680-691, 1998.

52. THE USE OF STIMULANTS IN PSYCHIATRIC PRACTICE


Hubert H. T h o ~ l a s o Ju., ~ , M.D.
1. List the common stimulants prescribed in psychiatric practice. Trade Name Generic Name Dexedrine; Dextrostat Dextroamphetamine Dextroamphetamine/amphetamine Adderall (mixture) Ritalin; Ritalin SR; Methylphenidate Metadate; Metadate ER Provigil Modafinil

Dose Range 5-60 mg/day 5-60 mg/day


5-60 mg/day

100400 mg/day

2. Describe the physiologic effects of stimulants. Stimulants increase catecholaminergic activity in the brain through inhibition of monoamine oxidase (MAO), blockade of neuronal catecholamine reuptake, and direct release of catecholamine from nerve terminals. Serotonin (5HT) activity at the neuronal level also is altered. The resultant physiologic state is characterized on electroencephalography (EEG) by increased power, especially in the alpha range. This finding is related to the clinical state of arousal associated with the use of stimulants. Patients taking stimulants typically report activation, increased motivation, improved mood, and even euphoria (which may be followed by a dysphoric crash when catecholamine stores are depleted in the brain), suppression of drowsiness, and decreased need for sleep. Blood pressure and heart rate may be increased, and appetite suppression is common. Among the unpleasant physiologic effects of stimulants are increased sweating, restlessness and agitation, and stereotypic movements such as teeth grinding, jaw-clenching, and skin picking. Sexual functioning may be impaired, with decreased libido in both men and women, inability to maintain an erection in men, and anorgasmia in women.