CURRENT PERSPECTIVES

A Guide to Benzodiazepine Selection. Part II: Clinical Aspects* ERIC TEBOUL, M.D., C.M. 1 AND GUY CHOUINARD, M.D., M.SC,(Phannacoli

To suit the specific needs of various clinical situations, selection ofan appropriate benzodiazepine derivative should be based on consideration oftheir different pharmacokinetic and pharmacodynamic properties. Benzodiazepine derivatives that are rapidly eliminated produce the most pronounced rebound and withdrawal syndromes. Benzodiazepines that are slowly absorbed and slowly eliminated are most appropriate for the anxious patient, since these derivatives produce a gradual and sustained anxiolytic effect. Rapidly absorbed and slowly eliminated benzodiazepines are usually more appropriate for patients with sleep disturbances, since the rapid absorption induces sleep and the slower elimination rate may induce less tolerance to the sedative effect. Rational selection ofa benzodiazepine for the elderly and for the suspected drug abuser is more problematic. The relevant pharmacokinetic and clinical considerations for these users are discussed. Certain derivatives may possess pharmacodynamic properties not shared by the entire benzodiazepine class; empirical studies have suggested the existence of anti-panic properties for alprazolam and clonazepam, antidepressant properties for alprazolam, and anti-manic properties for clonazepam and possibly lorazepam.

these derivatives which should form the basis for discriminating between them for use in different clinical situations. In Part I of this paper (l), we reviewed the pharmacological principles of benzodiazepines, focusing on those properties that differentiate the various derivatives. These included rate of onset, Iipophilicity, and elimination rate. In this paper, we will apply these principles to clinical practice, examining the combinations of pharmacological properties that are most desirable in certain clinical situations. Since rebound and . withdrawal syndromes have become an important concern in the use of benzodiazepines, we will begin with a review of these syndromes and their relationship to elimination (~) half-life. We will then consider the relevant issues in the selection of a benzodiazepine for anxious patients, patients with sleep disturbances, drug abusers, and elderly patients. Some benzodiazepines have recently been found efficacious in the treatment of panic disorder, depression, agitation and mania; this literature is also reviewed.

Rebound and Withdrawal Syndromes Rebound, withdrawal, and dependence are closely related phenomena, but these terms are not synonymous. "Rebound" is defined as the relative worsening of symptoms upon discontinuation of treatment as compared with symptoms present at baseline (2). The benzodiazepine withdrawal syndromes include not only rebound symptoms, but also new symptoms which were not present in the original illness and are not in the opposite direction to known benzodiazepine action. Rebound, withdrawal and the development of tolerance to certain pharmacodynamic effects (I) suggest that the brain develops some compensatory mechanisms to counteract the effects of the drug (3). An equilibrium is formed between the effects of the drug and the compensatory neurobiological mechanisms. Should this equilibrium be disrupted by abrupt discontinuation of the drug, rebound and/or withdrawal symptoms may develop as the compensatory mechanisms persist unopposed. These symptoms last until the induced compensatory mechanisms can return to the baseline state. With gradual discontinuation of the drug, however, these adaptive mechanisms have time to readjust in step with diminishing amounts of drug, and so rebound symptoms are attenuated or avoided (4,5). The term "physiological dependence" implies that biological adaptation to the effects of the drug occurs.

B

enzodiazepines are a widely used class of drugs with proven efficacy and safety for treating anxiety and sleep disorders. While just over 25 years ago the only choice to be made was between chlordiazepoxide and diazepam, today's clinician must choose among more than a dozen benzodiazepine derivatives currently available in Canada (l). Although this choice may appear arbitrary, there are certain pharmacokinetic and pharmacodynamic differences between

*Manuscript received June 1990. I Resident, Department of Psychiatry, McGill University, Montreal, Quebec. 2 Professor of Psychiatry, Psychiatric Research Center, Louis-H. Lafontaine Hospital; Clinical Psychopharmacology Unit, Allan Memorial Institute; Department of Psychiatry, McGill University; Department of Psychiatry, University of Montreal, Montreal, Quebec. Addressreprintrequeststo: Dr. Guy Chouinard, Louis-H. Lafontaine Hospital, 7401 Hochelaga Street, Montreal, Quebec HIN 3M5

Can. J. Psychiatry Vol. 36, February 1991

62

CHOOSE WELL.

When the patient history points to

D E POT

0

~HALDO[LA HALOPERIDOL

DECANOATE

When the patient history points to R A L

OropAY

* 2rNRNATlVE TO

PimozidePHENOTHIAZINES

\\... haloperidol decanoate is at least as effective as depot forms of fluphenazine, plpothlazlne, f1upenthixol and perphenazine in controlling the symptoms of psychosis. Extrapyramidal side effects and the need for concomitant anti-Parkinsonian drugs may be a problem, butmay be less frequent than with oral haloperidol or other depot antlpsychotics,'"

Aunique mode ofaction separates ORAp· pimozide from phenothiazines, and thisdifference may influence clinical results. In fact, pimozide has the most clinical support of any oral neuroleptic fora superior ability to improve negative symptoms.' This complements a well-documented capacity for posltlve symptom control. 3 In addition, highly specific D2 receptor binding' may make side effects such as sedation less Iikely.S

ONE MONTH OF CONTROL, ON ONE DAY'S COMPLIANCE.

AUNIQUE ALTERNATIVE TO PHENOTHIAZINES.

For brief prescribing Information see page A31, A32

IPMs1 lfillJ

A20

64

CANADIAN JOURNAL OF PSYCHIATRY

Tolerance develops during treatment, and rebound or withdrawal symptoms appear after discontinuation of the drug (3). "Psychological dependence" refers only to the patient's subjective need for the drug, independent of tolerance or withdrawal symptoms. Rebound Insomnia Rebound insomnia was first identified and defined in 1978 by Kales and associates (6) as a syndrome characterized by worsening of insomnia compared to baseline levels following abrupt discontinuation ofbenzodiazepine hypnotics that have rapid elimination rates. Since then, a large number of sleep laboratory studies using polygraphic sleep recordings have investigated the occurrence ofrebound insomnia with various benzodiazepine derivatives (7). Triazolam (0.5 mg), the most rapidly eliminated oral benzodiazepine derivative (~ half-life = two to six hours) has been most consistently associated with the emergence of rebound insomnia upon abrupt drug discontinuation after as little as one week of nightly use (8-13), although not all studies found evidence of rebound insomnia (14,15). At the lower dose of 0.25 mg, mild rebound insomnia was reported upon cessation after two weeks of use (16) but not after one week of use (17,18). At both 0.5 mg and 0.25 mg doses the rebound insomnia lasted only for the first one or two nights after withdrawal and returned to baseline thereafter. Gradual tapering off of the drug over a few days has been shown to attenuate or avoid triazolam-induced rebound insomnia in a study of insomniac volunteers in a non laboratory situation (5). The evidence for the occurrence of rebound insomnia with other benzodiazepines is less consistent than for triazolam. With temazepam (15 mg or 30 mg doses), a derivative with an elimination half-life of five to 20 hours (I), only nonsignificant trends have been reported suggesting the occurrence of a mild form of rebound insomnia during the first few nights after withdrawal (19-22). Lorazepam, a derivative with an elimination half-life often to 20 hours (1), was shown in one study (23), to have caused significant rebound insomnia on the third and fifth nights following withdrawal after one week of nightly use at the relatively high dose of 4 mg. Nitrazepam (5 mg), a derivative with an elimination half-life of 20 to 40 hours (I), was reported to cause rebound insomnia which was worse on the second withdrawal night, after ten weeks of nightly use (24). Flurazepam, a slowly eliminated derivative (~ half-life of the active desalkyl metabolite is 40 to 100 hours) (I) has not generally been found to cause rebound insomnia after discontinuation of either the 30 mg (12,25-30) or 15 mg (31) doses. In fact, hypnotic efficacy often persists for the first three nights after withdrawal (32,33). However, two studies reported evidence suggesting the occurrence of mild and delayed rebound insomnia between the fourth and tenth nights following withdrawal after discontinuation of the 30 mg dose (10,34). Rebound insomnia was originally defined as occurring after discontinuation of the drug. However, treatment does not always have to be discontinued for rebound phenomena to occur. Early morning insomnia, a form of rebound insomnia where the patient has a significant increase in wakefulness

