Benzodiazepine-induced persisting amnestic disorder: Are older aduls at risk?

Benzodiazepine-lnduced Persisting Amnestic Disorder: Are Older Adults at Risk? Deborah D. Sumner Currently there are approximately 31.5 million Americans 65 years and older. This number is expected to reach 39.3 million by 2010. This group represents 12% of the population, however, they use 25% to 40% of the prescription medications, averaging 4.5 medications daily; 75% of them use over-the-counter medications as well. This population has also experienced an increase in the prescription of central nervous system (CNS) medications. Benzodiazepines are the m o s t widely prescribed class of CNS antianxiety/sedative medication. This article examines the use of benzodiazepines in relation to physiological, pharmacokintic, and pharmacodynamic changes of the older adult. The amnestic properties of these drugs in relation to the already decreasing cognitive function of the older adult are explored in relationship to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for substance-induced persisting atonestic disorder. Copyright o 1998 by W.B. Saunders Company

LDER ADULTS ARE the fastest growing and largest age group of health care clients in the United States. Currently, there are approximately 31.5 million Americans 65 years old or older (Palmieri, 1991). This number is expected to reach 39.3 million by the year 2010. Older adults experience more physiological change, chronic illness, and are prescribed more medication than any other age group in the United States (Conn, Taylor, & Miller, 1994). Older adults comprise 12% of the population, however, they consume approximately 25% to 40% of the prescription medications, averaging 4.5 prescriptions daily (DeMaagd, 1995). The percentage of over-the-counter medication used by older adults in relation to total use is unknown. However, it is estimated that 75% of older adults use nonprescription medications (Palmieri, 1991; LeSage, 1991). One group of medications, in particular, those acting on the central nervous system (CNS), are increasingly prescribed for older adults (Dellasega & Stricklin, 1996). Given the changes in bodily function caused by aging--differences in absorption, distribution, metabolism, and excretion--

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these medications leave the older adult at higher risk for adverse reactions. Of the CNS medications prescribed, benzodiazepines remain the most widely prescribed class of antianxiety/sedative medications for older adults (See Table 1 for list of Benzodiazepines). This article examines the use of benzodiazepines in relation to the physiological, pharmacokinetic, and pharmacodynamic changes of the older adult. It will also focus on the amnestic properties of the drug and the relationship to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM IV, 1994) criteria for substanceinduced persisting amnestic disorder. PHYSIOLOGICAL, PHARMACOKINETIC, AND PHARMACODYNAMIC CHANGES OF AGING

Although each older adult must be assessed individually for physiological changes associated From Paradigm Health Services, Inc., Clearwater, FL. Address reprint requests to Deborah D. Sumner, MA, MS, ARNP, 6494 92 Place North, Suite 205, Pinellas Park, FL 33782. Copyright © 1998 by W.B. Saunders Company 0883-9417/98/1202-000353.00/0

Archives of Psyehiatric Nursing, Vol.Xll, No. 2 (April), 1998: pp 119-125

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DEBORAH D. SUMNER

Table 1. Benzodiazepines

Name

Active Metabolites Present

Average Half-Life Elimination

Length of Action

Aiprazolam Chloradiazepoxide Clonazepam Clorazepate Diazepam Estazolam Flurazepam Halazepam Lorazepam Midazolam Oxazepam Prazepam Temazepam Triazolam

12-15 50-100 20-50 30-300 30-100 10-20 100 30-200 10-20 2-3 3-20 30-200 6-20 1-3

+ + + + + ÷ + + -

Short Intermediate Intermediate Long Long Short Long Long Short Short Short Long Short Short

NOTE: The combination of the drug and its metabolites (if any) determines the length of action of the benzodiazepine in the body.

