European Neuropsychopharrnacology, 2 (1992) 167-169 © 1992 Elsevier Science Publishers B.V. All rights reserved 0924-977X/92/$05.00

ENP 00063

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Report Section

Impact of neuropharmacology in the 1990s - treatment strategies for anxiety disorders and insomnia

Task Force of the Collegium Internationale Neuro-Psychopharmacologicum (CINP)

(Received for publication 24 March, 1992)

1. Epidemiology and social impact of the anxiety and sleep disorders

Anxiety disorders are classified into: generalised anxiety disorder, panic disorders, obsessive compulsive disorder, and the phobias [1].

It is well documented that the life time prevalence rate for all the anxiety disorders in Europe and North America is approximately 14% of those over the age of 18 years [1]. In addition, such disorders are often associated with other types of mental illness such as depression, alcohol- ism and drug abuse. Despite the high prevalence of anxiety disorders and sleep disorders which may accom- pany such conditions, the seriousness of such disorders is often underestimated by the media and by society in general. It has been established, for example, that of those patients with anxiety disorders one-third recover but in the remainder the symptoms persist throughout their lives.

hTsomnia is an even greater problem in terms of its frequency than the anxiety disorders. Approximately one- third of the adult population in Europe and North Ameri- ca is affected at any time and it has been reported that 17% of the population consider insomnia to be seriously affecting their lives because of the emotional distress it causes [2]. Only 10% of the population with severe insom- nia are effectively treated with prescribed hypnotic drugs, while 5% use "over-the-counter" preparations. Surveys of

This report has been produced by a group of experts (J. Mendle- wicz, Belgium, chairman; H. 13eckmann, Germany, reporter; 13. Leon- hard, Ireland, reporter; D. Freedman, USA; C. Giurgea, Belgium; L. Judd, USA; S. Langer, France; G. Racagni, Italy; M. Toru, Japan) at the request of the European Communities. The report is seconded by the Executive Committee of the European College of Neuropsychophar- macology.

primary care practice show that most hypnotics are pres- cribed to patients and the elderly who have medical or mental disorders, while only a small proportion of pa- tients with a primary diagnosis of insomnia are appropri- ately treated [2].

The cost of artxiety and sleep disorders to the individual and to society is considerable and frequently underesti- mated. Thus, in addition to the direct costs that involve the increased use and misuse of the medical services, the cost and often the misuse of medication and the conse- quences of an inability to work, such conditions are com- plicated by increased morbidity for physical illness and increased mortality [3,5]. Recent studies have found that there is an increased incidence of cardiovascular and cerebrovascular disease and also frequency of accidents [4]. In addition, suicide attempts and successful acts of suicide in patients with panic disorder and panic attacks are frequently underestimated. Some 20% of patients with panic disorder attempted suicide, a proportion which is similar to that occurring in those with major depression [5]. Furthermore, in a detailed study of over 3000 patients with "pure" anxiety in Sweden, the risk of suicide was found to be as high as in those with depression or other diagnoses that require in-patient care [6]. Other social factors that add to the cost of anxiety disorders to the community include marital instability and an in- creased frequency of divorce [7].

The devastating impact of anxiety and sleep disorders on the community makes it imperative that such condi- tions are diagnosed and treated. It is now recognised that anxiety disorders are often chronic diseases that may last a life time [1], but treatment undoubtedly leads to consid- erable improvement. In such conditions it may be necess- ary to continue treatment for several years if relapse is to be avoided. Thus the cost of medication, and/or non-drug based therapies, must be balanced against the improved

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quality of life for the patient and family which such treat- ment ensures.

2. Treatment of anxiety and sleep disorders

Benzodiazepines are the most widely used group of drugs for the treatment of anxiety and sleep disorders. They are probably the most widely investigated of all classes of psychotropic drugs [8]. In addition to their use as anxiolytics and hypnotics, they also have clinical appli- cations in the treatment of such conditions as epilepsy, skeletomuscular disorders, and in post-cardiac surgery.

The efficacy and safety of the benzodiazepines in the treatment of anxiety and sleep disorders is well estab- lished and must be compared to the lack of safety of the alternative treatments (such as the barbiturates and me- probamate) that preceded them. It is disquieting to find that as a result of the social pressures against the benzo- diazepines in recent years, such drugs are being re-intro- duced in some countries with potentially serious conse- quences for the patient [9]. The adverse effects of the barbiturates, meprobamate, the sedative tricyclic antide- pressants, and the neuroleptics, which are sometimes being prescribed instead of the benzodiazepines, are not only severe but can be life-threatening if taken in over- dose. While there is evidence that the sedative antide- pressants may be efficacious in the treatment of some types of anxiety and sleep disorder, their long-term effi- cacy and safety in these conditions need to be further documented.

Ineffective treatment of anxiety and sleep disorders may result in the patient misusing alcohol and/or other drugs [3,6]. The consequences of this can be even more serious than the underlying condition which caused it. The life-time co-morbidity for alcohol and/or drug abuse in patients with panic disorder, for example, has been estimated to be as high as 36% [3].

It is well known that the chronic abuse of the benzo- diazepines, particularly if given in high therapeutic doses, can cause dependence, undue day-time sedation and withdrawal effects on abrupt discontinuation [10,11]. Such adverse effects can be minimised by limiting the dose of the drugs to the minimal necessary to control the symptoms and by carefully monitoring the duration of the treatment. Evidence shows that discontinuation, when elected by the patient, can generally be safely managed without undue discomfort to the patient.