Vol. 36, No. 1

during the final hours of the nights when the drug was used, was found by Kales and associates (35) after one to two weeks of nightly administration of the very rapidly eliminated derivatives, triazolam and midazolam. However, other sleep laboratory studies have found no evidence of early morning insomnia with triazolam or any other hypnotic (7). Rebound insomnia has been shown to occur after abrupt discontinuation of triazolam and other rapidly eliminated benzodiazepines. A milder, delayed rebound syndrome may occur less frequently after abrupt discontinuation of more slowly eliminated derivatives such as flurazepam. However, most of these studies looked at a relatively short duration of treatment and withdrawal. The true prevalence and severity of rebound insomnia may therefore be underestimated, especially in patients who have been taking short half-life benzodiazepines over a four week period. Although rebound insomnia is usually transient (lasting only a few days), the distress engendered may promote psychological dependence. Rebound Anxiety - Rebound anxiety is an acute worsening of anxiety beyond pretreatment baseline levels following the cessation of benzodiazepine anxiolytic treatment. The anxiety symptoms suddenly return all together and/or are more severe than in the original illness. This syndrome is usually transient, but may last up to three weeks following drug cessation (36). In some patients, the rebound anxiety may be so severe that drug therapy needs to be resumed. The introduction of short- and intermediate-elimination half-life benzodiazepines has led to a greater risk of rebound anxiety than is seen with the use of long-elimination half-life agents. Rebound anxiety has been described as occurring following abrupt cessation of daytime anxiolytic treatment, but it can occur together with rebound insomnia after discontinuation of regular nightly doses (23). Similarly, patients who develop rebound anxiety following discontinuation of a daytime benzodiazepine anxiolytic may also develop rebound insomnia at night (4). In the past ten years, many studies have looked at the consequences of discontinuing benzodiazepines, but a recent review found methodological problems in many of these studies (37). These studies are not always comparable, because they use different definitions of rebound anxiety and withdrawal syndromes. Four placebo-controlled studies carried out at the Clinical Psychopharmacology Unit of the Allan Memorial Institute in Montreal (126 patients in total) indicated that the risk of rebound anxiety after abrupt benzodiazepine withdrawal appears to be related to the rate of elimination (4,36,38). Rapidly eliminated derivatives such as lorazepam and bromazepam, had a 70% and 50% incidence of rebound anxiety, respectively, upon early termination, whereas diazepam, which is more slowly eliminated, had only a 25% incidence of rebound anxiety. The risk of developing rebound anxiety was independent of the length of previous benzodiazepine treatment (4). Impairment of subjective cognitive performance during benzodiazepine withdrawal was associated with rebound anxiety and persisted for at least three weeks after the therapy had been stopped (36). Gradual discontinuation by tapering

February. 1991

BENZODIAZEPINE SELECTION: CLINICAL ASPECTS

the dose over a period of a few days to weeks has been shown to prevent rebound anxiety (4). As was the case for rebound insomnia, rebound anxiety was originally defined as occurring after drug discontinuation, but it may also occur during ongoing treatment with rapidly eliminated derivatives. Increased daytime anxiety following a bedtime dose of triazolam 0.5 mg (39,40) and interdose rebound anxiety in alprazolam-treated panic disorder patients occurring three to four hours after their last dose ("clock-watching") (41) have been described. Withdrawal Symptoms: New Symptoms New symptoms observed during withdrawal of CNS depressant drugs (such as barbiturates and benzodiazepines) include dysphoria, depersonalization, loss of appetite, headache, muscle aches and twitches, nausea, tremor, and perceptual disturbances (such as metallic taste, paresthesias, and hypersensitivity to light, sound, touch and smell) (42). Upon benzodiazepine withdrawal, these new symptoms are frequently seen together with rebound symptoms of the original illness. These two syndromes, however, appear to be somewhat independent of one another, in that they do not always occur together, and can be of different durations even when they do occur together (4). Higher doses and a prolonged duration of use increase the risk of withdrawal or rebound symptoms, although they can be seen even after short term use at therapeutic doses (37). As is the case with rebound phenomena, withdrawal symptoms are more prominent after discontinuation of derivatives with rapid elimination rates. Tyreret al (43) found a greater incidence of withdrawal symptoms upon abrupt discontinuation of lorazepam than with diazepam, which has a much longer elimination rate (1). In contrast, Rickels et al (44) found that the severity (but not the incidence) of withdrawal symptoms was related to benzodiazepine elimination rates: 75% of patients withdrawn from benzodiazepines after long term use developed clear withdrawal symptoms regardless of whether they were withdrawn from rapidly eliminated or slowly eliminated derivatives. However, withdrawal from the rapidly eliminated derivatives produced symptoms that were clearly more severe. In a study by Busto et al (45), the elimination rates of the benzodiazepines predicted the time course of development of subsequent withdrawal symptoms: after discontinuation of rapidly eliminated benzodiazepines (lorazepam and oxazepam) withdrawal symptoms occurred the following day, whereas in patients using more slowly eliminated derivatives (mainly diazepam), the mean onset of withdrawal symptoms was five days after discontinuation, and the peak severity of symptoms occurred an average of 9.6 days after discontinuation. In most studies withdrawal symptoms are usually mild and subside completely by two to four weeks after abrupt benzodiazepine cessation (37). Gradual benzodiazepine tapering can minimize or eliminate rebound anxiety and withdrawal symptoms (4). Severe reactions to benzodiazepine withdrawal occur only rarely but can include psychosis (46-48) and seizures (37,49-

65

51). Withdrawal seizures occur more often in subjects with predisposing factors, such as a history of brain damage, alcohol addiction, or abnormal electroencephalograms (52), or in subjects who are also receiving drugs which lower the seizure threshold, such as tricyclic antidepressants or neuroleptics (53). Choosing the Most Appropriate Derivative for the Clinical Situation Anxious Patients Although some degree of anxiety in response to the stresses of daily life is unavoidable and may indeed be beneficial in optimizing performance and stimulating adaptive behaviour, for some people anxiety may become excessive, maladaptive, continuous, and only loosely related to external stressors. For patients with this pathological free-floating form of anxiety, benzodiazepine therapy may be a valuable component of the overall psychiatric treatment. In such patients, an appropriate benzodiazepine could provide a smooth onset of action with minimal perceptible CNS effects after acute dosing and a continuous plateau of anxiolytic action with multiple dosing (54). Such a derivative would have relatively slow absorption and elimination rates, such that accumulation occurs and plasma level fluctuations are minimized. Clonazepam and ketazolam, for example, would be logical choices. Halazepam and prazepam also have these properties and are available in the United States but not in Canada. While many patients take benzodiazepines for relatively brief periods, some patients with chronic anxiety are unable to function adequately without long term benzodiazepine therapy. These patients are seldom physiologically addicted, rarely show inappropriate drug-taking behaviour such as dose escalation (55), and rarely abuse the drug to get "high" (56). Most authors (53,56-59) agree that long term benzodiazepine therapy is often appropriate for such patients and is associated with less morbidity than untreated anxiety. Furthermore, if untreated, some patients may turn to the use of alcohol and/or cigarettes to relieve their anxiety, both of which carry a greater long term risk. Patients with Sleep Disturbances There are many reasons for which a patient may experience transient or long-lasting sleep disturbances, including a variety of psychiatric and medical conditions (60). Many of these cases of insomnia can be managed by treating the underlying cause and/or using a variety of non pharmacological methods. However, judicious use of a benzodiazepine as part of the overall management of patients with sleep-disturbances is often beneficial and appropriate. Flurazepam, nitrazepam, temazepam, and triazolam are the four benzodiazepines marketed in Canada as hypnotics. The other benzodiazepines may also be used for night-time sedation, since they possess some sedative properties, although not all to the same degree (53,61,62). Several pharmacologic factors are relevant in choosing a benzodiazepine. The time to peak plasma level gives some