with aging, several physiological systems show changes in performance as aging advances (Dellasega & Stricklin, 1996; DeMaagd, 1995). Hepatic, gastrointestinal, cardiac, renal, endocrine, sensory, and cognitive changes are likely to result from disease and/or aging processes. Aging changes affecting the pharmacokinetic aspects of benzodiazepine use include changes in absorption, distribution, metabolism, and excretion. Aging changes affecting the absorption of benzodiazepines occur in the gastrointestinal (GI) system. All benzodiazepines, except for clorazepate, are absorbed unchanged via the GI tract (Kaplan & Sadock, 1996). The rate of absorption varies with the particular benzodiazepine. Older adults experience, a change in the amount and acidity of hydrochloric acid in the stomach resulting in difficulty breaking down and absorbing medications (Dellasega & Stricklin, t996). Decreased peristalsis slows the movement of medications through the GI tract, and decreased GI blood flow will slow the absorption of benzodiazepines from the GI tract. Benzodiazepines are'distributed through the blood and the rapid onset of effects is caused, in part, by the high lipid solubility which allows the drug easy passage through the blood-brain barrier (Kaplan & Sadock, 1996; Ballenger, 1995; Greenblatt, Miller, & Shader, 1990). This:lipid solubility has a fivefold variability among the different benzodiazepines. Peak plasma levels vary from 1 to 6 hours depending on the particular benzodiazepine. Older adults tend to have less body water, decreased levels of

serum albumin, and more body fat (Dellasega & Stricklin, 1996). This will lead to higher concentrations of the benzodiazepine in the plasma and tissue. As benzodiazepines are predominantly bound to plasma proteins, there will be an increased amount of unbound biologically active drug in the system. Further risk of toxicity results from an accumulation of these fat soluble drags in the older adult's increased body fat stores which increase the half-life and action of the benzodiazepine when slowly released from the fat tissue (DeMaagd, 1995). Older adults experience less efficient liver function because of a decrease in liver mass from decreases in functional hepatocytes, thereby slowing the breakdown of the benzodiazepines, which are primarily metabolized in the liver (Dellasega & Stricklin, 1996; Ballenger, 1995; DeMaagd, 1995). Depending on the class of benzodiazepine, of which there are three, the metabolism differs. Most are biotransformed through phase I metabolism (oxidation). A small group are biotransformed by phase II metabolism (conjugation) to inactive and acetylated substances. A few are metabolized through both phase I and II metabolism. Phase I metabolism is decreased in the older adult, making those benzodiazepines going through this process more liver toxic with respect to liver function. Benzodiazepines are primarily excreted through the renal system into the urine. Older adults experience decreased renal function because of a decrease in the number of nephrons which result in changes in renal perfusion, glomerular filtration rate, and tubular secretion resulting in a decrease in creatinine clearance (DeMaagd, 1995). This leaves the potential for retention of drug and drug metabolites, thereby increasing the amount of time the drug is in the body. These medications also have widely divergent half-lives which affect the daily dosing amounts and schedules affecting the elimination time from the body (Kaplan & Sadock, 1996; Ballenger, 1995; Maxmen & Ward 1995). Also affecting elimination of the drug is the length of time the medication has been prescribed and the amounts taken. DeMaagd (1995) relates that the pharmacodynamic changes of aging are as yet poorly defined. Older adults have a greater variability to the pharmacodynamic effects of CNS medications, showing a greater sensitivity and enhanced response to these drugs. This greater sensitivity may

BENZODIAZEPINE-INDUCED AMNESIA

relate to changes in brain mass, decreased cerebral blood flow, or increased permeability in the bloodbrain barrier. Pharmacodynamic changes reported with benzodiazepines relate to changes in receptor sensitivity (DeMaagd, 1995). Benzodiazepines have been found to increase the risk of CNS toxicity, resulting in confusion, anterograde amnesia, dysphoria, oversedation, dependency, and hangover effects. The pharmacodynamic effects of the benzodiazepines are produced through binding to specific y-aminobutric acid (GABA) receptors and through an increased opening of chloride channels in the CNS. GABA is the major inhibitory neurotransmitter in the CNS (Ballenger, 1995). By binding with the GABA receptor, the benzodiazepine increases the affinity for the GABA receptor for GABA, thus allowing an increased flow of chloride ions into the neurons. Research has identified subunits of benzodiazepine receptors (BZ), BZ-1 and BZ-2, in the CNS (Kaplan & Sadock, 1996; Ballenger, 1995). BZ- 1 receptors, the most common GABA receptor class in the CNS, are found high in the cerebellum and low in the hippocampus, and are involved in the intervention for sleep. The BZ-2 receptors, found high in the hippocampus, striatum, and spinal cord, interact with cognition, memory, and motor control. A third class of BZ receptors have been found to be relatively insensitive to benzodiazepines. Peripheral-type BZ receptors have been identified in peripheral tissues and share some of the properties for high affinity for certain types of benzodiazepines, with, however, different binding requirements (Ballenger, 1995). It may be theorized, based on the different actions of the BZ-1 and BZ-2 receptors, that hypnotic benzodiazepines affecting only the BZ-1 receptor would have less cognitive impairment and amnestic adverse effects than benzodiazepines presently on the market. BENZODIAZEPINES AND ANTEROGRADE AMNESIA

