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van Balkom AJLM, de Beurs E, Koele P, Lange A, van Dyck R.
Long-Term Benzodiazepine Use Is Associated with Smaller Treatment Gain in Panic Disorder with Agoraphobia.
Journal of Nervous and Mental Disease 1996; 184: 133-135.
" Given the large number of patients with PA using benzodiazepines, the predictor "long-term benzodiazepine use" remains of clinical importance and deserves more attention in future research. " [p. 134]
[Key words; long-term effects]

van der Kroef C.
Reactions to Triazolam.
Lancet 1979; ii: 526.
" During the past nine months I have been confronted in my psychiatric practice with a syndrome which is almost certainly induced by the benzodiazepine triazolam ("Halcion")

Triazolam can produce the following symptoms: severe malaise; depersonalisation and derealisation; paranoid reactions; acute and chronic anxiety; continuous fear of going insane; depression and deterioration of existing depression; hyperaesthesia, especially for sound but also for smell, taste and light; sometimes hypoaesthesia for the same stimuli; nightmares; restlessness; inability to concentrate; verbal and physical aggression; conflicts with entourage; severe suicidal tendencies; hypnagogic hallucinations; impulse actions; amnesia; dysphagia, accompanied by nasty taste, painful tongue and mucous membranes, dry mouth, loathing of food, rigid feeling in the throat and emaciation up to 2\'ab stone; cervical pains; headaches that are often extremely sensitive to sound; pressure on the ears; numb and cold feeling in fingers and toes, extending to the distal parts of the extremities; tingling feeling, muscular cramps and paralyses, often at the sinistral side; catatonically impaired motor functioning; reading complaints and blurred vision; dysfunctional speaking and writing; sweating.

This syndrome must be classified with the exogenous syndrome of Bonhoeffer. Symptoms ususally disappear within a couple of days after stopping triazolam; sometimes there are withdrawal symptoms, such as rapidly mounting panic and heavy sweating.

These side-effects appear in patients who are taking other drugs and in those who are not and in patients who have never had psychiatric treatment as well as in those with a psychiatric history. Patients with this syndrome may be admitted on suspicion of brain tumour or schizophrenia. They impress the observer as seriously ill and the patients themselves often feel desperate and have to fight an almost irresistible impulse to commit suicide. I know of one patient who did commit suicide.

The Netherlands Centre for Monitoring of Adverse Reactions to Drugs has received several reports of patients with similar features while on triazolam and the centre issued (July 16) a letter to Dutch doctors, dealing with this matter. "
[Key words; Halcion, triazolam, depression, suicide, aggression, psychosis, paranoia, hallucinations]

Vellucci SV.
Chlordiazepoxide Loses Its Anxiolytic Action with Long-Term Treatment.
Psychopharmacology 1979; 62: 61-65.
" In short-term clinical trials (lasting 28 days or less) it has been demonstrated that the benzodiazepines are consistently more effective than placebo. However, in the long term, anxiolytic efficacy is still not well established, despite the fact that the benzodiazepines are so widely prescribed for the treatment of anxiety. There is an extreme paucity of data from both clinical and animal studies on the long-term effect of these drugs (---). The few clinical studies that have been carried out have suggested that there is a marked decrease in the drug-placebo difference during extended treatment. " [p. 65]
[Key words; tolerance]


Viscott DS. Chlordiazepoxide and Hallucinations.
Archives of General Psychiatry 1968; 19: 370-376.
Hallucinations are reported in seven cases of patients taking chlordiazepoxide. They were noted to occur during what would have been part of the patient's sleep cycle. This paper proposes that chlordiazepoxide causes a transient impairment of the ego's abi lity to suppress dream material into the waking state as hallucinations. Unlike the hallucinations seen in patien ts recovering from dextroamphetamine sulfate addition, these are weaker and no alteration of the sensorium is seen. Moreover, they are terminated with reality testing. Some speculations concerning the therapeutic action of the drug are also given. [SUMMARY p. 376]
[Key words; Librium, chlordiazepoxide, hallucinations, paradoxical effects]