66

CANADIAN JOURNAL OF PSYCHIATRY

indication ofthe time to onset ofsedative action, although the patient is usually asleep long before the peak plasma concentration is reached. A rapidly increasing plasma concentration culminating in a sharp peak, seen with such rapidly absorbed derivatives as diazepam, flurazepam, and clorazepate, produces a strong sleep-inducing effect, whereas the delayed, lower and more diffuse peak seen with slowly absorbed benzodiazepines such as oxazepam and ketazolam is much less effective for inducing sleep (I). The latter profile, however, may be effective for sleep maintenance, i.e. reducing the frequency of nightly awakenings. The development of chronic pharmacodynamic tolerance is another important consideration. During the first few days of use, both rapidly eliminated and slowly eliminated benzodiazepines are effective for inducing and maintaining sleep. The initial use of slowly eliminated benzodiazepines, such as flurazepam, is associated with impairment on performance tests the next day. After one week of nightly use, tolerance develops such that there is no longer significant impairment on performance tests (63), but sedative effi~cy is maintained with prolonged use (64). In contrast, rapidly eliminated benzodiazepines, while initially effective, tend to lose their sedative efficacy over the first few weeks of use (7,64,65) and may lead to early morning rebound inso~ia (35) and next-day rebound anxiety (39) as d~ri~ earh~r. Lorazepam and triazolam are the two derivatives which have been most often associated with cognitive impairment and anterograde amnesic effects (15,23,66-71). These amnesic effects may occasionally be desirable for pre-anaesthetic use or prior to endoscopic procedures. Oral diazepam or clorazepate do not appear to produce similar memory impairment (66,69,72). Further studies ~ n~eded t? cl:mfy the cognitive effects of the other benzodiazepine derivatives, In a series of anecdotal reports (73-80), triazolam was reported to cause global amnesic syndromes in travellers using triazolam to avoid jet lag, and in other triazolam users. Typically, on awakening from triazolam-induced sleep, the~e subjects were not confused and were able to go about their business in an appropriate manner; however, they would "come to" several hours later with no recollection of the preceding events, despite having frequently performed complex tasks in the interim. We recommend that rapidly absorbed but slowly eliminated benzodiazepines such as flurazepam, diazepam and clorazepate be used by most patients with insomnia, especially if carryover of daytime anxiolysis is desirable and they are to be used for a week or longer. Rapidly absorbed and rapidly eliminated benzodiazepines, such as bromazepam, may be preferable if optimal alertness and performance are important the next morning. However, they should not be used for more than a few nights, since tolerance to them develops rapidly and renders them ineffective. Tapering the dosage over a few days before cessation would be most prudent, especially for rapidly eliminated benzodiazepines used for nightly sedation for a period of one week or longer. Some patients may develop rebound symptoms despite gradual tapering of a rapidly eliminated

Vol. 36, No. I

benzodiazepine (81). In these cases, it is often helpful to switch to a slowly eliminated benzodiazepine and then taper the dose of this new drug. Drug Abusers Although the great majority of patients for whom benzodiazepines are prescribed will either use them as prescribed, less than prescribed, or reduce their use over time (55), patients with a history of drug abuse may treat a benzodiazepine as another drug of abuse. Such individuals appear to experience "reinforcing", "drug-liking," or mild euphoric effects from these drugs (55,82), whereas normal or anxious subjects who are not drug abusers experience no such effects and generally prefer placebo over diazepam in experimental studies (53,55,83). A rapidly absorbed drug, such as diazepam, will have a rapid onset of action and produce a more distinct peak effect than will a slowly absorbed derivative such as oxazepam whose onset of effect is very gradual and often imperceptible (I). The rapid peak effect is considered desirable by the drug abuser, since it may be associated with a subjective sensation of rush or euphoria (84). Experimental studies have demonstrated that diazepam is indeed preferred over oxazepam by sedative drug abusers (82). Other pharmacokinetic .properties which may be associated with increased abuse potential include a small volume ofdistribution and a short half-life (84). Thus, predictions ofabuse potential are not a simple matter, and empirical studies in sedative abusers are necessary to ascertain a drug's abuse potential. In a recent review of such studies (82), it was suggested that lorazepam may have potential for abuse as diazepam, whereas oxazepam, halazepam and chlordiazepoxide may be less likely to be abused. There is no evidence, however, that such differences in abuse potential apply to populations other than sedative abusers (55), and therefore such data should not be used for drug selection in a general patient population. The use of benzodiazepines by abstinent alcoholics to control anxiety or insomnia is controversial (85,86). Although some feel that benzodiazepine use by alcoholics or drug abusers is never justified (85), a recent critical review of the studies addressing the abuse potential of benzodiazepines among alcoholics found little to support this extreme po~ition (87). Although benzodiazepines as a group have a relatively low potential for abuse (88), the derivatives differ in their abuse potential. Alcoholics are less likely to abuse halazepam than diazepam (89) and may be more likely to abuse alprazolam (90). In a recent study (90), alcoholics given alprazolam rated it highly on a drug-liking scale and showed evidence of a positive change in affective state, while non alcoholics disliked the drug and showed little change in affect. As stressed by Marks (53), only very few drug abusers use benzodiazepines as their primary drug of abuse. The great majority of those who abuse benzodiazepines also abuse other drugs; they use benzodiazepines to counter the undesirable effects of other recreational drug abuse, such as anxiety provoked by an amphetamine or heroin-induced "bad

February, 1991

BENZODIAZEPINE SELECTION: CLINICAL ASPECTS

trip" or symptoms of withdrawal when the drug of primary dependence is unavailable. Elderly Patients The response to benzodiazepines increa~es wi~ no~al aging. Studies on the effect of regular dally dosing With diazepam, chlordiazepoxide, nitrazepam, flu!azepam or temazepam have shown a greater degre~ of sedation ~d CNS depression in the elderly (91,92). With normal aging the hepatic mixed function oxidase system become~ les~ e~­ dent whereas the efficiency of hepatic drug conJuga~lOn IS gene~lly unchanged. Thus, ~rugs undergoing oxidative metabolism (for example, diazepam, flurazepam, chlordiazepoxide) have a decreased clearance,. and th~s a prolonged elimination rate (reflected by an increase 10 ~ half-life) and greater accumulation with continued use (92). However, tolerance occurs such that the degree of clinical sedation does not increase in parallel with the extent of drug accumulation (1). Furthermore, the benzodiazepines which do not accumulate to a greater degree in the elderly (i.e. those not metabolized by oxidation) still cause a greater sedative effect in this population. Controlled clinical trials in the elderly (91,93) have confirmed that there is no correlation between drug accumulation and sedation. Healthy elderly subjects have been shown to have a peak response aft~r acute dosing two to three times greater than yo~nger subjects at similar benzodiazepine plasma concentrations (91). Thus, alterations in benzodiazepine pharmacokinetics occurring with age are not sufficient to explain the more pronounced effects of these drugs on the elderly. Although the mechanisms underlying this increased sensitivity to benzodiazepines are not known, animal experim~nts have fo.und that both benzodiazepine-induced increases 10 GAB A binding (94) and GAB A-induced increases in neu~onal inhibition (95) are greater in aged animals,suggestmg that pharmacodynamic changes such as these, rather than pharmacokinetic changes, may be responsible for greater benzodiazepine sensitivity. In recent years, there has been concern that the risk of hip fracture caused by falls increase when psychotropic drugs with sedative and autonomic effects are used in the elderly (96). Ray et aI (97) found a significantly greater risk of hip fracture in Michigan Medicaid enrollees aged 65 years or older who were currently using antipsychotics (odds ratio = 2.0), tricyclic antidepressants (odds ratio = 1.9), or hypnoticsanxiolytics with elimination half-lives exceeding 24 hours (odds ratio = 1.8). They found that the risk of hip fracture was no greater with current use of non benzodiazepine hypnoticsanxiolytics with elimination half-lives of less than 24 hours. In a subsequent study in Saskatchewan residents 65 years of age or older, they found a relative risk of hip fracture of 1.7 with the use of long elimination half-life benzodiazepines (greater than 24 hours), and 1.1 with the use of short elimination half-life benzodiazepines (less than 24 hours) (98). However, although statistically significant, the clinical significance of these results remains unclear because of the case-control design of these studies. A comparison of the absolute rates of hip fractures in patients on long- and short-

61

elimination half-life benzodiazepines compared with the general population of the sa~e age would be ?tore rel~vant than the relative risk, since If the prevalence IS sufficiently low, even a large relative risk may still not be clinically significant. These absolute rates have ~ot ~en calculated. However, since falls and frequently ensuing hip fractures are a major source of morbidity and mortality. in t~e elderly (~), the clinician should exercise special caution 10 the selection of a benzodiazepine for the elderly. For short term ~ypn~tic use, a rapidly absorbed and eliminated benzodiazepine derivative, such as bromazepam 1.5 109, should be safe an~ appropriate. Although rapidly eliminated, lorazepam and tnazolam should be avoided because of the greater reported cognitive impairment and antero~rade ~nesic eff~ts (15,23,66-71). As stated earlier, rapidly eliminated derivatives have been associated with a greater development of sedative tolerance when used for more than a few weeks (7,64,65). Thus, if more than short te~ use is envisa~ed, a slowly eliminated derivative such as diazepam may still be most appropriate and safe if use~ at a low d?se, sU~h as I mg at bedtime. At this dose level no increased risk of hip fracture could be demonstrated (97). In general, one-third to one-half of the adult dose should be used in the elderly to achieve the same clinical effects. The clinical response should always be closely monitored and the dose adjusted accordingly. The risk of falling increases linearly with the number of risk factors including dementia, visual impairment, postural hypotension, and neurological and musculoskeletal disability (96). The use of any psychotropic medication, including benzodiazepines, should be avoided in elderly patients with these risk factors.