One generally recognized change with aging is a decline in intelligence and memory (Hanninen, et al., 1994; Jutagir, 1994). These age associated changes in memory were once described by Kral (1958) as "benign senescent forgetfulness" and have more recently been referred to as ageassociated memory impairment (AAMI) by the National Institute of Mental Health (Hanninen, et al., 1994). In addition to an increased potential for

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memory impairment with aging, the prescription of CNS medications, such as the benzodiazepines, only confound the clinical picture. Polster (1993) presents a comprehensive history and literature review of the research on druginduced amnesia. The original focus of these studies were on identifying drugs that produce amnesia that could be used during surgical procedures. The most recent trend is to consider the cognitive nenropsychological approach to memory and amnesia. This approach establishes the relationship between brain structures and processes in relation to performance on specific cognitive tasks. Psychologically oriented and theoretically based studies set out to establish the differences between short- and long-term memory. Scopolamine, the drug used in these studies gave the first clear evidence of the distinction between short-term (immediate recall) and long-term (delayed recall) memory formation processes (Polster, 1993). The first incidents of benzodiazepine-induced amnesia were reported in the 1960s (Mejo, 1992). At first, the amnestic state was thought to be related only to the higher doses and the intravenous route of administration of the drug. The first benzodiazepine available was chlordiazepoxide. It appeared in the late 1950s for the treatment of anxiety (Mejo, 1992). With the safer side effects touted by this drug group, benzodiazepines quickly replaced the use of meprobamates and barbiturates. In 1973, 87 million prescriptions for benzodiazepines were filled (Mejo, 1992). These drugs have been used to treat a wide range of problems including sleep disorders, seizures, anesthesia, muscle spasms, alcohol withdrawal, anxiety, panic disorders, and stress. By 1987, 11% of American adults had used a medication from this group (Mejo, 1992). Emerging from the cumulating research on memory impairment are two drug models; the benzodiazepine model and the cholinergic model. These models are proving to be more similar than dissimilar (Rusted, Eaton-Williams, & Warburton, 1991). Both drug groups can disrupt the transfer of new information from short-term memory to storage in long-term memory, creating an amnestic effect. The older adult may be unaware of his or her memory loss unless a large block of time has passed, or the memory loss is pointed out by a family member. It became evident, through studies, that therapeutic doses and/or even a single dose could show memory impairment (Mejo, 1992).

