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Paton and disinhibition

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Psychiatric Bulletin (2002), 26,460^462 CAROL PATON Benzodiazepines and disinhibition: a review

AIMS AND METHODS with impulse control problems, when these drugs are administered To describe and attempt to neurological disorders, learning to patients known to be at quantify the incidence of disabilities, the under 18s and risk. In patients who have disinhibitory reactions to the over 65s are at significant experienced behavioural benzodiazepines and to identify risk. disinhibition with benzodiazepines, those at risk. Medline search, drugs should be used CLINICAL IMPLICATIONS 1966-January 2002. to modify behaviour in any future It is important to be aware of the emergencies. RESULTS ability of benzodiazepines to cause The overall incidence of disinhibitory behavioural disinhibition and to reactions is small, but those maintain a high degree of vigilance

Some psychiatric disorders are associated with patho- underlying characteristics of the person who consumes it. logical anger and . These include psychotic , methylphenidate, benzodiazepines and disorders, depression, bipolar disorder and various are examples. In the majority of recipients, personality disorders (Fava, 1997). Benzodiazepines have benzodiazepines have a calming effect but in a minority been widely used in the management of this behavioural they can cause paradoxical reactions (also called disinhi- disturbance (Pilowsky et al, 1992). However, no single bitory reactions) characterised by acute excitement and drug produces totally predictable sedation in all patients an altered mental state: increased , vivid dreams, (Van der Bijl & Roelofse, 1991) and a paradoxical increase hyperactivity, sexual disinhibition, hostility and rage. in hostility and aggression can occur after the adminis- Other that bind at the GABAA receptor, such as tration of benzodiazepines. This is obviously problematic alcohol, are robustly linked with aggressive behaviour. when the is administered to control Acute alcohol consumption is known to increase feelings behavioural disturbance. So, how common is this adverse of hostility and competitive and retaliatory behaviour, and effect, who is at risk and why? epidemiological data show that alcohol is involved in over 50% of acts of (Miczek et al, 1997). Mechanism of action of benzodiazepines Prevalence of paradoxical reactions Gamma-aminobutyric acid (GABA) is the most abundant neurotransmitter in the central nervous system (CNS) and Although the first reports of paradoxical reactions to GABA receptors are widely distributed throughout the benzodiazepines date back over 40 years (Boyle & Tobin, brain, with high concentrations in the cortex and limbic 1961), the incidence of this adverse effect remains uncertain. Some small studies in well-defined homo- system. Benzodiazepines bind to the GABAA receptor, reducing the quantity of GABA required to open the geneous patient groups report high rates of paradoxical chloride channel, hyperpolarise the neuron and inhibit reactions. In a placebo-controlled study of in neurotransmission. In contrast with drugs, such as barbi- the treatment of panic disorder, 13.7% of patients randomised to alprazolam experienced paradoxical turates, that bind at other sites on the GABAA receptor, benzodiazepines cannot directly open the chloride reactions compared with none given placebo (O’Sullivan channel, rendering them safer in overdose (Nutt & et al, 1994). In a further study of the efficacy of Malizia, 2001). alprazolam in borderline personality disorder, 58% of patients randomised to alprazolam experienced paradoxical reactions compared with 8% with placebo Paradoxical reactions (Gardner & Cowdrey,1985). While these studies, numerous case reports and A drug can have the potential to both decrease and published case series suggest that paradoxical reactions increase aggressive behaviour depending on the are common, large studies and systematic reviews have