New Indications for Benzodiazepines Panic Disorder The recognition by Klein (99,100) that imipramine could ther.apeu~ic discovery. This anti-panic effect was found to persist WIthlong term use (101), thus secondarily reducing phobic avoidance. Although most benzodiazepines do not appear to be effective in blocking panic attacks (102), Chouinard and associates (103) found that alprazolam possesses anti-panic properties. This finding was later confirmed by other investigators (104,105) and a major multicentre placebo-controlled study (106). Subsequently, we reported the efficacy of clon~z~pam in the treatment of this disorder (107-109). These preliminary results were confirmed in open trials (110, 111) and placebocontrolled (112,113) studies, one of which found a significant correlation between clonazepam plasma concentration and the decrease in number and intensity of panic attacks (113). This is especially interesting in view of the previous failure to find such concentration-effect correlations in benzodiazepine treatment of generalized anxiety disorder (114,115). Although both alprazolam and clonazepam h~ve demonstrated efficacy in panic disorder, they have SIgnificantly different pharmacokinetic properties. Clonazepam is much less lipophilic than alprazolam; thus, it should have

block panic attacks represented a major

68

CANADIAN JOURNAL OF PSYCHIATRY

a lesser tendency to enter adipose tissue and leave the central (plasma and brain) compartment (I). This would lead to a prolonged distribution phase (longer ex. half-life) and therefore a longer duration of action. Clonazepam is also more slowly metabolized, and hence more slowly eliminated (longer ~ half-life). These properties make bid dosing possible and reduce fluctuation in plasma concentrations, making the occurrence of interdose rebound anxiety less likely. Indeed, in a report by Herman and colleagues (116), 82% of the patients who were switched from alprazolam to clonazepam because of interdose anxiety symptoms rated clonazepam "better" because of decreased frequency of administration and lack of interdose anxiety. At this time, clonazepam should be the initial drug of choice for the treatment of panic disorder, since it has a more rapid onset than tricyclic antidepressants and fewer side-effects than either tricyclics or alprazolam. Depression Benzodiazepines are frequently useful in controlling anxiety and insomnia associated with depressive illnesses. Although some mood elevation may occur secondarily to relief of these symptoms, the core symptoms of major depression, including psychomotor retardation, guilt, suicidality and diurnal variation, remain relatively unaffected by most benzodiazepines (117,118). Alprazolam may represent an exception, in that, unlike the other benzodiazepines, it does appear to affect these core symptoms independently of its anxiolytic effect (119,120). Many studies have compared alprazolam to imipramine (121-127), amitriptyline (125,128), doxepin (120,129), desipramine (130), and diazepam (124) for the treatment of depression. The most convincing data comes from four major double-blind placebo-controlled studies (120-122,124), involving a total of over 1,600 depressed outpatients, which consistently found that alprazolam had antidepressant effects equivalent to the comparison tricyclics and superior to diazepam (124) and placebo. However, all four of these studies used average daily tricyclic doses ofless than 150 mg, which may not have been sufficient to produce maximal therapeutic benefit. Addressing this criticism, Fawcett and associates (130) compared therapeutic doses of desipramine (average 230 mg daily) with alprazolam and found them to have equivalent antidepressant efficacy. Although it has been suggested that alprazolam may be most appropriate for "anxious depression," and tricyclics for more "endogenous" forms of depression (125), this has not been confirmed. Initially, a major study involving 504 depressed outpatients found significant antidepressant effects for both alprazolam and the comparison tricyclics irrespective of the patients' initial anxiety, depression, or psychomotor retardation, and irrespective of the patients' assignment to various subtypes of depression, including the DSM-III melancholia subtype (120). Subsequently, smaller studies have found alprazolam to be less effective than tricyclics in depressed patients with neurovegetative signs (125) or shortened REM latencies (128). The latter finding is

Vol. 36, No. I

surprising in light of the reported lengthening of REM latency with alprazolam (131,132). The mechanism of alprazolam's antidepressant action is not known. However, animal data suggest that alprazolam affects cortical ~-adrenoreceptors in a manner similar to tricyclic antidepressants and electroconvulsive therapy. According to an animal model of depression, chronic treatment with either imipramine, desipramine or alprazolam blocks reserpine-induced increases in ~-adrenoreceptors, whereas diazepam has no such effect (133,134). Preliminary data suggest that both adinazolam, a triazolobenzodiazepine similar to alprazolam, and clonazepam may also have antidepressant properties (135,136). Paradoxically, patients undergoing long term treatment of panic disorder with alprazolam and clonazeparn have been reported to develop symptoms of major depression, despite remission of their panic symptoms (137,138). The existence of antidepressant properties for alprazolam seems sufficiently well established, despite a recent report to tlje contrary (139). Nevertheless, before recommending alprazolam for routine use in depression, three factors should be considered. First, none of the studies to date have exceeded six weeks' duration, so that alprazolam's long term efficacy has yet to be established. Second, alprazolam has not been adequately studied in depressed inpatients; one study suggested that, in this patient group, the initial improvement with alprazolam was not sustained beyond the first ten days, but the small sample size and inequalities between patient groups precludes any firm conclusions (123). Finally, although free of the anticholinergic side-effects seen with tricyclics, alprazolam causes its own set of problems, including the possible emergence of hostility (140,141), manic behaviour (142-147), and interdose anxiety (41) during treatment, and withdrawal symptoms after abrupt (148) and even gradual (81) discontinuation. Agitation and Mania The use of benzodiazepines and antipsychotics for the rapid tranquilization of acutely agitated patients has been recently reviewed by Dubin (149). He concluded that, although schizophrenic patients are best treated with antipsychotic medication, benzodiazepines can be very effective adjunctively in controlling associated agitation, thereby possibly reducing the total dose of antipsychotics required. For manic patients, there is growing evidence that clonazepam or lorazepam may be especially useful in the period prior to the onset of the beneficial effects of lithium or carbamazepine. Although there are no prospective studies of rapid tranquillization in cases of substance abuse, benzodiazepines are considered to be the drugs of choice for patients who are intoxicated from cocaine, amphetamines and phencyclidine, except for the most severely agitated for whom high potency neuroleptics, such as haloperidol, may be necessary. To our knowledge, a total of 100 patients treated with clonazepam for mania or manic spectrum behaviours (for example, agitation, pressured speech, increased motor activity) have been reported in the English language scientific literature. These reports include two controlled studies

February, 1991

69

BENZODIAZEPINE SELECTION: CLINICAL ASPECTS

(150,151) (28 patients) and II case reports (152-162) (72 patients). Success rates varied between 44% (153) and 66% (152). Recently, we completed a double-blind controlled study comparing intramuscular preparations of clonazepam and haloperidol for the rapid tranquilization of acutely agitated psychotic patients with manic spectrum symptoms (151). Three doses of clonazepam 1 mg to 2 mg 1M or haloperidol 5 mg.to 10 mg 1Mwere administered at 30 minute intervals. The two drugs produced significant improvement and were comparable in overall efficacy two hours after initial treatment. Clonazepam acted somewhat less rapidly, with haloperidol being superior after one hour. Modell et al (163) investigated lorazepam prescribed with lithium for the treatment of acutely manic patients and found it effective in calming agitation and promoting compliance. Later, they reported on the use of lorazepam in 75 agitated patients with a variety of diagnoses and found that, although non psychotic patients were well controlled at doses of 2 mg to 4 mg bid to qid, psychotic patients or those with histories of alcohol or substance abuse required two to three times that daily dose (164). Lorazepam should not be given in combination with loxapine, since this combination may induce respiratory depression (165). Its association with other drugs so far appears safe. Clonazepam can also be combined safely with other psychotropic drugs except alcohol and barbiturates. More recently, five cases were reported of a reversible neurotoxic syndrome with ataxia and dysarthria when relatively high doses of lithium and neuroleptics with clonazepam are combined (166). A non specific sedative effect has been suggested to explain the beneficial effect of clonazepam in mania. However, in the two double-blind studies that we conducted, there was no evidence of correlation between sedation and improvement on the manic scale (150,151). Originally, the rationale for using clonazepam to treat mania was that it possessed serotonin agonist and anticonvulsant properties, both thought to be potentially useful for treating mania (150). In fact, most ofthe agents found to be beneficial in the treatment of mania, including benzodiazepines, carbamazepine, valproic acid and calcium antagonists, possess anticonvulsant properties, which may constitute the basis of their therapeutic action for this condition.