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Research studies into benzodiazepine amnestic adverse reactions, along with other adverse reactions of the drug, now commonly agree that benzodiazepines are associated with anterograde amnesia (Kaplan & Sadock, 1996; Vgontzas, Kales, & Bixler, 1995; DeMaagd, 1995; Mejo, 1992). Anterograde amnesia occurs shortly after the administration of the benzodiazepine, at its peak concentration. The memory impairing effect of benzodiazepines is limited to recent events or to the loss of the ability to form memories (to learn), despite an apparent alert state of mind. This may also involve impaired retrieval of information occurring in hippocampal and related temporal lobe structures. This inability to learn and store new information is what is known as anterograde amnesia (Boss, 1988). A great deal of research has been generated concerning a media popularized benzodiazepine, triazolam. Rothschild (1992) completed a comprehensive review of the literature from 1975 concerning this benzodiazepine concluding that, despite the considerable publicity in the lay press, this particular benzodiazepine did not have a higher likelihood of producing adverse reactions, such as anterograde amnesia, than any of the other benzodiazepines. A study performed by Hindmarch, Sherwood and Kerr (1993) concurs with Rothschild's findings that the amnestic profile of triazolam is similar to other benzodiazepines, however, this drug may possess a distinct lack of residual effects because of it's short half-life. Much scientific debate has been spent on anterograde amnestic effects being related to route of administration, frequency of administration, and potency (length of half-life) of the benzodiazepine. Curren, Schiwy, and Lader (1987) examined the anterograde amnestic effects of lorazepam and oxazepam and found that there was no linear dose-related relationship between the two benzodiazepines. Another dose-related study examined the possibility that compounds with high benzodiazepine receptor affinity would be more likely to cause amnestic effects than those with lower affinity (Scharf, Fletcher, & Graham, 1988). Kumar, Mac, Gabrielli, and Goodwin (1987) did find a decrease in performance on an anterograde memory recall task after dosing for 6 days on both lorazepam and alprazolam. The review of the current literature generally supports the assumption that the route, dose, frequency, and potency of the

DEBORAH D. SUMNER

benzodiazepine does influence the degree of anterograde amnesia experienced.

SUBSTANCE-INDUCED PERSISTING AMNESTIC DISORDER

The American Psychiatric Association, DSM IV (1994), discusses three categories of Amnestic disorders. Inclusive to all three categories is the common symptom of memory impairment. The DSM IV (1994) stipulates two essential features of memory impairment: (1) there is an inability to learn new information or recall information learned previously, and (2) the memory impairment must cause considerable disturbance in social or occupational functioning. An individual suffering from an amnestic disorder may appear confused and disoriented to time and place. It is extremely rare, however, for the individual to lose orientation to person (self). If other cognitive impairments are present, it is probably not an amnestic disorder (Kaplan, Sadock, & Grebb, 1994). The difference in the three amnestic disorders is the etiology. Amnesia may be caused by systemic medical conditions, primary brain conditions, substance-related causes, or unknown cause. Neuroanatomical structures implicated with amnestic disorders and memory are the diencephalic structures (e.g., dorsomedial and midline nuclei of the thalamus) and the midline temporal lobe structures (e.g., the hippocampus, the mammillary bodies and the amygdala) (Kaplan, Sadock, & @ebb, 1994). Kaplan, Sadock, and Grebb (1994) report that there are no adequate studies available on general incidence or prevalence of amnestic disorders. Alcohol related disorders and head injuries will commonly exhibit amnesia. Alcoholic WeruickeKorsakoff syndrome related to a thiamine deficiency is a well-known example. CNS drugs have been implicated in the development of amnesia, of which the benzodiazepines are a prime example. The differentiation between amnestic syndrome and amnestic disorder has been eliminated in the DSM IV (1994). A diagnosis of substance-induced persisting amnestic disorder is made when the symptoms are caused by the use of a substance (see Table 2 for diagnostic criteria). The use of the term "persisting" indicates that the disturbance remains after the individual is no longer suffering the effects of substance intoxication or withdrawal. The diagnosis, when established, would include the specific

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BENZODIAZEPINE-INDUCED AMNESIA

Table 2. Substance-Induced Persisting Amnestic Disorder Diagnostic Criteria (American Psychiatric Association, 1994) 1. The development of memory impairment as manifested by impairment in the ability to learn new information or the ability to recall previously learned information. 2. The memory disturbance causes significant impairment in social or occupational functioning and represents a significant decline from previous level of functioning. 3. The memory disturbance does not occur exclusively during the course of a delirium or a dementia and persists beyond the usual duration of substance intoxication or withdrawal. 4. There is evidence from the history, physical examination, or laboratory findings that the memory disturbance is etiologically related to the persisting effects of substance use (e.g, a drug of abuse, a medication). Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Copyright 1994 American Psychiatric Association.

substance, e.g., benzodiazepine-induced persisting amnestic disorder (Kaplan, Sadock, & Grebb, 1994). As the older adult is unaware of the memory loss, recall of information not transferred to longterm memory after the administration of the benzodiazepine persists. This lack of recall has shown a decreased performance of tasks after both single and continued ingestion of the drug which, depending on the task, can pose considerable disturbance in social and occupational functioning.

