|
|
Vernon M Neppe MD, PhD, FFPsych, FRCPC
Director, Pacific Neuropsychiatric Institute, Seattle, Washington
Exploration of aggression spectrum concepts such as anger, aggression, hostility, dyscontrol, rage, irritability and impulsivity are compromised by the absence of an adequate diagnostic and therapeutic classification, the general equivalent use of these terms, their measuring difficulties and their lack of research. Without a current diagnostic framework for aggression in the Diagnostic and Statistical Manual III revision or DSM-IV, there are no FDA approved drugs for aggression. Classification of irritability and aggression is therefore limited by the lack of diagnoses in DSM3R, terminology confusion and unavailability of marketed drugs for aggression.
The advent of the OBRA legislation has particularly limited the use of inappropriate medications in the elderly nursing home context. This has led to a marked diminution in prescription of neuroleptics such as haloperidol for agitation and anger in the geriatric setting. Similarly, benzodiazepines have become unpopular, with their potential for sedation, aggravating cognitive impairments, amnesic effects and impairments of psychomotor responses (potential risks with driving and falls in the elderly) and frank dependence. Alcohol is still a poor self-prescribed alternative, and bromides, barbiturates and meprobamate have had benefits far outweighed by their risks such that they no longer have a place in geriatrics and they also have no place in irritability management. Legitimate alternatives exist such as antidepressants but the tricyclics are limited by anticholinergic side-effects and cardiotoxicity and the mono-amine oxidase inhibitors by their dietary dangers. Both groups are unproven in straight agitation without depression.
Geriatric drugs for irritability, impulsivity, anger, agitation and aggression should preferably be non-sedative, not induce dependence, be safe and have limited drug interactions, particularly in specialized groups such as addicts, medically ill and geriatric patients. Irritability is an especially difficult and common problem in the elderly, yet there are no approved agents for aggression or irritability. The past few years has led to an increasing emphasis on use of safer alternatives. Additionally, one approach to irritability and agitation management involves a re-evaluation of past management to eliminate side-effects and develop customized treatment.
Drugs such as carbamazepine have enormous potential in the management of episodic disorders particularly those linked with hostility. Preliminary research suggests its use is particularly apposite in "Paroxysmal Neurobehavioral Disorders" as a prototype organic illness with epilepsy like phenomena. Unfortunately, it does have significant sedative effects in the elderly and will work well only in a minority subpopulation.
Psychopharmacology is rapidly approaching the age of specialized receptorology and serotonin subtypes play a major role in management of both anxiety and depression, both of which are commonly linked with irritability and agitation. Moreover, evidence exists for serotonin receptor involvement in the aggression spectrum using animal models and human clinical and post-mortem studies.
The serotonin receptors modulate a variety of basic functions at a large number of levels. These functions reflect serotonin 1A neuromodulators as well. Because of the low toxicity, remarkable toleration, significant experience in geropsychiatry and the medically ill, and the ostensible lack of abuse, serotonin 1A related compounds have significant potential application in geriatric psychiatry and medical illness.
Serotonin 1A receptor action can be measured relatively specifically by the azapirones. These act as partial agonists postsynaptically and full agonists at the autoreceptor. Non-specifically, beta2-adrenergic receptor blockers (like propranolol) produce overall serotonin 1A receptor antagonist effects. Beta-blockers have limited application in the elderly, despite their role of serotonin 1A. The perspectives in akathisia and aggression may be relevant. The benzodioxines act as partial agonists postsynaptically on both 5HT 1A and 1B receptors, and have potential application in aggression. Particularly interesting is a possible link of the neural growth factor S100ß with serotonin 1A and Alzheimerâs disease.
Beta-adrenergic blockers are useful but to a limited degree because of side-effects in high doses in organic populations. This limits their use in the geriatric context. Biphasic effects are seen with the lipid soluble propranolol - low doses probably relate to simple alleviation of frustration, but, high doses seem to have a central, possibly non-beta effect. Their action may have links with serotonin 1A or 1B. An alternative more likely mechanism may relate to down regulation of serotonin 2 - a mechanism which may take weeks and may explain the delayed effects of propranolol in rage including geriatric organic patients.
A new unmarketed group, the benzodioxines, epitomized currently by eltoprazine, also has actions linked to serotonin 1A or 1B- but likely serotonin 1A in man because 1B receptors probably do not exist in primates. This may be the group of the future.
Additionally, lithium cation is commonly used in similar populations for affective illness and aggression has serotonin 1A agonist effects. Lithium's action may be diverse but its use in non-bipolar elderly patients is limited by toxicity.
Animal models of aggression suggest the azapirones are potent anti-aggressive agents. This should be via components of their specific serotonin 1A partial agonist effects. Irritability is an early target symptom of response with buspirone in generalized anxiety disorder possibly implying persistent low-dose effects. The advent of the azapirones has been a significant advance and may exemplify the neuromodulating roles played by varying doses of drug impinging on a specific receptor, in this instance serotonin 1A. The azapirones are potent anti-aggressive and anti-anxiety agents in animal models probably via components of their specific serotonin 1A effects. Irritability is an early target symptom of response with low-dose buspirone in generalized anxiety disorder.
In our earliest study, open experience suggests a biphasic dose effect for buspirone: Low doses of buspirone (15-25 mg per day) were effective after a few days in alleviating irritability, anger and hostility without associated significant anxiety in nine successive inpatients (p<0.001, but many inpatients improve with milieu) and a further 11 outpatients. Higher doses such as 60-90 mg per day almost immediately greatly relieved manic irritability, agitation, restlessness and mood lability in ten subjects. If real, these two effects can be explained in a unified serotonin theory. Subsequently, our database has enlarged enormously both for low and high dose buspirone and we have a series with geriatric patients as well. This data requires adequate controlled studies as buspirone as the only marketed azapirone is approved for use only in anxiety and mixed anxiety depressive states.
The use of selective serotonin re-uptake inhibitors for anger is controversial at best. Fluoxetine because of its long half life could be argued to be absolutely contra-indicated in the geriatric context. Sertraline and paroxetine are unproven but may have a place in the retarded depressive who exhibits episodic anger. However, because of their non-specific serotonin receptor effects the theoretical potential for paradoxic reactions (which can also rarely occur with buspirone) should be noted. Trazodone may be the most logical antidepressant in geriatric agitated depressives, but hypotension should be watched for by giving the lowest possible doses.
Geriatric psychopharmacology should be seen as an important adjunct to behavioral interventions in both episodic conditions such as agitation and irritability as well as in more chronic impairments like dementia and depression. In this regard we have recently developed a promising measure to monitor inpatients, the Problem Behaviors Rating Scale, which has been particularly adapted for geriatric use.
© Copyright 1997 Pacific Neuropsychiatric Institute.