Ward MG, Schuckit MA.
Factors Asociated with Suicidal Behavior in Polydrug Abusers.
Journal of Clinical Psychiatry 1980; 41: 379-385.
In 155 polydrug abusers, druguse patterns that were associated with serious suicidal behavior included preference for depressant drugs, history of withdrawal from barbiturates, and lower frequency of PCP use. Diagnostic factors associated with increased suicidal behavior included history of depression in the subject's mother and a diagonosis of antisocial personality in the subjects themselves. These findings are discussed in relation to Winokur's concept of broad spectrum depressive disease. [ABSTRACT p. 379]
[Key words; dependence, addiction, abuse, depression, suicide]

Wardle J.
Behaviour Therapy and Benzodiazepines: Allies or Antagonists?
British Journal of Psychiatry 1990; 156: 163-168.
Behaviour therapy and benzodiazepines are directed towards common problems and are often used in combination. At present we know little about the beneficial or adverse interactions of these two treatments. This paper reviews the available literature and suggests that there are important theoretical and clinical issues to be resolved. [ABSTRACT p. 163]

" The result of the post-treatment assessment indicated that patients on benzodiaepines did worse overall. This it not surprising in view of the likelihood that long-term users of benzodiazepines have more serious and resistant disorders. However, there was also a trend in the data for a more deleterious effect of concurrent benzodiazepine use in the behaviour therapy than in the cognitive therapy. The results from the one-year follow-up revealed these differences more clearly. Only 8 percent of the behaviour therapy patients who had received benzodiazepines were in the "markedly improved" category at follow-up compared with 86 percent of those who had not been taking benzodiazepines; the cognitive therapy group showed a 50 percent marked improve ment rate regardless of concurrent medication. This study was not designed to investigate these questions, so there was of course no random assignment of patients. Nevertheless this result cast concurrent benzodiazepine use in a less benevolent light than the studies using short-term administration of benzodiazepines."
[Key words; long-term effects]

Weedle PB, Poston JW, Parish PA.
Use of Hypnotic Medicines by Elderly People in Residential Homes.
Journal of the Royal College of General Practioners 1988; 38: 156-158.
Data relating to the use of hypnotic medicines from a descriptive epidemiological study of drug use in 55 residential homes for elderly people were analysed. Of the 1888 residents included in the study, 435 (23,0%) were receving a total of 448 hypnotic medicines. There was preferential prescribing of short-acting benzodiazepines but long-acting benzodiazepines represented 31,7% of all hypnotic drugs prescribed. The median duration of treatment with temazepam was 0,8 years and with nitraze pam 2,5 years. The proportion of residents receiving hypnotic medicines in each home varied from 3,6% to 60,0% with a median of 24,1%. This study indicates a need for general practioners to review their prescribing of hypnotic medicines for elderly people, paying particular attention to the duration of treatment. [ABSTRACT p. 156]
[Key words; Euhypnos, Mogadon, Normison, nitrazepam, temazepam, hypnotics, the elderly]

Whitcup SM, Miller F.
Unrecognized Drug Dependence in Psychiatrically Hospitalized Elderly Patients.
JAGS 1987; 35: 297-301.
" Although underlying medical illness could not be completely ruled out as the etiology of symptoms and signs interpreted as evidence of complicated withdrawal, the patients did not have symptoms or history of underlying cardiac, respiratory, or CNS disease, and their medical evaluations on admission were normal. As a result of their clinical condition, three patients with complicated withdrawal were transferred to medical intensive care units and two to medical floors. Nevertheless, a thorough medical work-up of patients with complicated withdrawal did not reveal a diagnosis other than withdrawal to explain their clinical course, making the possibility of significant and confounding underlying medical illness u nlikely. "

" Women may be at increased risk for misdiagnosis because they use benzodiazepines rather than alcohol resulting in an underestimation of their chemical dependence. "

" Finally, when chemical dependence was recognized and treated, complications were minimal, but when unrecognized, withdrawal lead to significant morbidity. " [p.300]
[Key words; addiction, dependence, withdrawal, the elderly]