LITERATURE

REVIEW SUMMARY

Clinical differences among the benzodiazepines largely reflect differences in pharmacokinetic properties. The onset of action after single oral doses reflects the rate of absorption from the GI tract which is slowed with the aging process. The duration of action is determined by the rate and extent of drug distribution to brain and peripheral tissues, as well as by the rate of elimination and clearance, all of which are subject to the effects of the aging process. The clinical relevance of the benzodiazepine-induced anterograde amnesia is underscored by the fact that the older adult taking this medication is most often unaware of the memory impairment. Given the decline in memory function as a normal part of aging, the anterograde amnestic effects of benzodiazepines, and the D S M / V (1994) criteria for substance-induced persisting amnestic disorder, it is more than plausible that with the continued use of benzodiazepines in this population, older adults should be assessed for benzodiaz-

epine-induced persisting amnestic disorder as part of an evaluation of memory impairment. IMPLICATIONS

FOR CLINICAL

PRACTICE

CNS medications and benzodiazepines with known potential for increased adverse effects, as well as for abuse, accounted for 30% of the prescriptions written for adults older than the age of 60. The Federal Drug Administration reports that older adults (older than 60) were responsible for 33% of the hospitalizations resulting from adverse medication effects and 50% of the fatalities (LeSage, 1991). Confusion, cognitive impairment, and distortions of memory, may easily be attributed by the practitioner to the changing physiological stares or chronic illnesses of the older adult (LeSage, 1991; Palmieri, 1991; Mejo, 1992). Given the frequent use of CNS medications, particularly the benzodiazepines with older adults, the practitioner must be skilled in neuro-cognitive assessment. A thorough physical examination, laboratory battery, and medication history that includes over-the-counter medications, is the imperative. One of the most common complaints that older adults have concerns sleep disorders for which benzodiazepines are the most frequently prescribed medication (Vogel, 1992). It is not unusual for the older adult to attempt to apply pressure to receive a prescription from the practitioner for a mild tranquillizer or sleep aid. Should a thorough assessment uncover problems with insomnia, stress and anxiety, or even depression, there are a number of nonpharmacological and pharmacological alternatives to benzodiazepines. Nonpharmacological interventions include setting regular routine times for rising in the morning and going to bed at night. Also, not watching TV or reading in bed before attempting to fall asleep is recommended. Not napping in the daytime and increasing exercise by walking may help to alleviate stress, anxiety, and depression, as well as promote better sleeping habits. Should these alternatives not work, pharmacological alternatives still remain for these problems for the older adult. Often small doses of medications like trazadone, an antidepressant, or buspirone, a nonbenzodiazepine anxiolytic will help to eliminate the problem. It is important to remember to start older adults on small doses, often lower than the usual adult dose, and titrate up as tolerated. Before starting any medication with the potential for memory impair-

