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The history of the development of anti-aggressive agents for clinical use


The idea that it is possible to selectively eradicate violent behavior exhibited by some individuals is not new. Of course, we know about a large number of animal experiments in different models of aggression that have shown that some drugs are able to suppress offensive aggression towards conspecifics without suppressing defensive behavior or other forms of activity. But what about humans? Can the results obtained in animals be transferred to humans, and have there ever been clinical trials on the use of such drugs for the treatment of violent behavior?

There has been at least one major project in the past that aimed to develop a selective anti-aggressive agent[1]. The project was organized by Berend Olivier, a Dutch researcher working at the time for the pharmaceutical company “Duphar,” together with a number of other researchers. The launch of the project in the mid-70s of the past century was prompted by the lack of effective means for “inhibition of destructive behavior without other significant behavioral, psychiatric, or somatic side effects.” The agents already used for this purpose in clinical practice were associated with severe side effects, for example, neuroleptics with tardive dyskinesia (involuntary movements), beta-blockers with hypotension (decreased blood pressure), lithium with renal problems, and most importantly, they did not have a selective effect on behavior.

The necessary effect on animals was produced by agents affecting the serotonergic system. They were also called “serenics.” In 1980, the drug fluprazine was synthesized, which was probably an agonist (leading to activation) of serotonin 1A and 1B receptors. It had potential for development but was later rejected due to toxic effects when administered to rats. In 1984, the closely related drug eltoprazine was selected for further development. In various experiments in mice and rats, including social isolation and resident-intruder paradigms, this drug had a selective anti-aggressive effect that did not impair the social or non-social activity of individuals. It was also safe. It is worth noting that later, in more recent studies, the function of the violence inhibition mechanism in humans would be associated with the serotonergic system[2]. Apparently, a similar mechanism is activated in animals when such agents are used.

In the 1990s, a number of pilot clinical trials were conducted on various groups of aggressive patients with the administration of eltoprazine. The results were as follows:

– on 20 patients with dementia, it was shown that eltoprazine did not lead to improvements in their overall condition but significantly reduced aggression, especially in individuals exhibiting high levels of it, with no side effects;

– eltoprazine showed a similar result in 17 mentally retarded patients, especially in the case of those who exhibited medium to high levels of aggression;

– the same was observed in 23 patients suffering from psychotic and personality disorders; however, a slight decrease in aggression was also observed in the control group taking placebo, and among the side effects, sleep disturbances and anxiety at the end of the treatment were occasionally observed;

– in the case of eltoprazine administration to patients with depression, there was a general improvement in their condition (decrease in depression and increase in mood), and on patients with chronic psychotic and personality disorders, it was shown that combined administration of eltoprazine with neuroleptics has no additional side effects (and causes an anti-aggressive effect in patients with medium to high levels of aggression);

– when eltoprazine was administered to 119 mentally retarded patients, a significant reduction in aggression was also observed in the control group (which consisted of 41 patients), although the results were slightly better in the group taking eltoprazine.

As a result, eltoprazine was shown to be somewhat effective, especially in patients who exhibited high levels of aggression. However, the clinical trials were abandoned at this point. Some problems arose, such as the observation of improvements in control groups, the limited availability of useful tools to assess patients, and the unwillingness of regulatory agencies to approve medicines for a “non-disease”[1][3]. Of course, we can now easily link violent behavior to a pathology such as violence inhibition mechanism dysfunction and impairments in the serotonergic system in general. But back then, this made the field of aggression risky for clinical research and investment in drug development.

Practically all further experiments in this direction were and still are conducted on animals, and in the case of some agents, they, as before, demonstrate excellent results. We can mention an attempt to start in 2006 clinical trials on the administration of naratriptan, which is a full agonist of serotonin 1B/1D receptors and a partial agonist of serotonin 1A receptors, to violent offenders undergoing psychiatric treatment. It should be noted that Berend Olivier can also be seen among the co-authors of this study. But it was terminated due to the lack of the required number of test subjects[4]. Although triptans definitely have potential in the therapy of violent behavior, given that a drug called zolmitriptan has been successful in selectively reducing aggression in mice and attenuating alcohol-heightened aggression in humans[5][6]. As an exception, we can also mention a study in which aggressive patients with Alzheimer's disease received eltoprazine; the results, published in 2015, showed a clinically significant reduction in aggressive behavior[7].

Some researchers have characterized this state of affairs as “calamitous.” At least, that is what Miczek, Faccimodo, Almeida, Bannai, Fish, and Debold said in a study of new pharmacotherapeutic approaches and opportunities for the problem of escalated aggressive behavior[3]. As Tuinier and Verhoeven write in their review of the history of serenic development, “modern research suggests that aggressive behavior should be studied as a separate functional disorder”[8]. And Coccaro, Fanning, Phan, and Lee, in a study of serotonin and impulsive aggression, express hope “that new insights into the neurobiology of aggression will reveal novel avenues for treatment of this destructive and costly behavior”[9].

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1), 1) Olivier, B., Mos, J., Raghoebar, M., de Koning, P., Mak, M. (1994). Serenics. Prog Drug Res. 42:167-308. doi:10.1007/978-3-0348-7153-2_6
2) Siegel, J. Z., Crockett, M. J. (2013). How serotonin shapes moral judgment and behavior. Ann N Y Acad Sci. Sep;1299(1):42-51. doi:10.1111/nyas.12229
3), 3) Miczek, K. A., Faccimodo, S., Almeida, R. M. M., Bannai, M., Fish, E. W., & Debold, J. F. (2006). Escalated Aggressive Behavior: New Pharmacotherapeutic Approaches and Opportunities. Annals of the New York Academy of Sciences, 1036(1), 336–355. doi:10.1196/annals.1330.021
5) De Almeida, R., Nikulina, E., Faccidomo, S., Fish, E., & Miczek, K. (2001). Zolmitriptan - a 5-HT 1B/D agonist, alcohol, and aggression in mice. Psychopharmacology, 157(2), 131–141. doi:10.1007/s002130100778
6) Gowin, J. L., Swann, A. C., Moeller, F. G., & Lane, S. D. (2010). Zolmitriptan and human aggression: interaction with alcohol. Psychopharmacology, 210(4), 521–531. doi:10.1007/s00213-010-1851-6
8) Verhoeven, W.M.A. & Tuinier, S. (2007). Serenics: Anti-aggression drugs throughout history. Clinical Neuropsychiatry. 4:135-143
9) Coccaro, E. F., Fanning, J. R., Phan, K. L., Lee, R. (2015). Serotonin and impulsive aggression. CNS Spectrums. 20: 295-302. doi:10.1017/S1092852915000310
Last modified: 2024/04/29 19:03 by Volunto

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