WHO Review Group.
Use and Abuse of Benzodiazepines.
Bulletin of the World Health Organization 1983; 61: 551-562.
Benzodiazepines are widely used for the treatment of anxiety, insomnia, and certain neuromuscular and convulsive disorders. However, their widespread availability has given rise to fears that they are over-prescribed. The problem is compounded by the fact that there is no universal agreement among medical practitioners as to the clinical indications warranting the use of these drugs. Although most industrialized countries exercise control over the sale and manufacture of benzodiazepines, many developing countries do not have sufficient control of these drugs. As a result, information on drug utilization and associated problems is difficult to obtain and there is a lack of comparative data on drug consumption in different countries. The present article describes the current knowledge on the pharmacological, clinical, and epiemiological characteristics of benzodiazepines, and the problems associated with their use, and indicates areas where more research is needed. Recommendations are made for f uture work. [ABSTRACT p. 551]

"Various benzodiazepines have been demonstrated to have an adverse effect on psychomotor and cognitive functions. Performances on a vigilance task for exampe where impaired in normal human subjects given diazepam at doses employed therapeutically. The benzodiazepines vary in the degree to which they produce sedation and behavioural impairment. Comparative studies of these drugs employing a range of doses, will be necessary to detemine the extent and significance of these differences.

Substantial intoxication and gross behavioural and cognitive impairments have been noted in people abusing high doses of benzodiazepines on an acute or chronic basis. Striking deterioration in personal care and social interactions has been reported. Other studies suggest that chronic administration of benzodiazepines produces impairment in learning, memory and psychomotor functions.

Studies have shown that benzodiazepines, alone and particularly in combination with alcohol, have deleterious effects on driving performance. On the basis of such observations health authorities in Scandinavia, in collaboration with the drug manufacturers, have decided to label benzodiazepine preparations with a special warning symbol.

When some benzodiazepines are given at bed time for the treatment of insomnia deficits in psychomotor and cognitive performances have been observed in tests the following morning. Studies have revealed marked differences among the benzodiazepines in terms of their production of such "hangover" effects, which are presumably related to their duration of action.

A variety of behavioural and mode disturbances have been reported in association with repeated administration of some benzodiazepines in clinical situations, including increased hostility, depression, antisocial behviour, paranoid ideation, and suicidal tendencies. Because the frequencey of such observations has been relatively low, it has often been assumed that these effects represent idiosyncratic reactions. However, a series of controlled studies of chlordiazepoxide and diazepam in non-anxious subjects, has suggested that increased hostility may represent a regular rather than an idiosyncratic, effect of some of these drugs. Several reports have mentioned an aggrevation of dpressive symptoms by certain benzodiazepines in patients not treated concurrently with antidepressants." [p. 560]
[Key words; Valium, Librium, diazepam, chlordiazepoxide, cognitive impairment, amnesia, memory impairment, psychomotor impairment, depression, aggression, hostility, paranoia, disinhibition, paradoxical effects, long-term effects, traffic]

Wilbur R, Kulik V.
Abstinence Syndrome from Therapeutic Doses of Oxazepam.
Canadian Journal of Medicine 1983; 28: 298-300.
A patient developed severe anxiety, moodswing, depression, and thinking disorder 24 hours after abruptly stopping oxazepam, of which he had taken 30 mg 3 times a day for two months, for anxiety and panic attacks. Oxazepam was restarted and tapered off gradually; nevertheless, a relatively severe abstinence syndrome occurred. Muscular fasciculations and moodswing were very marked. The patient also experienced significant anxiety, depression, moodswing, and muscular fasciculations for two months after detoxification from oxazepam. Subsequently, the patient's panic attacks were treated successfully with propranolol hydrochloride. This report concludes with a brief review of the literature on benzodiazepine withdrawal. [SUMMARY p. 298]
[Key words; Serax, Serenid, Serepax, oxazepam, dependence, withdrawal, depression]