Summary Rebound and withdrawal symptoms are most prominent after the sudden discontinuation of benzodiazepines with rapid elimination rates (i.e. short ~ half-lives). Although these syndromes may also be observed after sudden discontinuation of slowly eliminated derivatives, they are generally less severe, if they occur. Gradual tapering before drug discontinuation may prevent or greatly attenuate such symptoms. Benzodiazepines that are slowly absorbed and eliminated are most useful for the anxious patient in achieving a gradual and sustained anxiolytic effect. Rapidly absorbed and slowly eliminated benzodiazepines are usually better for the sleepdisturbed patient as the rapid absorption may help induce

sleep and the slower elimination rate may induce less tolerance to the sedative effect. Drug selection for the suspected drug abuser is often problematic. Empirical studies, however, have demonstrated oxazepam, halazepam, and chlordiazepoxide to have a lesser abuse potential than diazepam and lorazepam. Alcoholics are less likely to abuse halazepam than diazepam, and may be prone to abuse alprazolam. The elderly are more sensitive to the effects of benzodiazepines and have a greater risk of hip fracture due to falls associated with the use of slowly eliminated derivatives. Rapidly eliminated derivatives for short term use, or very low doses of slowly eliminated derivatives for more prolonged use, in the elderly are recommended. Certain derivatives may possess pharmacodynamic properties not shared by the entire benzodiazepine class. Alprazolam and clonazepam have been reported to be efficacious in the treatment of panic disorder. Although alprazolam has been shown to have antidepressant effects, its place in the treatment of major depression remains unclear. Clonazepam and lorazepam have been shown to be useful in the treatment of acute agitation and mania. In summary, benzodiazepine selection should not be an arbitrary process, but rather a rational choice based on the known pharmacological differences between the various derivatives and on clinical verification of efficacy in empirical studies.

References I.

2. 3. 4. 5. 6. 7. 8. 9. 10.

11.

Teboul EA, Chouinard G. Principles of benzodiazepine selection. Part I: pharmacological aspects. Can J Psychiatry 1990; 35(8):700-710. Lopolover R, Diazzi H, Ward J. Rebound phenomena: results of a 10 year (1970-1980) literature review. Int Pharmacopsychiatry 1982; 17: 194-237. Lader M, File S. The biological basis of benzodiazepine dependence. Psychol Med 1987; 17:539-547. Fontaine R, Chouinard G, Annable L. Rebound anxiety in anxious patients after abrupt withdrawal of benzodiazepine treatment. Am J Psychiatry 1984; 141:848-853. Greenblatt OJ, Harmatz JS, Zinny MA, et al. Effectof gradual withdrawal on the reboundsleepdisorderafterdiscontinuation oftriazolam. N Engl J Med 1987; 317: 722-728. Kales A, Scharf MB, Kales JD. Rebound insomnia: a new clinicalsyndrome. Science 1978; 201: 1039-1041. Gillin JC, SpinweberCL, JohnsonLC. Rebound insomnia: a criticalreview. J Clin Psychopharmacol 1989; 9: 161-172. Adam K, Oswald I, Shapiro C. Effects of loprazolam and of triazolam on sleepand overnighturinary cortisol.Psychopharmacology 1984;82: 389-394. Mamelak M, Csima A, Price.V, A comparative 25-nightsleep lab study on the effectsof quazepam and triazolam on chronic insomniacs. J Clin Pharmacol 1984; 24: 65-75. Mitler MM, Seidel WF, Van Den Hoed J, et al. Comparative hypnotic effectsof flurazepam, triazolam, and placebo: a longterm simultaneous nighttime and daytime study. J Clin Psychopharmacol 1984;4: 2-16. Vogel GW, BarkerK, GibbonsP, et al. The effectof triazolam on the sleep of insomniacs. Psychopharmacology 1975; 41: 65-69.

70

CANADIAN JOURNAL OF PSYCHIATRY

12. Vogel GW, Barker K, Gibbons P, et al. A comparison of the effects of flurazepam 30 mg and triazolam 0.5 mg on the sleep of insomniacs. J Clin Pharmacol 1976; 47: 81-86. 13. Kales A, Kales JD, Bixler EO, et al. Hypnotic efficacy of triazolam: sleep laboratory evaluation of intermediate-term effectiveness. J Clin Pharmacol1976; 16: 399-406. 14. Pegram V, Hude P, Linton P. Chronic use of triazolam: the effects on the sleep patterns of insomniacs. J Int Med Res 1980; 8: 224-231. 15. Spinweber CL, Johnson LC. Effects of triazolam (0.5 mg) on sleep, performance, memory, and arousal threshold. Psychopharmacology 1982; 76: 5-12. 16. Kales A, Bixler EO, Vela-Bueno A, et at. Comparison of short and long half-life benzodiazepine hypnotics: triazolam and quazepam. Clin Pharmacol Ther 1986; 40: 378-386. 17. Roth T, Kramer M, Lutz T. The effects of triazolam (.25 mg) on the sleep of insomniac subjects. Drugs Exp Clin Res 1977; I: 271-277. 18. Roehrs T, Zorick F, Witty R, et al. Dose determinants of rebound insomnia. Br J Clin Pharmacol1986; 22: 143-147. 19. Bixler EO, Kales H, Soldatos CR, et al. Effectiveness of temazepam with short-, intermediate-, and long-term use: sleep laboratory evaluation. J Clin Pharmacol 1978; 18: 110-118. 20. Mitler MM, Carskadon MA, Philips RL, et al. Hypnotic efficacy of temazepam: a long-term sleep laboratory evaluation. Br J Clin Pharmacol1979; 8: 63-68. 21. Roehrs T, Lamphere J, Paxton C, et al. Tempazepam's efficacy in patients with sleep onset insomnia. Br J Clin Pharmacol1984; 17: 691-696. 22. Kales A, Bixler EO, Soldatos CR, et al. Quazepam and temazepam. Effects of short- and intermediate-term use and withdrawal. Clin Pharmacol Ther 1986; 39: 345-352. 23. ScharfMB, Jacoby JA. Lorazepam - efficacy, side effects, and rebound-phenomena. Clin Pharmacol Ther 1982; 31: 175-177. 24. Adam K, Adamson L, Brezinova V, et al. Nitrazepam: lastingly effective but trouble in withdrawal. Br Med J 1976; 1: 15581560. 25. Kales JD, Kales A, Bixler EO, et al. Effects of placebo and flurazepam on sleep patterns in insomniac subjects. Clin Pharmacol Ther 1971; 12: 691-697. 26. Kales A, Kales JD, Bixler EO, et al. Effectiveness of hypnotic drugs with prolonged use: flurazepam and phenobarbital. Clin Pharmacol Ther 1975; 18: 356-363. 27. Kales A, Bixler EO, Scharf M, et al. Sleep laboratory studies of flurazepam: a model for evaluating hypnotic drugs. Clin Pharmacol Ther 1976; 19: 576-583. '28. Dement WC, Carskadon MA, Mitler MM, et al. Prolonged use of flurazepam: a sleep laboratory study. Behav Med 1978; 5: 25-31. 29. Mendelson WM, Weingartner H, Greenblatt DJ, et al. A clinical study of flurazepam. Sleep 1982; 5: 350-360. 30. Adam K, Oswald I. Effects of lormetazepam and of flurazepam on sleep. Br J Clin Pharmacol 1984; 17: 531-538. 31. Roehrs 1, Zorick F, Kaffeman M, et al. F1urazepam for shortterm treatment' of complaints of insomnia. J Clin Pharmacol 1982; 22: 290-296. 32. Kales A, Soldatos CR, Bixler EO, et al. Rebound insomnia and rebound anxiety: a review. Pharmacology 1983; 26(3): 121137. 33. Kales A, Kales JD. Sleep laboratory studies of hypnotic drugs: efficacy and withdrawal effects. J Clin Psychopharmacol 1983; 3: 140-150.