460 Paton Benzodiazepines and disinhibition

generally found them to be rare. For example, published to, and indeed can, increase the severity of this reaction case series report that disinhibition occurs in 10^20% of (Medawarn & Rassaby, 1991). Several randomised patients treated with alprazolam but Cassano et al (19 94) placebo-controlled clinical studies provide support for the drug found no difference in the incidence of aggressive above: Blair & Curran (1999) found that when diazepam information behaviour between imipramine and alprazolam in 1168 was administered to healthy volunteers, it selectively quarterly patients treated for panic disorder. Similarly, when impaired the ability of subjects to recognise angry facial Greenblatt et al (1984) reviewed 45 controlled trials, expressions. Recognition of other emotions was not they found no difference in the incidence of behavioural impaired. The authors suggested that failure to recognise disinhibition between patients given triazolam, anger could lead to failure to moderate behaviour to flurazepam and placebo. In a review of this subject, conform to social rules. Weisman et al (19 98) repor ted Dietch & Jennings (1988) conclude that, in the general that healthy volunteers who had taken diazepam 10 mg population, the incidence of aggressive dyscontrol after were more likely to behave aggressively under low levels administration of a benzodiazepine is less than 1%, similar of provocation than those who had taken , to the incidence with placebo, and because overt rage or placebo. All were equally aggressive when reactions are rare, they are difficult to quantify. These subject to a high level of provocation. Bond et al (19 95) apparently contradictory findings may be explained by found that patients who received alprazolam were more the differences in the populations exposed (see below). likely to respond to provocation than those who received placebo. The alprazolam group rated themselves as more tolerant and friendly, the same dissociation between Who is most at risk? behaviour and feelings that is found after alcohol Genetic factors may be important. Short et al (1987) consumption. reported similar disinhibitory reactions to benzodiaze- Dderman & Lidberg (1999) reported that, in a pines in monozygotic twins and Dietch & Jennings (1988) population of young violent offenders, - reported that a mother and daughter both experienced abuse led to self-reported feelings of power, over- behavioural disinhibition with temazepam. whelming self-esteem and increased suggestibility. Mood and environment may also contribute, as may Rickert & Wiemann (1998) reported that flunitrazepam the presence of neurological disorders, being young (Rohypnol), particularly when used with alcohol, renders (Litchfield, 1980; Hawkridge & Stein, 1998) or over women more likely to be victims of sexual assault due to 65 or having a learning disability or CNS degenerative diminished ability to respond to social cues. disease (Bond, 1998). Perhaps the single most important Antisocial personality disorder is associated with a factor is underlying personality, as those with a history of high prevalence of aggressive behaviour, possibly aggression and poor impulse control may be more prone mediated through underactivity of serotonin (5HT) to experiencing paradoxical reactions to benzodiazepines. neurotransmission (Fava, 1997). Benzodiazepines can This association has been demonstrated with alprazolam reduce 5HT neurotransmission, which may in turn in borderline personality disorder (Gardner & Cowdrey, precipitate aggressive behaviour. It therefore follows that 1985) and flunitrazepam in subjects with high scores on people with antisocial personality disorder may be at boredom susceptibility and verbal aggression (Dderman increased risk of paradoxical reactions to benzodiaze- & Lidberg, 1999). Animal studies also provide support for pines (Bond, 1998). There is evidence that acetylcholine this association. Chlordiazepoxide has been shown to (Ach) is involved in the paradoxical excitement seen in increase aggressive behaviour in pre-selected aggressive some patients. The cholinesterase inhibitor physostigmine male mice but not in control mice (Ferrari et al, 1997). has been used to reverse benzodiazepine-induced delirium (Van der Bijl & Roelofse, 1991). A similar reversal has been reported with flumazenil, a benzodiazepine Mechanism of paradoxical reactions antagonist (Soderpalm & Svensson, 1999; Fulton & The mechanism by which paradoxical reactions occur is Mullen, 2000). not completely understood, but several theories exist. Dose is also likely to be important. The majority of The most likely explanation is that the and case reports of behavioural disinhibition are in patients amnesic effects of benzodiazepines lead to a loss of the treated with high doses of high-potency benzodiaze- restraint that governs normal social behaviour and a pines, such as alprazolam, clonazepam, flunitrazepam and reduced ability to concentrate on the external social cues triazolam (Bond, 1998), particularly when they are that guide appropriate behaviour. This is supported by the administered intravenously or intranasally. There is also an observation that children and those with learning increased risk from drugs with a short half-life. Very high disabilities are at increased risk of disinhibitory reactions. and/or rapidly fluctuating plasma levels may be These patient groups may not have developed the skills responsible (Van der Bijl & Roelofse, 1991; Bond, 1998). to control their behaviour in adverse circumstances. Bond et al (1995) highlighted four factors associated Benzodiazepine-induced inhibition of neurotransmission with benzodiazepine-induced aggression: it occurs in may result in a decrease in the restraining influence of the response to provocation; it is recognised by others but cortex, leading to excitement, agitated toxic psychosis, not by the patient; it usually occurs with high doses; and increased anxiety, hostility and rage. Ingestion of alcohol, high-potency drugs cause particular problems. Blair & which also binds to GABAA receptors, would be expected Curran (1999) postulated that disinhibition may be