Wolf B, Griffiths RR.
Physical Dependence on Benzodiazepines: Differences within the Class.
Drug and Alcohol Dependence 1991; 29: 153-156.
" As stated earlier, there is a concordance in the literature that quickly eliminated BZD are associated with a higher incidence of physical dependence and more severe withdrawal syndromes. In addition to pharmacokinetic properties, pharmacodynamic factors may be important. The potency of a compound, which correlates with receptor affinity seems to covary with the liability of a BZD to induce physical dependence. Thus, there seem to be at least three factors which may be predictive of the severity of the withdrawal syndrome: (1) short elimination half-life; (2) high potency; (3) use of relatively high doses. " [p.155]
[Key words; addiction, dependence, withdrawal]

Wysowski DK, Barash D.
Adverse Behavioral Reactions Attributed to Triazolam in the Food and Drug Administrations Spontaneous Reporting System.
Archives of Internal Medicine 1991; 151: 2003-2008.
Reports of adverse behavioral reactions to triazolam, a triazolobenzodiazepine ultra-short-acting hypnotic, were examined in the postmarketing surveillance Spontaneous Reporting System of the Food and Drug Administration. Reports for triazolam of confusion, amnesia, bizarre behavior, agitation, and hallucinations were compared with reports of these reactions for temazepam, another short-acting hypnotic. Analysis of individual case reports from marketing through 1985 for triazolam vs temazepam showed 133 vs two for bizarre behavior, 58 vs four for agitation, and 40 vs one for hallucinations. Considering extent of use, reporting rates for triazolam were 22 to 99 times those for temazepam, depending on the reaction. Reactions to triazolam tended to occur at higher doses and in older patients. This and an updated analysis of aggregate reports for the first 7 years of marketing of each drug with reporting rates and adjustment for various factors suggest a higher occurrence of these reactions with triazolam, but selection factors cannot be completely ruled out. When treating insomnia, physicians should emphasize sleep hygiene practices as alternatives to drug therapy; if drug therapy is required, they should prescribe hypnotics at the lowest recommended doses for the shortest clinically necessary durations and discontinue medication use should any adverse reactions occur. [SUMMARY p. 2003]
[Key words; Halcion, triazolam, aggression, paradoxical effects, hypnotics]

Zipursky RB, Baker RW, Zimmer B.
Alprazolam Withdrawal Delirium Unresponsive to Diazepam: Case Report
. A case is presented in which a 68-year-old man became delirious after being withdrawn from a low dosage of alprazolam. The delirium was not affected by administration of diazepam but resolved promptly after reinstitution of alprazolam. The authors suggest that alprazolam may have enhanced specificity for a subpopulation of benzodiazepine receptors. [ABSTRACT p. 344]
[Key words; Xanax, alprazolam, addiction, dependence, withdrawal]

Zisook S, DeVaul RA.
Adverse Behavioral Effects of Benzodiazepines.
Journal of Family Practice 1977; 5: 963-966.
" Ayd suggests that "there are infinitesimally few abusers of chlordiazepoxide and Valium ... and these abusers are unstable inadequate personalities with prior histories of abuse of alcohol and/or drugs." Woody, Finer, and Kryspin-Exner have presented dat a supporting the particular vulnerability of this patient group ;

However, additional reports suggest that dependency may well be a problem for a broad range of patients who are not necessarily unstable, or alcohol or drug abusers. " [p. 963]

[regarding paradoxical effects]
Case Illustration and discussion. The patient is a 22-year-old black male referred for psychiatric evaluation by his attorney after being apprehended for "going berserk and trying to kill his first sergeant". The patient comes from a socioculturally deprived background and spent most of his formative years fending for himself in the streets. After completing high school, he decided to leave the streets, join the army and "make something of myself". During the first 2 1/2 years of military service, he had an exemplary record, got along well with peers and authorities, avoided any drugs or alcohol, and was generally considered an outstanding soldier.

Four weeks before the first psychiatric evaluation the patient fell of a truck while on maneuvers. That evening he went to the Emergency Room because of continued low back pain. X-rays and examinations were negative. He was put on 24 hours rest, aspirin, health therapy, and diazepam, 5 mg every six hours as needed. Two days later he went to the dispensary because of continued pain. Diazepam was increased to 30 mg a day, and an appointment was made for the orthopedic clinic the following week. By this next appointment, he complained of feeling "funny inside", a feeling which he was unable to further define . He was told that this was "nerves" and diazepam was increased to 40 mg a day. Three days later he returned to the orthopedic clinic complaining of feeling jumpy and irritable. He was sleeping poorly and was argumentative with friends and feeling defiant of authorities. He was told to stay on diazepam and return for follow-up visits to the dispensary in one month.