Vol. 36, No. 1

34. Kales A, Bixler EO, Soldatos CR, et al. Quazepam and flurazepam: a sleep laboratory study. Behav Med 1978; 5: 25-31. 35. Kales A, Soldatos CR, Bixler EO, et al. Early morning insomnia with rapidly eliminated benzodiazepines. Science 1983; 220: 95-97. 36. Chouinard G. Rebound anxiety: incidence and relationship to subjective cognitive impairment. J Clin Psychiatry Monograph Series 1986; 4: 12-16. 37. Noyes R, Garvey MJ, Cook BL, et al. Benzodiazepine withdrawal: a review of the evidence. J Clin Psychiatry 1988; 49: 382-389. 38. Chouinard G. Additional comments on benzodiazepine withdrawal. Can Med Assoc J 1988; 139:119-120. 39. Morgan K, Oswald I. Anxiety caused by a short half-life hypnotic. Br Med J 1982; 284: 942. 40. Fontaine R, Beaudry P, Beauclair L, et al. Efficacy and rebound anxiety of zopiclone and triazolam. Paper presented at the 37th Annual Meeting of the Canadian Psychiatric Association, London ON, September 1987. 41. Herman 18, Brotman AW, Rosenbaum IF. Rebound anxiety in panic disorder patients treated with shorter-acting benzodiazepines. J Clin Psychiatry 1987(Suppl); 48(10): 22-26. 42. Petersson H, Lader M. Dependence on tranquilizers. New York: Oxford University Press, 1984. 43. Tyrer R, Rutherford D, Huggett T. Benzodiazepine withdrawal symptoms and propranolol. Lancet 1981; i:520-522. 44. Rickels K, Case G, Schweizer EE, et al. Low-dose dependence in chronic benzodiazepine users: a preliminary report in 119 patients. Psychopharmacol Bull 1986; 22: 407-415. 45. Busto V, Sellers EM, Naranji CA, et al. Withdrawal reaction after long term therapeutic use of benzodiazepines. N Engl J Med 1986; 315(14): 854-859. 46. Tyrer P, Owen R, Dawling S. Gradual withdrawal of diazepam after long-term therapy. Lancet 1983; i: 1402-1406. 47. Fruensgaard K. Withdrawal psychosis: a study of 30 consecutive cases. Acta Psychiatr Scand 1976; 53: 105-118. 48. Preskorn SH, Denner LJ. Benzodiazepines and withdrawal psychosis. JAMA 1977; 237: 36-38. 49. Noyes R, Perry PJ, Crowe RR, et al. Seizures following the withdrawal of alprazolam. J Nerv Ment Dis 1986; 174: 50-52. 50. Hollister LE, Motzenbecker FP, Degan RO. Withdrawal reactions from chlordiazepoxide. Psychopharmacologia 1961; 2: 63-68. 51. Perry PJ. Assessment of addiction liability of benzodiazepines and buspirone. Drug Intell Clin Pharm 1985; 19: 657-659. 52. Fialip J, Aumaitre 0, Eschalier A, et al. Benzodiazepine withdrawal seizures: analysis of 48 case reports. Clin Neuropharmacol 1987; 10: 538-544. 53. Marks 1. The benzodiazepines: use, overuse, misuse, abuse, second edition. Lancaster: MTP Press, 1985. 54. Weiershausen U. Pharmacokinetic considerations in the treatment of chronic anxiety. In: Smith DE, Wesson DR, eds. The benzodiazepines: current standards for medical practice. Lancaster: MTP Press, 1985. 55. Woods JH, Katz JL, Winger G. Use and abuse of benzodiazepines: issues relevant to prescribing. JAMA 1988; 260; 3476-3480. 56. Greenblatt DJ, 'Shader RI, Abernethy DR. Current status of benzodiazepines (second oftwo parts). New Engl J Med 1983; 309: 410-415. 57. Busto U, Isaac P, Adrian M, et al. Psychotropic drug utilization in Canada: 1978-1984 (abstract). Acta Pharmacol Toxicol (Copenh) 1986(Suppl); V: 203.

February, 1991

BENZODIAZEPINE SELECTION: CLINICAL ASPECTS

58. Gelenberg AJ. Anxiety. In: Bassuk EL, Schoonover SC, Gelenberg AJ, eds. The practitioner's guide to psychoactive drugs, second edition. New York: Plenum Publishing Co, 1983. 59. Rickels K. The clinical use of hypnotics: indications for use and the need for a variety of hypnotics. Acta Psychiatr Scand I986(Suppl); 74(332): 132-141. 60. Gillin JC, Byerley WF. The diagnosis and management of insomnia. N Engl J Med 1990; 322: 239-248. 61. Babbini M, Gaiardi M, Bartoletti M. Anxiolytic versus sedative properties in the benzodiazepine series:differences in structureactivity relationships. Life Sci 1979; 5: 15-22. 62. Ongini E, Bamett A. Hypnotic specificity of benzodiazepines. Clin NeuropharmacoI1985(Suppl); 8(11): 517-525. 63.' Roehrs T, Kribbs N, Zorick R, et al. Hypnotic residual effects of benzodiazepines with repeated administration. Sleep 1986; 9: 309-316. 64. Kales A, Soldatos CR, Vela-Bueno A. Clinical comparison of benzodiazepine hypnotics with short and long elimination halflives. In: Smith DE, Wesson DR, eds. The benzodiazepines: current standards for medical practice. Lancaster: MTP Press, 1985. 65. Kales A, Bixler EO, Vela-Bueno A, et al. Alprazolam: effects on sleep and withdrawal phenomena. J Clin Pharmacol 1987; 27: 508-515. 66. Healey M, Pickens R, Meisch R, et al. Effects of c1orazepate, diazepam, lorazepam and placebo on human memory. J Clin Psychiatry 1983; 44: 436-439. 67. Mac OS, Kumar R, Goodwin OW. Anterograde amnesia with orallorazepam. J Clin Psychiatry 1985; 46: 137-138. 68. Spinweber CL, Johnson LC, Webb SC. Triazolam (.25 and .5 mg): effects on memory, performance, and subjective mood. Sleep Res 1985; 14: 60. 69. Scharf MB, Khosla N, Brocker N, et al. Differential amnestic properties of short- and long-acting benzodiazepines. J Clin Psychiatry 1984; 45: 51-53. 70. ScharfMB, Khosla N, Lysaght, et al. Anterograde amnesia with orallorazepam. J Clin Psychiatry 1983; 44: 362-364. 71. Lister RG, File SE. The nature of lorazepam-induced amnesia. Psychopharmacology 1984; 83: 183-187. 72. Scharf MB, Hirschowitz J, Woods M, et al. Lack of amnestic effects of clorazepate on geriatric recall. J Clin Psychiatry 1985; 46: 518-520. 73. Morris HH, Estes ML. Traveler's amnesia: transient global amnesia secondary to triazolam. JAMA 1987; 258: 945-946. 74. Kushner MJ. You don't have to be a neuroscientist to forget everything with triazolam - but it helps (letter). JAMA 1988; 259: 350. 75. Ewing JA. You don't have to be a neuroscientist to forget everything with triazolam - but it helps (letter). JAMA 1988; 259: 350. 76. Elliott WJ. You don't have to be a neuroscientist to forget everything with triazolam - but it helps (letter). JAMA 1988; 259: 351. 77. Di Maio L. You don't have to be a neuroscientist to forget everything with triazolam - but it helps (letter). JAMA 1988; 259: 351. 78. Radack HB. You don't have to be a neuroscientist to forget everything with triazolam - but it helps (letter). JAMA 1988; 259: 351. 79. Morris HH, Estes ML. You don't have to be a neuroscientist to forget everything with triazolam - but it helps (letter). JAMA 1988; 259: 352.