461 Paton Benzodiazepines and disinhibition

mediated via GABAA pathways in the right orbitofrontal References cortex. BLAIR, R. J. R. & CURRAN, H.V. (1999) HAWKRIDGE, S. M. & STEIN, D. J. (1998) drug Selective impairment in the recognition A risk^benefit assessment of information of anger induced by diazepam. pharmacotherapy for anxiety disorders quarterly Psychopharmacology, 147, 335^338. in children and adolescents. Drug Safety, 19,283^297. BOND, A. J. (1998) Drug-induced Clinical management of paradoxical behavioural disinhibition. CNS Drugs, 9, LITCHFIELD, B. (1980) Complications of 41^57. intravenous diazepam. An overall reactions assessment of16000 cases and , CURRAN, H.V., BRUCE, M. S., et al. detailed studies of 6000 cases. Dental (1995) Behavioural aggression in panic The patient should be kept safe, with constant nursing Anaesthesia & Sedation, 10,7-24. disorder after 8 weeks treatment with supervision, until their behaviour returns to normal. In alprazolam. Journal of Affective MEDAWARN, C. & RASSABY, E. (1991) extreme cases, flumazenil may be used, but its half-life is Disorders, 35,117^123. Triazolam overdose, alcohol and manslaughter. Lancet, 339, 1515^1516. much shorter than that of , clonazepam or BOYLE, D. & TOBIN, J. M. (1961) Pharmaceutical management of MICZEK, K. A., DEBOLD, J. F.,VAN ERP, diazepam and the patient is likely to require repeated behavioural disorders: A. M. M., et al (1997) Alcohol, doses. chlordiazepoxide in covert and overt benzodiazepine^GABAA receptor Paradoxical reactions may not always be recognised expressions of aggression. Journal of complex, and aggression. In Recent the Medical Society of New Zealand, Developments in Alcoholism.Vol. XIII. at the time of occurrence, but may be suspected in 58,427^429. Alcohol andViolence, pp.139^171. New York: Plenum Publishing. retrospect. It is important that this suspicion is CASSANO, G. B.,TONI, C., PETRACCA, documented, along with the dose of benzodiazepine A., et al (19 94) Adverse effec t s NUTT,D.J.&MALIZIA,A.L.(2001) associated with the short term New insights into the role of the used and its route of administration, in order that the treatment of panic disorder with GABAA^benzodiazepine receptor in patient can be protected from future reactions of this imipramine, alprazolam or placebo. psychiatric disorder. BritishJournal of European Neuropsychopharmacology, Psychiatry, 179,390^396. type. 4,47^53. O’SULLIVAN, G. H., NOSHIRVANI, H., D—DERMAN, A. M. & LIDBERG, L. (1999) BASOGLU, I. M., et al (1994) Safety and Flunitrazepam (Rohypnol) abuse in side-effects of alprazolam: controlled combination with alcohol causes study in agoraphobia with panic premeditated, grevious violence inmale disorder. BritishJournal of Psychiatry, Implications for practice juvenile offenders. Journal of the 165,79^86. American Academy of Psychiatry and PILOWSKY, L. S., RING, H., SHINE, P. J., the Law, 27,83^99. The association between benzodiazepines and et al (1992) Rapid tranquillisation. A behavioural dyscontrol has important implications for DIETCH, J.T. & JENNINGS, R. K. (1988) survey of emergency prescribing in a Aggressive dyscontrol in patients general psychiatric hospital. British practice. We need to be able to predict who is at risk, as treated with benzodiazepines. Journal Journal of Psychiatry, 160,831^835. of Clinical Psychiatry, 49,184^187. benzodiazepines are widely used as the first line to RICKERT,V. I. & WIEMANN, C. M. (1998) control acute behavioural disturbance. FAVA, M. (1997) Psychopharmacologic Date rape among adolescents and True paradoxical reactions to benzodiazepines are treatment of pathologic aggression. young adults. Journal of Pediatric Psychiatric Clinics of North America, 20, Adolescent Gynecology, 11,167^175. probably uncommon, but are not completely unpredict- 427^451. SHORT,T. G., FORREST, P. & GALLETLY, able. Known risk factors include high-potency drugs, high FERRARI, P. F., PARMIGIANI, S., D. C. (1987) Paradoxical reactions to doses being administered by parenteral routes to the very RODGERS, R. J., et al (1997) Differential benzodiazepines - a genetically effects of chlordiazepoxide on determined phenomenon? young, elderly, those with pre-existing CNS damage and aggressive behaviour in male mice: the Anaesthesia and Intensive Care, 15, those with a history of aggression or impulsivity. influence of social factors. 330^331. Psychopharmacology, 134,258^265. It is important to be aware of the ability of SODERPALM, B. & SVENSSON, A. I. benzodiazepines to cause behavioural disinhibition and to FULTON,S.A.&MULLEN,K.D.(2000) (1999) Naloxone reverses disinhibitory/ Completion of upper endoscopic aggressive behaviour in 5,7-DHT maintain a high degree of vigilance when these drugs are procedures despite paradoxical lesioned rats: involvement of GABAa administered to patients known to be at risk. Failure to reactions to : a role for receptor blockade? flumazenil? AmericanJournal of Neuropharmacology, 38,1851^1859. recognise such a reaction could lead to the administration Gastroenterology, 95,809^811. VAN DER BIJL, P. & ROELOFSE, J. A. of higher doses of benzodiazepines in an attempt to GARDNER, D. L. & COWDREY, R.W. (1991) Disinhibitory reactions to control the behavioural disturbance. In patients who have (1985) Alprazolam-induced dyscontrol benzodiazepines: a review. Journal of in borderline personality disorder. Oral and Maxillofacial Surgery, 49, experienced a paradoxical reaction to benzodiazepines, AmericanJournal of Psychiatry, 142, 519^523. 98^100. future behavioural emergencies should be managed with WEISMAN, A. M., BERMAN, M. E. & antipsychotic drugs. GREENBLATT, D. J., SHADER, R. I., TAYLOR, S. P. (1998) Effects of DIVOLL, M., et al.(1984)Adverse clorazepate, diazepam, and oxazepam reactions to triazolam, flurazepam and on a laboratory measure of aggression placebo in controlled clinical trials. in men. International Clinical Journal of Clinical Psychiatry, 45, Psychopharmacology, 13,183^188. 192^195. Declaration of interest Carol Paton Chief Pharmacist, Oxleas NHS Trust, c/o Pinewood House, None. Pinewood Place, Dartford, Kent DA2 7WG

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