Although there is some evidence that non-pharmaco- logical treatments are effective in attenuating the symp- toms of some anxiety disorders (i.e., phobias), there is no convincing evidence from controlled clinical trials that such treatments are efficacious in all types of anxiety disorder. Apart from useful advice on good sleep hygiene,

there is no reliable evidence that non-pharmacological treatments are efficacious in the treatment of persistent sleep disorders. Furthermore, as some 90% of all anxio- lyric and hypnotic drugs are prescribed by community physicians, it seems unlikely that time constraints will allow the widespread application of non-pharmacological methods to the treatment of anxiety disorders in the com- munity. It should be emphasised that for chronic, severe insomnia there is currently no effective treatment.

Because of the danger that the non-specialised physi- cian is more likely to misuse the benzodiazepines than the specialist physician, it is essential that professional con- tacts between the specialist and community based physi- cian be improved. Clearly there is an urgent need to facilitate the spread of information and to educate the medical community in general on the appropriate use of the benzodiazepines.

3. The adverse effects of drugs used to treat anxiety and sleep disorders

The well documented side-effects of the anxiolytic and hypnotic benzodiazepines are believed to be mainly asso- ciated with sedation and are dose-related [12,13]. These include anterograde amnesia, cognitive dysfunction, and occasionally rebound effects which are more pronounced when the drugs are abruptly withdrawn. Data from con- trolled studies, and from epidemiological surveys, in which equi-effective doses of short half-life benzodia- zepines were used, show that in general there is no objec- tive difference in the side-effect profiles of these drugs [14]. When such side-effects occur, they can usually be managed by gradually reducing the dose and slowly with- drawing the medication. It should be emphasised that despite reports of rare behavioural side-effects of short half-life hypnotics (e.g., triazolam), the scientific evidence from large population studies and objective controlled trials show that such changes, when they occur, may re- flect the status of the individual patient (for example, drug or alcohol abuser, personality disorder or major psychia- tric disorder) and not the innate toxicity of the drug [15]. Nevertheless, such reactions still require further evalu- ation.

While there is a need to minimise the use of long half-life benzodiazepines in the elderly to avoid undue day-time sedation and cognitive dysfunction, such drugs may be particularly useful in the treatment of patients whose sleep disorders arc complicated by day-time anxiety [16].

It is well established that the long-term use of anxioly- tics and hypnotics can cause dependence in some individ- uals. However, a significant number of patients suffering from chronic anxiety and insomnia rcquirc continuous

treatment for periods exceeding the 4 to 6 weeks usually recommended by regulatory authorities [17]. Such long- term treatments may together with other health measures improve the quality of life of such patients and there is no clear evidence that the efficacy of long-term medication diminishes with time or that escalation of the dose may occur in such a way that it may create a clinical or public health problem.

4. New developments in the search for anxiolytics and hypnotics

The search for novel anxiolytic and hypnotic drugs that combine efficacy without producing dependence or other adverse effects found with the benzodiazepines, is being actively pursued by various pharmaceutical companies. Some non-benzodiazepine compounds have been de- veloped with proven efficacy in the treatment of anxiety and sleep disorders. With advances in research it seems likely that novel and very selective drugs acting through specific receptor subtypes will be introduced in the near future. Nevertheless, with the advent of such novel com- pounds, the need for objective measurement, e.g. sleep EEG, psychophysiology, etc., and clinical data regarding their efficacy, safety and long-term use remains.

5. Conclusions

Anxiety and sleep disorders can cause long lasting disability that has a significant social cost both to the individual and to the community. Although there is a need to accurately define the social cost of such disorders there is already significant evidence that these disorders are not trivial conditions that can easily be removed, but that they often require prolonged treatment. Despite their well es- tablished limitations, as far as safety and long-term ad- ministration is concerned, the benzodiazepines are still very useful in the management of these disorders due to their efficacy and safety. There is still a need for the dissemination of guidelines of good clinical practice in the treatment of anxiety and sleep disorders.

6. Recommendations

It is the opinion of the CINP Task Force that policy decisions made with regard to psychotropic drugs should be based on informed opinion and in accordance with the scientific evidence that is available.

It is our recommendation that a standardised proce- dure be adopted by regulatory health authorities by which future policy and regulatory decisions covering psycho- tropics involve the participation of expert professional

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scientific organisations in the field of neuropsychophar- macology.

These organisations offer the scientific expertise of its members which is always available to assist the Com- mission in its deliberations over psychoactive medica- tions. Such advise is particularly required when con- troversial issues arise regarding psychotropic drugs.

References

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2 Office of Medical Applications of Research, NIH, USA (1984) Drugs and Insomnia: Consensus Conference on the Use of Medi- cations to Promote Sleep. J. Am. Med. Assoc. 252, 2410-2414.

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11 Lader, M.H. (1992) Abuse potential, tolerance and dependence on chronic anxiolytic treatment. In: Mendlewicz, J. and Racagni, G. (Eds.), Target Receptors for Anxiolytics and Hypnotics: from Molecular Pharmacology to Therapeutics, S. Karger, Basel, in press.

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