71

80. Cohen M. You don't have to be a neuroscientist to forget everything with triazolam - but it helps (letter). JAMA 1988; 259: 352. 81. Mellman TA, Uhde TW. Withdrawal syndrome with gradual taperingofalprazolam.AmJPsychiatry 1986; 143: 1464-1466. 82. Griffiths RR, Roache JD. Abuse liability of benzodiazepines: a review of human studies evaluating subjective and/or reinforcing effects. In: Smith DE, Wesson DR, eds. The benzodiazepines: current standards for medical practice. Lancaster: MTP Press, 1985. 83. Uhlenhuth EH, DeWit H, Balter MB, et al. Risks and benefits of long-term benzodiazepine use. J Clin Psychopharmacol 1988; 8: 161-167. 84. Busto A, Sellers E M. Pharmacokinetic determinants of drug abuse and dependence: a conceptual perspective. Clin Pharmacokinet 1986; 11: 144-153. 85. Annitto WJ. Alcoholics use of benzodiazepines (letter). Am J Psychiatry 1989; 145: 683. 86. Ciraulo DA, Sands BF, Shader RI. Dr. Ciraulo and associates reply (letter). Am J Psychiatry 1989; 145: 684. 87. Ciraulo DA, Sands BF, Shader RI. Critical review of liability for benzodiazepine abuse among alcoholics. Am J Psychiatry 1988; 145: 1501-1506. 88. Kryspin-Exner K, Demel I.. The use of tranquilizers in the treatment of mixed drug abuse. Int J Clin Pharmacol1975; 12: 13-18. 89. Jaffe JH, Ciraulo DA, Nies A, et al. Abuse potential of halazepam and of diazepam in patients recently treated for alcohol withdrawal. Clin Pharmacol Ther 1983; 34: 623-630. 90. Ciraulo DA, Barnhill JG, Greenblatt OJ, et al. Abuse liability and clinical pharmacokinetics of alprazolam in alcoholic men. J Clin Psychiatry 1988; 49: 333-337. 91. Cook PJ. Benzodiazepines hypnotics in the elderly. Acta Psychiatr Scand 1986(Suppl); 74(332): 149-158. 92. Meyer BR. Benzodiazepines in the elderly. Med Clin North Am 1982; 66: 1017-1035. 93. Salzman C, Shader RI, Greenblatt OJ, et al. Long v short half-life benzodiazepines in the elderly. Arch Gen Psychiatry 1983; 40: 293-297. 94. Calderini G, Bonetti AC, Aldinio A, et al. Functional interaction between benzodiazepine and GABA recognition sites. Neurobiol Aging 1981; 2: 309-313. 95. Lippa AS, Critchett OJ, Ehlert F, et al. Age-related alterations in neurotransmitter receptors: an electrophysiological and biochemical analysis. Neurobiol Aging 1981; 2: 3-8. 96. Tinetti ME, Speechley M, Ginter SF. Risk factors for falls among elderly persons living in the community. N Engl J Med 1988; 319: 1701-1707. 97. Ray WA, Griffin MR, Schaffner W, et al. Psychotropic drug use and the risk of hip fracture. N Engl J Med 1987; 316: 363-369. 98. Ray WA,Griffin MR, Downey W. Benzodiazepines oflong and short elimination half-life and the risk of hip fracture. JAMA 1989; 262: 3303-3307. 99. Klein OF, Fink M. Psychiatric reaction patterns to imipramine. Am J Psychiatry 1962; 119:432-438. 100. Klein OF. Delineation of two drug-responsive anxiety syndromes. Psychopharmacologia 1964; 53: 397-408. 10I. Zitrin CM, Klein OF, Woerner MG, et al. Treatment of phobias: I. Comparison of imipramine hydrochloride lind placebo. Arch Gen Psychiatry 1983; 40: 125-138. 102.McNair OM, Kahn RJ. Imipramine compared with a benzodiazepine for agoraphobia. In: Klein OF, Rabkin J, eds. Anxiety: new research and changing concepts. New York: Raven Press, 1981: 69-79.

72

CANADIAN 10URNAL OF PSYCHIATRY

103. Chouinard G, Annable L, Fontaine R, et al. Alprazolam in the treatment of generalized anxiety and panic disorders: a doubleblind, placebo-controlled study. Psychopharmacology 1982; 77: 229-233. 104. Sheehan DV. Current views on the treatment of panic and phobia disorders. Drug Ther Hosp 1982; 7: 74-93. 105. Liebowitz MR, Fyer AI, Gorman 1M, et al. Alprazolam in the treatment of panic disorders. 1 Clin Psychopharmacology 1986; 6: 13. 106. Ballenger lC, Burrows GD, DuPont RL Jr, et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial: I. Efficacy in short-term treatment. Arch Gen Psychiatry 1988; 45: 413-422. 107. Chouinard G, Labonte A, Fontaine R, et al. New concepts in benzodiazepine therapy: rebound anxiety and new indications for more potent benzodiazepines. Prog Neuropsychopharmacol Bioi Psychiatry 1983; 7: 669. 108. Fontaine R, Chouinard G. Antipanic effect of clonazepam (letter). Am 1 Psychiatry 1984; 141: 149. 109. Beaudry P, Fontaine R, Chouinard G, et al. Clonazepam in the treatment of patients with recurrent panic attacks. 1 Clin Psychiatry 1986; 47: 83-85. 110. Pollack MH, Tesar GE, Rosenbaum IF, et al. Clonazepam in the treatment of panic disorder and agoraphobia: a one year followup. 1 Clin Psychopharmacol 1986; 6: 302-304. III. Tesar GE, Rosenbaum IE Successful use of clonazepam in patients with treatment-resistant panic disorder. 1 Nerv Ment Dis 1986; 174: 473-482. 112. Tesar GE, Rosenbaum IF, Pollack MH, et al. Clonazepam versus alprazolam in the treatment of panic disorder: interim analysis of data from a prospective double-blind, placebo-controlled clinical trial. 1 Clin Psychiatry 1987; 48: 16S-19S. 113. Annable L, Beauclair L, Fontaine R, et al. Clonazepam in panic disorder. VIII World Congress of Psychiatry, Book of Abstracts 1989; 422: 116. 114. Fontaine R, Mercier P, Beaudry P, et al. Bromazepam and lorazepam in generalized anxiety: a placebo-controlled study with measurement of drug plasma concentrations. Acta Psychiatr Scand 1986; 74: 451-458. 115. Fontaine R, Annable L, Chouinard G, et al. Bromazepam and diazepam in generalized anxiety: a placebo-controlled study with measurement of drug plasma concentrations. 1 Clin Psychopharmacol1983; 3: 80-87. 116. Herman JB, Rosenbaum IF, Brotman AW. The alprazolam to clonazepam switch for the treatment of panic disorder. 1 Clin Psychopharmacol 1987; 7: 175-178. 117. Schatzberg AF, Cole 10. Benzodiazepines in depressive disorders. Arch Gen Psychiatry 1978; 35: 1359-1365. 118. Cassano GB, Castrogiovanni P, Conti L. Drug responses in different anxiety states under benzodiazepine treatment. Some multivariate analyses for the evaluation of "rating scale for depression" scores. In: Garattini S, Mussine E, Randall LO, eds. The benzodiazepines. New York: Raven Press, 1973. 119. Fabre LE Pilot open-label study with alprazolam (U-3 I,889) in outpatients with neurotic depression. Curr Ther Res 1976; 19: 661-668. 120. Rickels K, Feighner JP, Smith WT. Alprazolam, amitriptyline, doxepin and placebo in the treatment of depression. Arch Gen Psychiatry 1985; 42: 134-141. 121. Fabre LF, Mcl.endon DM. A double-blind study comparing the efficacy and safety of alprazolam with imipramine and placebo in primary depression. Curr Ther Res 1980; 27: 474-482.

Vol. 36, No. I

122. Feigher IP, Aden GC, Fabre LF, et al. Comparison of alprazolam, imipramine and placebo in the treatment of depression. lAMA 1983; 249: 3057-3064. 123. Lenox RH, Shipley JE, Peyser 1M, et al. Psychopharmacol Bull 1984; 20: 79-82. 124. Rickels K, Chung HR, Csanalosi IB, et al. Alprazolam, diazepam, imipramine and placebo in outpatients with major depression. Arch Gen Psychiatry 1987; 44: 862-866. 125. Goldberg SC, Ettigi P, Schulz PM, et al. Alprazolam versus imipramine in depressed out-patients with neurovegetative signs. 1 Affective Disord 1986; 11: 139-145. 126. Overall JE, Donachie ND, Faillace LA. Implications of restrictive diagnosis for compliance to antidepressant drug therapy: alprazolam versus imipramine. 1 Clin Psychiatry 1987; 48: 51-54. 127. Overall JE, Biggs 1, lacobs M, et al. Comparison of alprazolam and imipramine for treatment of outpatient depression. 1 Clin Psychiatry 1987; 48: 15-19. 128. Rush AI, Erman MK, Schlesser MA, et al. Alprazolam vs amitriptyline in depressions with reduced REM latencies. Arch Gen Psychiatry 1985; 42: 1154-1159. 129. Ansseau M, Ansoms C, Beckers G, et al. Double-blind clinical . study comparing alprazolam and doxepin in primary unipolar depression. 1 Affective Disord 1984; 7: 287-296. 130. Fawcett 1, Edwards JH, Kravitz HM, leffriess H. Alprazolam: an antidepressant? Alprazolam, desipramine, and an alprazolam-desipramine combination in the treatment of adult depressed outpatients. 1 Clin Psychopharmacol 1987; 7: 95310. 131. Bonnet MH, Dramer M, Roth T. A dose response study of the hypnotic effectiveness of alprazolam and diazepam in normal subjects. Psychopharmacol1981; 75: 258-261. 132.Zarcone VP, Benson KL, Csernansky IG, Faull KF. Alprazolam: treatment response, CSF metabolites, and sleep variables. Bioi Psychiatry 1989; 25: 54a. 133. Sethy VH, Hodges DH. Role of ~-adrenergic receptors in the antidepressant activity of alprazolam. Res Commun Chern Pathol Pharmacol 1982; 36: 329-332. 134. Sethy VH, Hodges DH. Antidepressant activity of alprazolam in a reserpine-induced model of depression. Drug Dev Res 1985; 5: 179-184. 135. Dunner D, Hyers 1, Khan A, et al. Adinazolam - a new antidepressant: findings of a placebo-controlled, double-blind study in outpatients with major depression. 1 Clin Psychiatry 1987; 7(3): 170-172. 136. Kishimoto A, Kamata K, Sugihara T. Treatment of depression with clonazepam. Acta Psychiatr Scand 1988; 77: 81-86. 137. Lydiard RB, Lovoia MT, Ballenger lC. Emergence of depressive symptoms in patients receiving a1prazolam for panic disorder. Am 1 Psychiatry 1987; 144: 664-665. 138. Falk WE. Clonazepam (K1onopin): a treatment potpourri. Biological Therapies in Psychiatry 1986; 9: 6-7. 139. Borison RL, Sinha P, Geber S, et al. Double-blind evaluation of alprazolam versus placebo in outpatients with major depressive disorder. Bioi Psychiatry 1989; 25: 54a. 140. Rapaport M, Braff DL. Alprazolam and hostility (letter). Am 1 Psychiatry 1985; 141: 146. 141. Rosenbaum IF, Wood SW, Groves JE, et al. Emergence of hostility during alprazolam treatment. Am 1 Psychiatry 1984; 141: 792-136. 142. Strahan A, Rosenthal 1, Kaswan M, et al. Three case reports of acute paraoxysmal excitement associated with alprazolam treatment. Am 1 Psychiatry 1985; 142: 859-861.