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ment, a baseline Mini-Mental State Exam (MMSE) should be completed. This provides the practitioner with a tool for reassessing any changes or adverse reactions should they occur. It is inevitable that the practitioner will encounter older adults on benzodiazepines, some having been on them for long periods of time and often taking larger doses than expected. They may complain that the medication is no longer working and have increased their dose because of development of tolerance to the medication. Even if the older adult experiences memory deficits caused by the benzodiazepine use, he or she may be too embarrassed to say so (Scharf, Fletcher, &: Graham, 1988). It will become the task of the practitioner to assess the older adult for cognitive impairment and begin the process of titrating down, taking the individual off the benzodiazepine. This will be a slow and arduous process, and not always successful. The presence of endogenous benzodiazepinelike molecules are suggested by the presence of benzodiazepine receptors in the brain (Vgontzas, Kales, & Bixler, 1995). These authors speculate that the production and level of these molecules would be regulated by the circulating concentrations or a feedback mechanism. With the introduction of exogenous benzodiazepines, the production of the endogenous molecules would be decreased. The abrupt withdrawal of the benzodiazepine drugs with short duration of action is likely to result in an intense form of rebound insomnia and anxiety. It is possible, that the longer acting benzodiazepines may allow for partial restoration of the endogenous molecules, thus reducing the intensity of the rebound insomnia and anxiety. The practitioner, with cooperation of the older adult, must set a detoxification schedule for safely eliminating the drug. Detoxification from benzodiazepines should not be done quickly and may take as long as 4 to 6 months depending on the amount and frequency of the drug taken. The practitioner needs to be aware that this will take intense monitoring of overt symptoms, such as pulse and blood pressure, and may require the use of other medications, such as antidepressants, to decrease the rebound insomnia and anxiety created by the withdrawN. A sample withdrawal protocol is presented in Table 3.

DEBORAH D. SUMNER

Table 3. Sample Withdrawal Protocol for Benzodiazepines

Day 1 Day 2 Day 3-6 Day 7-10 Day 11-14 Day 15-18

A.M.

Noon

RM.

1 mg .75 mg .75 mg .75 mg .50 mg .50 mg

1 mg 1 mg 1 mg .75 mg .75 mg .75 mg

1 mg 1 mg .75 mg .75 mg .75 mg .50 mg

NOTE: Dose at beginning of detox protocol: Klonopin 1 mg three times dally. The decreases in doses continue to drop gradually, using the same pattern. The number of days that the older adults remains at a certain dosage level will depend on their response to the detoxification process, level of tolerance for rebound symptoms, and physiological parameters. Detox protocol adapted from 2/4/97 Pharmacology lecture provided by Christine E Svenson ARNP, MS, CS.

IMPLICATIONS FOR RESEARCH

With the discovery of benzodiazepine receptors BZ-1, BZ-2, and others, the possibility of endogenous benzodiazepine-like molecules that interact with these receptors warrants further exploration. The evaluation and development of medications that specifically act with one of the BZ receptors may lead to better medications that have diminished amnestic as well as other cognitive impairing properties. Although most studies conducted on the benzodiazepines have been performed on young healthy adults as opposed to older adults, the conclusion that this amnestic effect is of minor consequence to the individual's functioning and cannot be determined without neuro-cognitive screening remains to be challenged. The age related memory impairment associated with aging predisposes the older adult to a more intense amnestic reaction which may generate confusion that would lead to a substantial disruption of the older adult's ability to function. The use of benzodiazepines in older adults, given this anterograde amnestic reaction, requires further investigation as to the possibility that this continued use of benzodiazepines puts the older adult at risk for the DSM IV diagnosis of benzodiazepine-induced persistent amnestic disorder. CONCLUSION

Given that 25% to 40% of the prescribed medications are consumed by 12% of the population, those older than 60 years of age, it is imperative that the pharmacokinetics and pharmacodynamics of the aging process are understood. The increasing use of