Two days after this visit he was getting dressed for a party when his first sergeant confronted him about this recent lackadaisical negativistic attitude. He suddenly "went into a rage", grabbed a knife, and attacked his first sergeant. That night he was apprehended, incarcerated, and diazepam was discontinued. The following day, results from his physical examination, neurologic evaluation, and laboratory studies were all within normal limits. The next two of three days he continued to feel "funny and in a fog", a feeling which gradually cleared. During six months of follow-up there was no recurrence of hostile or overly aggressive behavior. " [p. 965]

[regarding depression]
"That benzodiazepines have a relatively high safety index has lulled many physicians into a false sense of complacency regarding the risk of suicide. Few "successful" overdoses are reported, despite the great number of people abusing these drugs and a large number of suicidal gestures or attempts. This "safety" at least partially explains why physicians are so generous in prescribing benzodiazepines, even to patients who may be mildly depressed. However, this generosity needs to be reexamined. Most drug overdoses presenting to Emergency Rooms involve benzodiazepines. Although the benzodiazepines may not be intrinsically lethal, combinations with other central nervous system depressants can be lethal. Whether other forms of suicide, such as gunshot wounds or automobile accidents are significantly associated with benzodiazepines has not been adequately tested. But clinical experience raises this possibility." [p. 965]
[Key words; Librium, Valium, chlordiazepoxide, diazepam, addiction, abuse, dependence, aggression, hostility, disinhibition, depression, suicide, insomnia, paradoxical effects]

Zisselman MH, Rovner BW, Kelly KG, Woods C.
Benzodiazepine Utilization in a University Hospital.
American Journal of Medical Quality 1994; 3: 138-141.
" Benzodiazepines are widely prescribed in the hospital setting in the absence of appropriate documentation. Older patients are as likely to receive benzodiazepines as younger patients, despite the known morbidity associated with their use in this population. " [p. 138]

" First, we found that 41 % of the sample received benzodiazepines and that older patients were as likely as younger patients to receive them. This rate of utilization is consistent with other studies reporting that 20 to 50 % of inpatients receive benzodiazepines. This high rate of utilization is of concern because in-hospital benzodiazepine prescriptions have been shown to contribute to long-term use after discharge. "

" Furthermore, that benzodiazepines are implicated in 10 % of drug-associated emergency room admissions underscores the worrisome nature of these findings. "

" Third, older patients were as likely as younger persons to receive 0.25 mg of triazolam. Triazolam use has been particularly controversial because it impairs memory, causes behavioral changes, and has enhanced central nervous system effects in the elderly. "

" Finally, we found that 1 in 5 elderly patients received 5 mg diazepam, a long-acting benzodiazepine whose half-life and volume of distribution are known to increase with age. "

" Taken together, these findings reveal a variety of problems in how benzodiazepines are prescribed to elderly hospitalized patients. Given their documented adverse effects in this population, the data highlights a potential problem area that requires furt her study. " [p. 140]
[Key words; Halcion, Valium, triazolam, diazepam, amnesia, memory impairment, drug accumulation, the elderly]

Zucker HS.
Strange Behavior with Oxazepam.
New York State Journal of Medicine 1972; 72: 974.
" In the course of prescribing this tranquilizer for several hundred people, several were encountered with unusual results.

One patient returned with the story that after taking several doses, she disrobed in public and had to be recovered from a police station. Another patient described a severe altercation with her husband after taking oxazepam, 30 mg., for a period of time. A third patient had strange sensations and felt her behavior toward her family was altered. These cases do not alter the general effectiveness of the drug in the vast majority of people. It raises the question of whether or not we have available a sufficiently potent preparation for selected use. In England I am told oxazepam, 50 mg., (Serax 50) is marketed. Surely there is ample reason to consider it for the American market, too. "
[Key words; Serax, Serenid, Serepax, oxazepam, aggression, paradoxical effects]

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