February, 1991

73

BENZODIAZEPINE SELECTION: CLINICAL ASPECTS

143.Arana GW, Pearlman C, Shader Rl. Alprazolam-induced mania: two clinical cases. Am J Psychiatry 1985; 142: 368-369. 144. France RD, Krishnan KRR. Alprazolam-induced manic reaction (letter). Am J Psychiatry 1984; 141: 1127-1128. 145. Pecknold JC, Fleury D. Alprazolam-induced manic episode in two patients with panic disorder. Am J Psychiatry 1986; 143: 652-653. 146.Mayerhoff D, Vital-Heme J, Lesser M, et aI. Alprazolam-induced manic reaction. NY State J Med 1986; 86: 320. 147.Goodman WK, Charney DJ. A case of alprazolam, but not lorazepam, inducing manic symptoms. J Clin Psychiatry 1987; 48: 117-118. 148. Noyes R, Clancy J, Coryell WH, et aI. A withdrawal syndrome . after abrupt discontinuation of alprazolam. Am J Psychiatry 1985; 142: 114-116. 149. Dubin WR. Rapid tranquilization: antipsychotics or benzodiazepines? J Clin Psychiatry I988(Suppl); 49: 5-11. 150.Chouinard G, Young SN, Annable L. Antimanic effect of c1onazepam. Bioi Psychiatry 1983; 4: 451-466. 151.Chouinard G, Tumier L, Beauclair L, et aI.Clonazepam in acute mania and manic spectrum diseases. VIII World Congress of Psychiatry, Book of Abstracts, No. 1206, 1989: 315. 152.Chouinard G. Use of clonazepam in the maintenance treatment of manic depressive illness. In: Shagass C, Josiassen RC, Bridger WH, et ai, eds. Biological psychiatry 1985. New York: Elsevier Science Publishing Co., 1986: 723-725. 153. Harms L. Clonazepam and mania (letter). Pharmabulletin (Health Department of Victoria, Australia) 1985; 104: 117-119. 154. Freinhar JP, Alvarez ·WA. Clonazepam: a novel therapeutic adjunct. Int J Psychiatry Med 1985-86; 15: 321-329. 155.Zetin M, Freedman MJ. Clonazepam in bipolar affective disorder (letter). Am J Psychiatry 1986; 143: 1055. 156. Victor BS, Link NA, Binder RL, et aI. Use of clonazepam in mania and schizoaffective disorders. Am J Psychiatry 1984; 141: 1111-1112. 157.Jones BD, Chouinard G. Clonazepam in the treatment of recurrent symptoms of depression and anxiety in a patient with systemic lupus erythematosis. Am J Psychiatry 1985; 142: 354-355. ' 158.Laporta M, Chouinard G, Goldbloom D, et aI. Hypomania induced by sertraline, a new serotonin reuptake inhibitor (Ietter). AmJ Psychiatry 1987; 144: 1513-1514. 159.Frykholm B. Clonazepam - antipsychotic effect in a case of schizophrenia-like psychosis with epilepsy and in three cases of atypical psychosis. Acta Psychiatr Scand 1985; 71: 539-542. 160. Freinhar JP, Alvarez WHo Use of clonazepam in two cases of acute mania. J Clin Psychiatry 1985; 46: 29-30.

161.Greenspan D, Levin D. Use of clonazepam in a patient with schizoaffective disorder (letter). Am J Psychiatry 1985; 142: 774. 162. Viswanathan R, Glickman L. Clonazepam in the treatment of steroid-induced mania in a patient after renal transplantation. N . Engl J Med 1989; 320: 319-320. 163. Modell JG, Lenox RH, Weiner S. Inpatient clinical trial of lorazepam for the management of manic agitation. J Clin Psychopharmacol1985; 5: 109-113. 164. Modell JG. Further experience and observations with lorazepam in the management of behavioral agitation (letter). J Clin Psychopharmacol 1986; 6: 385-387. 165.Cohen S, Khan A. Respiratory distress with use of lorazepam in mania (letter). J Clin Psychopharmacol 1987; 7:,199-200. 166. Koczerginski D, Kennedy SH, Swinson RP. Clonazepam and lithium - a toxic combination in the treatment of mania. Int J Clinic Psychopharmacol1989; 4: 195-199.

Resume Selon les auteurs, pour repondre aux exigences propres aux diverses situations cliniques, la prescription des benzodiazepines doit se fonder sur les proprietes pharmacocinetiques et pharmacodynamiques des divers composes appartenanta cette classe de medicaments. Les benzodiazepines eliminees le plus rapidement provoquent les syndromes de rebond et de sevrage les plus intenses. Les derives absorbes et elimines lentement sont ceux qui conviennent le mieux au patient anxieux, car leur eifet anxiolytique est progressif et soutenu. Les benzodiazepines absorbees rapidement et eliminees lentement sont habituellement les plus indiquees pour le patient dont le sommeil est perturbe, puisqu' une absorption rapide declenche le sommeil tandis qu'une elimination plus lente entraine probablement une tolerance moins marquee envers l' eifet sedatif, Faire un choix rationnel devient plus problematique lorsque la personne est agee ou soupconnee de toxicomanie. Les auteurs examinent les parametres pharmacocinetiques et pharmacodynamiques pertinentspour ces malades. Il semble que certains composes possedent des proprietes pharmacodynamiques qui ne sont pas l' attribut de toute la classe des benzodiazepines; des etudes empiriques donnent a penser que l' alprazolam et le clonazepam agissent contre la panique, que l' alprazolam est un antidepresseur, et que le clonazepam et, peut-etre, le lorazepam ont un eifet antimaniaque. Table I

ERRATUM In the article entitled Eifects of Trihexyphenidyl on Plasma Chlorpromazine in Young Schizophrenics by Lawrence Rockland, M.D., Thomas Cooper, M.A., Fred Schwartz, Ph.D., David Weber, Ph.D. and Timothy Sullivan, M.D. (October 1990, page 604-607) a misprint inadvertently occurred in Table 1. The figure for the "Medium" SUbheading under the "Active" column should have been 150.6.

Chlorpromazine Plasma Level (ng/mL) Geometric Means Stages by Chlorpromazine Oral Dose (mg!24 hours)

Stage III and Oral Dose Low (150 to 450 mg) Medium (600 to 900 mg) High (1000 to 1500 mg)

Stage 11* 31.9 96.5 131.4

Stage Placebo 24.0 96.6 105.4

IV Active 34.5 150.6 128.5

Stage V* 23.6 93.5 121.6

85.7

62.5

(n=6)

Total Sample

71.8

60.9

*Patients received placebo trihexyphenidyl during Stages II and V.