BENZODIAZEPINE-INDUCED AMNESIA

CNS medications, in particular the benzodiazepines, implores the practitioner to further understand and examine the cognitive impairments experienced by older adults. Although some are the associated memory changes of aging, many are created by the use of medications that overload the sensitive homeostasis of the older adult's system. Research today is expanding the base of knowledge concerning the brain and its neurotransmitter system. Practitioners must keep abreast of this ever growing body of knowledge and be prepared to apply this knowledge base to the treatment of older adults. REFERENCES American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: Author. Ballenger, J.C. (1995). Benzodiazepines. In A.E Schatzberg & C.B. Nemeroff (Eds.), Textbook of Psychopharmacology (pp. 215-230). Washington, DC: American Psychiatric Press, Inc. Boss, B.J. (1988). Memory impairments: Forgetfulness versus amnesia. Journal of Neuroscience Nursing, 20(3), 151158. Corm, V., Taylor, S., & Miller, R. (1994). Cognitive impairment and medication adherence. Journal of Gerontological Nursing, 20 (7), 41-47. Curran, H.V., Schiwy, W., & Lader, M. (1987). Differential amnestic properties of benzodiazepines: A dose response comparison of two drugs with similar elimination halflives. Pharmacology, 92, 358-364. Dellasega, C. & Stricklin, M.L. (1996). Use of central nervous system medications among elderly home health clients. Applied Nursing Research, 9 (3), 130-135. DeMaagd, G. (1995). High-risk drugs in the elderly population. Geriatric Nursing, 16 (5), 198-207. Greenblatt, D.J., Miller, L.G., & Shader, R.I. (1990). Neurochemical and pharmacokinetic correlates of the clinical action of benzodiazepine hypnotic drugs. The American Journal of Medicine, 88 (Suppl. 3A), 3A-18S. Hanninen, T., Reinikinen, K.J., Helkala, E.L., Koivisto, K., Mykkanen, L., Laakso, M., Pyorala, K., & Rie!ddnen, P.J. (1994). Subjective memory complaints and personality traits in normal elderly subjects. Journal of the American Geriatric Society, 42(1), 1-4.

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Hindmarch, 1., Sherwood, N., & Kerr, J.S. (1993). Amnestic effects of triazolam and other hypnotics. Progress in Neuro-Psychopharmacological and Biological Psychiatry, 17 (3), 407-413. Jutagir, R. (1994). Psychological aspects of aging: When does memory loss signal dementia? Geriatrics, 49(3), 45-52. Kaplan, H.I. & SMock, B.J. (1996). Pocket Handbook of Psychiatric Drug Treatment (2nd ed.). (pp. 49-56). Baltimore, MD: Williams & Wilkins. Kaplan, H.I., SMock, B.J. & Grebb, J.A. (1994). Synopsis of psychiatry: Behavioral sciences clinical psychiatry (7th ed.). (pp. 357-361). Baltimore, MD: Williams & Wilkins. Kral, V.A. (1958). Neuropsychiatirc observations in an old people's home. Journal of Gerontology 13, 169-176. Kumar, R., Mac, D.S., Gabrielli, W.E, & Goodwin, D.W. (1987). Anxiolytics and memory: A comparison of lorazepam and alprazolam. Journal of Clinical Psychiatry, 48 (4), 158-160. LeSage, J. (1991). Polypharmacy in geriatric patients. Nursing Clinics of North America, 26 (2), 273-287. Maxmen, J.S. & Ward, N.G. (1995). Antianxiety Agents. In Psychotropic Drugs Fast Facts (2nd ed.) (pp. 255-312). New York: W.W. Norton & Company, Inc. Mejo, S.L. (1992). Anterograde amnesia linked to benzodiazepines. Nurse Practitioner, 17 (10), 44, 49-50. Palmieri, D.T. (1991). Clearing up the confusion: Adverse effects of medications in the elderly. Journal of Gerontological Nursing, 17 (10), 32-35. Polster, M.R. (1993). Drug-induced amnesia: Implications for cognitive neuropsychological investigation of memory. Psychological Bulletin, 114 (3), 477-493. Rothschild, A.J. (1992). Disinhibition, amnestic reactions, and other adverse reactions secondary to triazolam: A review of the literature. Journal of Clinical Psychiatry, 53 (Suppl. 12), 69-79. Rusted, J.M., Eaton-Williams, R, & Warburton, D.M. (1991). A comparison of the effects of scopolamine and diazepam on working memory. Psychopharrnacology, 105 (3), 442-445. Scharf, M.B., Fletcher, K., & Graham, J.R (1988). Comparative amnestic effects of benzodiazepine hypnotic agents. Journal of Clinical Psychiatry, 49 (4), 134-137. Vgontzas, A.N., Kales, A., & Bixler, E.O. (1995). Benzodiazepine side effects: Role of pharmacokinetics and pharmacodynamics. Pharmacology, 51, 205-223. Vogel, G. (1992). Clinical uses and advantages of low doses of benzodiazepine hypnotics. Journal of Clinical Psychiatry, 53 (Suppl. 6), 19-23.